Distal procto-colitis, natural cytotoxicity, and essential fatty acids.

Almallah YZ, Richardson S, O'Hanrahan T, Mowat NA, Brunt PW, Sinclair TS, Ewen S, Heys SD, Eremin O. Department of Surgery, University of Aberdeen, United Kingdom.

Am J Gastroenterol 1998 May;93(5):804-9

OBJECTIVES: Recently, it has been postulated that patients with ulcerative colitis have altered natural cytotoxicity, in particular natural killer (NK) and lymphokine-activated killer (LAK) cell activities. These cellular mechanisms have been postulated to play an etiological role in the pathogenesis of the disease process. We have shown previously that the essential fatty acids (EFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) specifically inhibit natural cytotoxicity. Our aim was to evaluate the role of omega-3 EFA in the modulation of natural cytotoxicity and disease activity in patients with distal procto-colitis. METHODS: In this pilot study patients were randomized into two groups. Each patient received either fish oil extract (EPA, 3.2 g, and DHA, 2.4 g) (n = 9) or sunflower oil (placebo) (n = 9) daily in a double-blind manner for 6 months. Monthly assessments of disease activity (clinical and sigmoidoscopic scores) and histological evaluation of mucosal biopsies were carried out. Also, the circulating levels and activities of NK and LAK cells, using flow cytometric analysis (CD16+ CD56+) and in vitro 51 chromium release assays (K562), respectively, were monitored. RESULTS: After 6 months' supplementation with EFA, there was improvement in the clinical activity compared with pretreatment evaluation. There was significant reduction in the sigmoidoscopic and histological scores in the EFA group compared with the placebo group. Essential fatty acid supplementation for 6 months also induced significant reduction in the circulating numbers of CD16+ and CD56+ cells and the cytotoxic activity of NK cells, compared with the placebo group. CONCLUSIONS: This pilot study has demonstrated that omega-3 fatty acids can suppress natural cytotoxicity and reduce disease activity in patients with distal procto-colitis. These findings suggest a therapeutic strategy for managing patients with inflammatory bowel disease.

Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study.

Aslan A, Triadafilopoulos G. Gastroenterology Section, Martinez VA Medical Center, 150 Muir Road, Martinez, CA 94553 U.S.A.

Am J Gastroenterol (USA) 1992;87(4):432-437

Arachidonic acid metabolites formed by both the cyclooxygenase and lipoxygenase pathways may contribute to the clinical diarrhea and colitis of inflammatory bowel disease. Patients with active ulcerative colitis have increased levels of leukotriene B4 in their rectal mucosa, and these levels tend to correlate with severity of the disease. In this study, we evaluated the efficacy of ingestion of fish oil n-3-omega-fatty acids, inhibitors of leukotriene synthesis, in the treatment of ulcerative colitis. Eleven patients with ulcerative colitis of mild to moderate severity were studied in a 8-month, double-blind, placebo-controlled, crossover trial of dietary supplementation with fish oil, which provided about 4.2 g of omega-3- fatty acids per day. A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mucosal leukotriene B4 production was measured by radioimmunoassay. Mean disease activity index declined 56% for patients receiving fish oil and 4% for patients on placebo (< 0.05). There were no statistically significant differences in histopathologic scores or colonic mucosal leukotriene B4 levels. All patients tolerated fish oil ingestion and showed no alteration in routine blood studies. No patient worsened; anti-inflammatory drugs could be reduced or eliminated in eight patients (72%) while receiving fish oil. We conclude that fish oil dietary supplementation results in clinical improvement of active mild to moderate ulcerative colitis but is not associated with significant reduction in mucosal leukotriene B4 production, compared with placebo therapy. Further studies are needed to elucidate the mechanism of action and optimal dose and duration of fish oil supplementation in ulcerative colitis.

Interleukin 10 gene transfer prevents experimental colitis in rats.

Barbara G, Xing Z, Hogaboam CM, Gauldie J, Collins SM. The Intestinal Disease Research Program, Division of Gastroenterology, Departments of Medicine and Pathology, McMaster University Faculty of Health Sciences, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada.

Gut 2000 Mar;46(3):344-9

BACKGROUND: The development of colitis in interleukin 10 (IL-10) deficient mice, together with the known anti-inflammatory and immunomodulatory properties of this cytokine have prompted consideration of IL-10 as a treatment for inflammatory bowel disease (IBD). However, studies using hrIL-10 in IBD models have yielded inconsistent results. AIMS: To examine the therapeutic potential of overexpressing the IL-10 gene before and after the induction of experimental colitis in rats. METHODS: Gene transfer was achieved by intraperitoneal injection of non-replicating human type 5 adenovirus bearing the IL-10 gene, either 24 hours before or one hour after intrarectal administration of dinitrobenzene sulphonic acid in rats. Colonic damage and inflammation was assessed macroscopically and by measuring myeloperoxidase activity and leukotriene B4 concentrations. RESULTS: Gene transfer increased IL-10 protein in serum for up to six days. IL-10 gene transfer prior to colitis improved colitis macroscopically and histologically, and significantly reduced colonic myeloperoxidase activity and leukotriene B4 concentrations. In contrast, IL-10 gene transfer after the onset of colitis had no beneficial effect. CONCLUSIONS: Gene therapy using an adenovirus-IL-10 construct was successful in preventing but not in reversing experimental colitis in the rat.

Altered bone metabolism in inflammatory bowel disease.

Bischoff SC, Herrmann A, Goke M, Manns MP, Von Zur Muhlen A, Brabant G. Dr. S.C. Bischoff, Dept. of Gastroenterology/Hepatology, Medical School of Hannover, D-30623 Hannover Germany.

Am J Gastroenterol(USA) 1997/;92(7):1157-1163

A reduced bone mineral density has been reported in inflammatory bowel disease (IBD). Objective: To assess the mechanisms of bone disease in IBD. Methods: We studied in 90 patients (61 with Crohn's disease, 22 with ulcerative colitis, 7 with indeterminate colitis) biochemical markers of bone metabolism in serum and bone mineral density by peripheral quantitative computed tomography at the forearm. Results: Forty-five percent of the patients had a reduced bone density (Z score < -1). Serum calcium was normal in most patients, vitamin D deficiency was documented in 17%. Osteocalcin, a serum marker of bone formation, was decreased in 26% (1.2 plus or minus 0.1 ng/ml), whereas the carboxyterminal cross-linked telopeptide of type I collagen (ICTP), a recently described serum parameter of bone breakdown, was stimulated in 38% (10.4 plus or minus 2.3 microg/L). Of 33 patients with increased ICTP levels, 19 showed a decreased bone density (Z score < -1), and 2 of them never received steroids. An active status of the underlying disease in most patients with increased ICTP levels suggests a direct effect of the underlying IBD. In the whole series of patients with a history of active disease (n = 34), 47% had signs of an increased bone degradation (ICTP < 5 microg/L; mean, 12.9 plus or minus 4.7 microg/L). Data derived from a retrospective survey of 245 patients with IBD suggest that the prevalence of bone fractures in IBD is unexpectedly high, particularly in patients with a long duration of disease, frequent active phases, and high cumulative doses of corticosteroid intake. Conclusions: Several mechanisms may be involved in IBD-associated bone disease: (1) a high inflammatory activity directly induces bone degradation via yet unknown pathways, (2) treatment with corticosteroids may exert catabolic effects on the bone, or (3) malabsorption and vitamin D deficiency may activate bone turnover.

Nutrition and ulcerative colitis.

Burke A, Lichtenstein GR, Rombeau JL. Prof. J.L. Rombeau, Department of Surgery, Hospital University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104 U.S.A.

Bailliere's Clin Gastroenterol (United Kingdom) 1997;11(1):153-174

The role of diet in the aetiology and pathogenesis of ulcerative colitis (UC) remains uncertain. Impaired utilization by colonocytes of butyrate, a product of bacterial fermentation of dietary carbohydrates escaping digestion, may be important. Sulphur-fermenting bacteria may be involved in this impaired utilization. Oxidative stress probably mediates tissue injury but is probably not of causative importance. Patients with UC are prone to malnutrition and its detrimental effects. However, there is no role for total parenteral nutrition and bowel rest as primary therapy for UC. The maintenance of adequate nutrition is very important, particularly in the peri-operative patient. In the absence of massive bleeding, perforation, toxic megacolon or obstruction, enteral rather than parenteral nutrition should be the mode of choice. Nutrients may be beneficial as adjuvant therapy. Butyrate enemas have improved patients with otherwise recalcitrant distal colitis in small studies, Non-cellulose fibre supplements are of benefit in rats with eperimental colitis. Eicosapentaenoic acid in fish oil has a steroid-sparing effect which, although modest, is important, particularly in terms of reducing the risk of osteoporosis, but it seems to have no role in the patient with inactive disease. gamma-Linolenic acid and anti-oxidants also are showing promise. Nutrients may also modify the increased risk of colorectal carcinoma. Oxidative stress can damage tissue DNA but there are no data published at present on possible protection from oral anti-oxidants. Butyrate protects against experimental carcinogenesis in rats with experimental colitis. Folate supplementation is weakly associated with decreased incidence of cancer in UC patients when assessed retrospectively. Vigilance should be maintained for increased micronutrient requirements and supplements given as appropriate. Calcium and low-dose vitamin D should be given to patients on long-term steroids and folate to those on sulphasalazine.

The value of an elimination diet in the management of patients with ulcerative colitis.

Candy S, Borok G, Wright JP, Boniface V, Goodman R. Gastro-intestinal Clinic, Department of Medicine, Groote Schuur Hosp., Univ. Cape Town, Cape Town South Africa.

South Afr Med J (South Africa) 1995;85(11):1176-1179

Debate exists about the role of diet in both the aetiology and the management of ulcerative colitis. To examine the latter, a group of patients with documented ulcerative colitis was studied at the Groote Schuur Hospital Gastro-intestinal Clinic. A total of 18 subjects, 9 female and 9 male, were randomised into active or control groups and followed up weekly for 6 weeks. Subjects in the control group were asked to document but not alter their intake of food and drink. Those in the experimental group had their diets systematically manipulated to exclude foods that appeared to provoke symptoms. The symptoms, sigmoidoscopy and biopsy findings of all subjects were compared before and after. 'Remission' was defined as the passage of normal stools with absence of rectal bleeding. 'Improvement' was defined as a decrease in the number of diarrhoeal stools and/or a diminution of rectal bleeding. At the end of the trial the diet group displayed significantly fewer symptoms than did the controls (P = 0.009; Fisher's exact test). Sigmoidoscopic findings improved in 8 subjects in the diet group compared with 2 of the controls. Histological findings improved in 3 of the diet group as well as in 3 of the controls. There were no foods that provoked symptoms in all patients, though spiced and curried foods and fruits, especially grapes, melon and the citruses, commonly caused diarrhoea. In only 2 patients were symptoms reproduced consistently on reintroduction of a particular food, pork in 1 case and yellow cheese in another.

Butyrate oxidation is impaired in the colonic mucosa of sufferers of quiescent ulcerative colitis.

Chapman MAS, Grahn MF, Boyle MA, Hutton M, Rogers J, Williams NS. Surgical Unit, 4th Floor Alexandra Wing, Royal London Hospital, Whitechapel, London E1 1BB United Kingdom.

Gut (United Kingdom) 1994;35(1):73-76

The short chain fatty acids, acetate, propionate, and butyrate are produced by colonic bacterial fermentation of non-starch polysaccharides. Butyrate is the major fuel source for the colonic epithelium and there is evidence to suggest that itx oxidation is impaired in ulcerative colitis. Triplicate biopsy specimens were taken at colonoscopy from five regions of the large bowel in 15 sufferers of ulcerative colitis. These patients all had mild or quiescent colitis as assessed by clinical condition, mucosal endoscopic and histological appearance. The rate of oxidation of glucose, glutamine, and butyrate through to carbon dioxide was compared with that in biopsy specimens from 28 patients who had no mucosal abnormality. Butyrate (272 (199-368)) was the preferred fuel source for the colitic mucosa followed by glutamine (33 (24-62)) then glucose (7.2 (5.3-15)) pmol/microg/hour; medians and 95% confidence intervals, < 0.01. There was no regional difference in the rate of utilisation of these metabolites. In the group with colitis the rate of butyrate oxidation to carbon dioxide was significantly impaired compared with that in normal mucosa decreasing from 472 (351-637) pmol/microg/hour to 272 (199-368) pmol/microg/hour; median and 95% confidence intervals, p = 0.016. The rate of glucose and glutamine utilisation were not significantly different between normal and colitic mucosa. These data confirm that in quiescent ulcerative colitis there is an impairment of butyrate oxidation.

Butyrate metabolism in the terminal ileal mucosa of patients with ulcerative colitis.

Chapman MAS, Grahn MF, Hutton M, Williams NS. Department of Surgery, University Hospital, Queen's Medical Centre, Nottingham NG7 2UH United Kingdom.

Br J Surg (United Kingdom) 1995; 82(1):36-38

The rate of oxidation of butyrate, glutamine and glucose was investigated in terminal ileal mucosal biopsy samples from nine patients with ulcerative colitis undergoing restorative proctocolectomy and from 12 patients undergoing laparotomy for reasons other than ulcerative colitis. Substrate oxidation was assayed using a radiolabelled isotope technique. Butyrate was the preferred fuel substrate, followed by glutamine and then glucose (median 95 per cent confidence interval) 567 (262-894), 63 (35-123) and 8.1 (5.1-18) pmol microg-1 h-1 respectively; < 0.01, Mann-Whitney U test) in normal terminal ileal mucosa. The patients with ulcerative colitis had a significantly reduced rate of butyrate oxidation compared with the control group (194 (81-321) versus 567 (262-894) pmol microg-1 h-1 < 0.05). Normal terminal ileal mucosa oxidized butyrate in greater quantities than glucose and glutamine. Ulcerative colitic terminal ileal mucosa exhibited an impaired rate of butyrate oxidation.

Metabolic adaptation of terminal ileal mucosa after construction of an ileoanal pouch.

Chapman MAS, Hutton M, Grahn MF, Williams NS. United Kingdom

Br J Surg (United Kingdom) 1997; 84(1):71-73

Background - The major nutrients for the large bowel and small bowel mucosa are, respectively, butyrate and glutamine. The degree of mucosal adaptation that may occur in response to changes in nutrient supply and faecal stasis after the formation of an ileoanal pouch is poorly understood. Method - The ability of ileal mucosal biopsies, from nine patients with ulcerative colitis and from 18 with an ileoanal pouch, to oxidize (14C)-glucose, glutamine and butyrate to carbon dioxide was quantified. Results - Glucose, glutamine and butyrate were oxidized respectively at a median of 12.5 (95 per cent confidence interval (4-22), 77 (34-207) and 194 (81-321) pmol microg-1 h-1 by ileal mucosa and 12.9 (6-21), 35 (11-57) and 194 (73-737) pmol microg-1 h-1 by pouch mucosa. Conclusion - Ileoanal pouch construction and subsequent bacterial colonization and faecal stasis resulted in a significant (< 0.05) reduction in the mucosal ability to oxidize glutamine whereas there was no difference in the rate of butyrate oxidation.

Antagonistic effects of sulfide and butyrate on proliferation of colonic mucosa: a potential role for these agents in the pathogenesis of ulcerative colitis.

Christl SU, Eisner HD, Dusel G, Kasper H, Scheppach W.

Dig Dis Sci 1996 Dec; 41(12):2477-81I

It has been shown that feces of patients with ulcerative colitis uniformly contain sulfate reducing bacteria. Sulfide produced by these bacteria interferes with butyrate-dependent energy metabolism of cultured colonocytes and may be involved in the pathogenesis of ulcerative colitis. Mucosal biopsies from the sigmoid rectum of 10 patients (no cancer, polyps, inflammatory bowel disease) were incubated with either NaCl, sodium hydrogen sulfide (1 mmol/L), a combination of both sodium hydrogen sulfide and butyrate (10 mmol/L), or butyrate. Mucosal proliferation was assessed by bromodeoxyuridine labeling of cells in S-phase. Compared to NaCl, sulfide increased the labeling of the entire crypt significantly, by 19% (< 0.05). This effect was due to an expansion of the proliferative zone to the upper crypt (compartments 3-5), where the increase in proliferation was 54%. Sulfide-induced hyperproliferation was reversed when samples were coincubated with sulfide and butyrate. The study shows that sodium hydrogen sulfide induces mucosal hyperproliferation. Our data support a possible role of sulfide in the pathogenesis of UC and confirm the role of butyrate in the regulation of colonic proliferation and in the treatment of UC.

Osteoporosis, corticosteroids and inflammatory bowel disease.

Compston JE. Department of Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ United Kingdom

Aliment Pharmacol Ther (United Kingdom) 1995;9(3):237-250

Osteoporosis is a serious complication of inflammatory bowel disease which has not received adequate recognition despite its high prevalence and potentially devastating clinical effects. Its pathogenesis remains poorly defined although corticosteroid therapy and sex hormone deficiency are likely to play a major role. Recent advances in the diagnosis and management of osteoporosis have facilitated early detection of bone loss and identified means by which this may be prevented. Bone density measurements to predict fracture risk and define thresholds for prevention and treatment should be performed routinely in patients with inflammatory disease. Hormone replacement therapy is effective in prevention of bone loss in peri- and post-menopausal patients, but the treatment of younger women and men of all ages requires further study.

Allergy and mucosal eosinophil infiltrate in ulcerative colitis.

D'Arienzo A, Manguso F, Astarita C, D'Armiento FP, Scarpa R, Gargano D, Scaglione G, Vicinanza G, Bennato R, Mazzacca G. Institute of Gastroenterology, Faculty of Medicine, Federico II University, Naples, Italy.

Scand J Gastroenterol 2000 Jun;35(6):624-31

BACKGROUND: Data on allergy in ulcerative colitis (UC) have led to conflicting conclusions without proving any causal association. In this report we have investigated the presence of allergy and its possible relation with chronic colonic inflammation in patients with UC. METHODS: Fifty UC patients underwent clinical, endoscopic, and histologic evaluations. The allergologic study included family/personal history; prick/patch exposition to airborne, food, and contact allergens; total serum IgE; and quantification of eosinophils in peripheral blood and intestinal mucosa. Diagnosis of rhinitis, conjunctivitis, and asthma was confirmed by specific provocation tests. Fifty healthy subjects were studied as control group. RESULTS: A higher prevalence of allergic symptoms was found in patients (56%) and their first-degree relatives (52%) than in controls (18% and 26%) (< 0.0001; P = 0.008). In patients skin tests showed increased rates of immediate (54%) and delayed-type (20%) hypersensitivity compared with controls (30% and 6%) (P= 0.01; P= 0.03). Diagnosis of allergic IgE-mediated disease was made in 19 cases and 6 controls (P= 0.01), and allergic contact dermatitis in 10 and 3, respectively (P= 0.03). IgE levels were higher in UC patients than in controls (P=0.02). No dose-response relationship was found between degree of colonic tissue eosinophilia and clinical. endoscopic, and histologic disease severity. The degree of colonic tissue eosinophilia was higher in the presence of skin reactivity to food allergens. CONCLUSIONS: UC patients frequently show several markers of allergy. In particular, our data suggest an association between ulcerative colitis, tissue eosinophilia, and type-I allergy.

Novel drug therapies in inflammatory bowel disease.

Debinski HS, Kamm MA. St. Mark's Hospital, City Road, London EC1V 2PS United Kingdom.

Eur J Gastroenterol Hepatol (United Kingdom) 1995;7(2):169-182

This paper reviews the published data on novel drug treatments for inflammatory bowel disease. Steroids that are topically active or rapidly metabolized have a definite therapeutic role and have fewer long-term side-effects than other steroids. Methotrexate can promote remission in approximately 50% of patients, but is less effective in maintaining remission. Cyclosporin is valuable for treating patients with severe ulcerative colitis but is less valuable for patients with Crohn's disease. None of the drugs that modify specific inflammatory mediators have proven efficacy but tumour necrosing factor and CD4 antibodies may be promising. In patients with distal colitis, lignocaine appears to be effective.

Effect of chronic nicotine administration on trinitrobenzene sulphonic acid-induced colitis.

Eliakim R, Karmeli F, Rachmilewitz D, Cohen P, Fich A. Department of Medicine, Hadassah University Hospital on Mount Scopus, Jerusalem, Israel.

Eur J Gastroenterol Hepatol 1998 Dec;10(12):1013-9

BACKGROUND: Smoking, probably due to nicotine, has a bivalent effect on inflammatory bowel disease, ameliorating disease activity in ulcerative colitis and with a deleterious effect on Crohn's disease. The effect of nicotine patches in ulcerative colitis is controversial. AIM: To investigate the effect of chronic nicotine use in a rat model of colitis. METHODS: Colitis was induced in Sprague-Dawley rats by rectal administration of 30 mg trinitrobenzene sulphonic acid (TNBS) in 50% ethanol. Nicotine was dissolved in drinking water (2.5, 12.5, 25 and 250 microg/ml), with rats drinking ad libitum. Nicotine administration started 10 days prior to damage induction and had no effect on weight gain or daily food intake of rats. Rats were sacrificed 1 and 5 days after TNBS administration, their colons resected, rinsed, weighed, damage assessed macroscopically (mm2) and microscopically and tissue processed for myeloperoxidase (MPO) and nitric oxide synthase (NOS) activities, leukotriene B4 (LTB4), prostaglandin E2 (PGE2) generation and interleukin-1 (IL-1) serum levels. RESULTS: Nicotine, by itself, caused no damage to the colon. Nicotine had a dose-dependent bivalent effect on colitis, significantly reducing macroscopic damage from 983 +/- 10 mm2 on TNBS alone to 429 +/- 118 mm2 on TNBS plus 12.5 microg/ml of nicotine, and escalating to 1086 +/- 262 mm2 on 250 microg/ml of nicotine. Segmental weight declined significantly (from 2.4 +/- 0.2 to 1.65 +/- 0.20 g/10 cm), on 12.5 microg/ml nicotine, as did MPO activity (from 3.2 +/- 0.4 to 0.7 +/- 0.1 units/g). All these parameters returned to the levels of TNBS alone when the dose of nicotine was increased to 250 microg/ml. Nicotine had no effect on NOS activity, PGE2 generation and serum IL-1 levels, but increased LTB4 generation. CONCLUSIONS: Nicotine has a dose-dependent bivalent effect on TNBS-induced colitis which is not due to reduction in IL-1 serum levels or PGE2 generation, and is not NOS-mediated.

Colonic mucin synthesis is increased by sodium butyrate.

Finnie IA, Dwarakanath AD, Taylor BA, Rhodes JM. Department of Medicine, University of Liverpool, PO Box 147, Liverpool L69 3BX United Kingdom

Gut (United Kingdom) 1995;36(1):93-99

The effects of sodium butyrate and sodium bromo-octanoate (an inhibitor of beta oxidation) on colonic mucus glycoprotein (mucin) synthesis have been assessed using tissue from colonic resection samples. Epithelial biopsy specimens were incubated for 16 hours in RPMI 1640 with glutamine, supplemented with 10% fetal calf serum and N-acetyl-(3H)glucosamine ((3H)-Glc NAc), and differing concentrations of sodium butyrate. Incorporation of (3H) Glc NAc into mucin by normal epithelium at least 10 cm distant from colonic cancer was increased in the presence of sodium butyrate in a dose dependent manner, with maximum effect (476%) at a concentration of 0.1 number of,specimens = 24 from six patients, < 0.001). The increase in response to butyrate was not seen when specimens were incubated in the presence of the beta oxidation inhibitor sodium bromo-octanoate 0.05 M. The striking increase in mucin synthesis that results when butyrate is added to standard nutrient medium suggests that this may be an important mechanism affecting the rate of mucin synthesis in vivo and may also explain the therapeutic effect of butyrate in colitis.

Efficacy of glutamine-enriched enteral nutrition in an experimental model of mucosal ulcerative colitis.

Fujita T, Sakurai K. First Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105 Japan.

Br J Surg (United Kingdom) 1995;82(6):749-751

Intact intestinal epithelium and associated lymphatic tissue act as body defences against luminal toxins. This barrier may become threatened or compromised in inflammatory bowel disease, leading to an increase in mucosal permeability and subsequent translocation of endotoxins. The effect of oral glutamine on gut mucosal ornithine decarboxylase activity and on endotoxin levels in portal vein blood was studied in a guinea-pig model of carrageenan- induced colitis. Despite failure to show induction of ornithine decarboxylase activity by glutamine administration, the mean endotoxin level of portal vein blood in guinea-pigs fed a glutamine-enriched elemental diet was 25.3 pg/ml compared with 71.2 pg/ml in animals given a standard elemental diet (< ;0.01). A glutamine-enriched elemental diet may be therapeutically beneficial in patients with inflammatory bowel disease.

Influence of intravenous n-3 lipid supplementation on fatty acid profiles and lipid mediator generation in a patient with severe ulcerative colitis.

Grimminger F, Fuhrer D, Papavassilis C, Schlotzer E, Mayer K, Heuer K-U, Kiss L, Walmrath D, Piberhofer S, Lubbecke F, Kramer H-J, Stevens J, Schutterle G, Seeger W. Department of Internal Medicine, Justus-Liebig-University, Klinikstrasse 36, D-6300 Giessen Germany

Eur J Clin Investig (United Kingdom) 1993;23(11):706-715

N-3 fatty acids were supplied to a 36-year-old female patient suffering from ulcerative colitis and severe steroid side-effects, in a sequence of parenteral and enteral administration. During a moderately active period of disease, 200 ml d-1 fish oil-derived lipid emulsion (eicosapentaenoic acid (EPA), 4.2 g; docosahexaenoic acid (DHA), 4.2 g) was infused for 9 days, in parallel with rapid tapering of the steroid dose. Disease activity declined rapidly, and the patient was subsequently provided with 16 fish oil capsules per day (EPA, 2.9 g; DHA, 1.9 g) for 2 months. At the end of this period of therapy, severe colitis recurred with intestinal and extraintestinal manifestations. The n-3 lipid emulsion was then used for intravenous alimentation (29 days, maximum dose 300 ml per day); during this time, marked improvement of the inflammatory bowel disease was noted. During both periods of parenteral n-3 lipid administration, total plasma EPA and DHA contents increased several-fold, surpassing that of arachidonic acid; this plasma n-3 fatty acid enrichment was only maintained to a minor extent during the intermediate period of dietary fish oil supplementation. The intravenously administered EPA-containing triglycerides were rapidly hydrolyzed, as evidenced by the appearance of substantial quantities of EPA in the plasma free fatty acid fraction. Platelet and neutrophil total membrane content of EPA and DHA as well as n-3 fatty acid/AA membrane ratios similarly increased during the periods of intravenous n-3 lipid administration and declined during oral fish oil uptake. In contrast, erythrocyte membrane enrichment in EPA and DHA occurred only after the prolonged (2 month) period of dietary n-3 lipid supplementation. Ex vivo stimulation of neutrophils with A23187 showed progressive increase in 5-series leukotriene- and 5-HEPE-generation during both periods of n-3 lipid infusion, in parallel with the rise of plasma EPA contents. Maximum 5-series/4-series leukotriene ratios surpassed 0.25. Similarly, ratios of thromboxane B3/B2 liberated from ex vivo stimulated platelets surpassed 0.4 during ongoing n-3 lipid infusion. The profound changes in fatty acid profiles and lipid mediator generation may be related to the reduction in colitis activity observed during the periods of intravenous n-3 lipid supplementation.

Anti-inflammatory effect of interleukin-10 in rabbit immune complex-induced colitis.

Grool TA, van Dullemen H, Meenan J, Koster F, ten Kate FJ, Lebeaut A, Tytgat GN, van Deventer SJ. Dept. of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands.

Scand J Gastroenterol 1998 Jul;33(7):754-8

BACKGROUND: Interleukin-10 (IL-10) is an anti-inflammatory cytokine that downregulates the secretion of pro-inflammatory cytokines and additionally induces the secretion of anti-inflammatory cytokines, thus possibly leading to reduction of chronic inflammation in inflammatory bowel disease. In this study we evaluated the anti-inflammatory effect of IL-10 in a model of acute colitis in rabbits. METHODS: Colitis was induced by rectal instillation of formalin, 0.65%, followed by intravenous infusion of 0.85 ml heat-aggregated rabbit immunoglobulin. Rabbits were treated with an intravenous bolus of recombinant human IL-10 (SCH52000), 100 microg/kg (n=14) or 500 microg/kg (n=14), 1 h before induction of colitis (control group, n=12). RESULTS: High-dose IL-10 improved macroscopic scores of inflammation and decreased tissue myeloperoxidase levels and leukotriene B4 levels in dialysate fluid. Thromboxane B2 and prostaglandin E2 levels remained unaffected. CONCLUSION: IL-10 ameliorates acute colitis in this model. Consequently, this anti-inflammatory cytokine may have a role in the therapy of acute inflammatory bowel disease.

Stress-induced enhancement of colitis in rats: CRF and arginine vasopressin are not involved.

Gue M, Bonbonne C, Fioramonti J, More J, Del Rio-Lacheze C, Comera C, Bueno L. France

Am J Physiol Gastrointest Liver Physiol (USA) 1997;272(1):35-1(G84-G91)

Because exacerbation of colitis seems to be associated with stress, we proposed evaluating the influence of stress and the involvement of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) on experimental colitis in rats. Partial restraint stress was applied during 4 consecutive days, before or after intracolonic 2,4,6-trinitrobenzenesulfoni c acid (TNB) instillation (15 mg) in rats. Finally, two groups of rats were centrally injected with alpha-helical CRF-(9-41) (5 microg) or AVP antagonist (5 microg) before each session of stress. Stress was applied before or right after TNB enhanced colitis, with an increase in macroscopic and histological scores and myeloperoxidase activity. alpha-Helical CRF-(9-41) or AVP antagonist had no effect on TNB-induced colitis but enhanced the effects of stress on colitis. These results show that stress may exacerbate experimental colitis in rats and that CRF and AVP are not responsible for this effect.

Treatment of ulcerative colitis with fish oil supplementation: a prospective 12 month randomised controlled trial.

Hawthorne AB, Daneshmend TK, Hawkey CJa, Belluzzi A, Everitt SJ, Holmes GKT, Malkinson C, Shaheen MZ, Willars JE. Department of Therapeutics, University Hospital, Nottingham NG7 2UH United Kingdom

Gut (United Kingdom) 1992;33(7):922-928

The effect of fish oil on the course of ulcerative colitis was investigated in a randomized blinded controlled study. Eighty seven patients received supplements of 20 ml HiEPA fish oil as triglyceride (4.5 g of eicosapentaenoic acid) or olive oil placebo daily for one year. The oils were given in addition to standard drug therapy and trial entry was stratified for disease activity. Fish oil significantly increased the eicosapentanoic acid content of rectal mucosa to 3.2% of total fatty acids at six months, compared with 0.63% for patients on olive oil. This was associated with increased synthesis of leukotriene B5, and 53% suppression of leukotriene B4 synthesis by ionophore-stimulated neutrophils. Leukotriene B4 suppression persisted for at least two months after treatment was stopped. Treatment with fish oil resulted in measurable, but only limited clinical benefit. For patients entering the trial in relapse (n = 53), there was a significant reduction in corticosteroid requirement after one and two months treatment. There was a trend towards achieving remission (off corticosteroids) faster in the patients on fish oil, although differences were not significant. For patients in remission at trial entry or during the trial (n = 69), there was no significant difference in the rate of relapse by log rank analysis. We conclude that fish oil supplementation produces a modest corticosteroid sparing effect in active disease, but there is no benefit in maintenance therapy.

Incorporation of fatty acids from fish oil and olive oil into colonic mucosal lipids and effects upon eicosanoid synthesis in inflammatory bowel disease.

Hillier K, Jewell R, Dorrell L, Smith CL. Clinical Pharmacology Group, Faculty of Medicine, University of Southampton, Southampton SO9 3TU United Kingdom.

Gut (United Kingdom) 1991;32(10):1151-1155

The incorporation of the fatty acids in fish and olive oil into the colonic mucosa of patients with inflammatory bowel disease was examined during 12 weeks' dietary supplementation with the oils, and the influence on colonic mucosal prostaglandin and thromboxane generation was measured. With a dietary supplement of 18 g fish oil daily, concentrations of the major polyunsaturated fatty acids in fish oil, eicosapentaenoic acid and docosahexaenoic acid, were significantly raised in mucosal lipids. The first time these were measured, after three weeks' supplementation, the mean increases in eicosapentaenoic and docosahexaenoic acid were seven fold and 1.5 fold respectively, and these increases were maintained during the 12 week study. Arachidonic acid values fell throughout the study and this reduction was significant at 12 weeks. Mucosal prostaglandin E2 (PGE2), thromboxane B2, and 6-keto prostaglandin F(1alpha) synthesis were suppressed, and this reached significance (< 0.05) at three and 12 weeks for PGE2 and at 12 weeks for thromboxane B2. The predominant fatty acid in olive oil is oleic acid. Supplementation with 18 g/day resulted in a significant increase in oleic acid in colonic mucosa at 12 weeks (< 0.05) and a fall in stearic acid and docosahexaenoic acid; there was no significant change in eicosanoid synthesis. It is concluded that colonic lipids and prostaglandin and thromboxane synthesis can be readily altered by dietary supplementation with fish oil. The extent of incorporation of the fatty acids present in oils is dependent upon the individual fatty acid.

Effect of arginine on toxin production by Clostridium difficile in defined medium.

Karasawa T, Maegawa T, Nojiri T, Yamakawa K, Nakamura S. Dr. S. Nakamura, Department of Bacteriology, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920 Japan.

Microbiol Immunol (Japan) 1997; 41(8):581-585

Twenty strains of Clostridium difficile were examined for the effect of arginine on toxin production in a defined medium. In three strains, the production of toxins A and B was greatly enhanced in the absence of arginine. These strains showed distinctively poorer growth in the absence of arginine in com-parison with the remaining 17 strains, indicating that the presence of arginine is required for good growth among the three strains. From the present results, test strains were divided into two groups: a group in which arginine insufficiency caused distinctly poor growth and enhanced toxin production, and another group in which there was neither distinctly poor growth nor enhanced toxin production. The phenomenon is discussed in relation to the biosynthesis and catabolism of arginine.

Beneficial intervention of experimental colitis by passive cigarette smoking through the modulation of cytokines in rats.

Ko JK, Sham NF, Guo X, Cho CH. Department of Pharmacology, Faculty of Medicine, University of Hong Kong, 5 Sasson Road, Hong Kong, China. jksko@hkucc.hku.hk

J Investig Med 2001 Jan;49(1):21-9

BACKGROUND: Epidemiologic observations have indicated that cigarette smoking decreases the risk of ulcerative colitis, but the modes of action remain anonymous. The present study aimed to investigate the beneficial effects of passive cigarette smoking using an animal colitis model. We hypothesized that the underlying mechanisms may involve immunoregulation of cytokines. METHODS: Experimental colitis was induced in rats by enema administration of 2,4-dinitrobenzene sulfonic acid (DNBS). Passive cigarette smoking by rats was performed for 1 hour once daily, from 3 days before DNBS enema until they were sacrificed on day 8. Other groups of DNBS-treated rats received therapeutic treatment of cyclosporin A or pentoxifylline, a tumor necrosis factor (TNF)-alpha inhibitor. Macroscopic and histologic damage were graded, and the colonic levels of different cytokines and the levels/activities of parameters related to neutrophil activation were also measured. RESULTS: DNBS-induced colonic damage was improved in passive-cigarette-smoking rats. This was accompanied by attenuation of the elevated colonic myeloperoxidase and inducible nitric oxide synthase activities and leukotriene B4 level. Likewise, the augmentation in colonic levels of TNF-alpha, interleukin (IL)-1 beta, and IL-6 in colitis rats was also alleviated by passive cigarette smoking. In contrast, the deprivation of colonic IL-10 during colitis was preserved in cigarette-smoking rats. These effects were similarly accomplished by pentoxifylline and, to some degree, by cyclosporin A. CONCLUSIONS: The results support the idea that the beneficial effects of passive cigarette smoking in experimental colitis involved immunoregulation of cytokines in colonic tissues.

Is interleukin-6 important in inflammatory bowel disease?

Koss K, Satsangi J, Welsh KI, Jewell DP. Gastroenterology Unit, Radcliffe Infirmary, Oxford, UK. konradkoss@yahoo.com

Genes Immun 2000 Feb;1(3):207-12

The IL-6 gene maps to an area of chromosome 7 known to be significant for susceptibility to inflammatory bowel disease. The functional effects of interleukin-6 (IL-6) polymorphisms in the 4th intron and in the 3' flanking region of IL-6 gene were studied in 192 inflammatory bowel disease patients and healthy subjects. A polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to determine a G to A polymorphism (* at position 4470 in intron 4 of IL-6 gene). Four alleles in the 3' flanking region were studied using a variable number of tandem repeats PCR (VNTR-PCR) amplification. Production of IL-6was measured in lipopolysaccharide (LPS) stimulated whole blood samples by an enzyme-linked immunosorbent assay (ELISA). A modest increase in the frequency of the IL-6* G allele was noted in Crohn's disease (CD) patients (50%) and ulcerative colitis (UC) patients (46.1%) as compared to controls (39.8%, P = 0.025). We were unable to find any significant functional effect of the IL-6 polymorphisms tested on IL-6 protein production. We postulate that the IL-6 polymorphisms investigated here may be in linkage disequilibrium with a susceptibility gene and that they may be utilised as genetic markers.

IL-5 and TNF-alpha participate in recruitment of eosinophils to intestinal mucosa in ulcerative colitis.

Lampinen M, Carlson M, Sangfelt P, Taha Y, Thorn M, Loof L, Raab Y, Venge P. Department of Medical Sciences, University of Uppsala, Sweden.

Dig Dis Sci 2001 Sep;46(9):2004-9

There is an increased influx of activated eosinophils to the intestinal mucosa in active ulcerative colitis, and an increased release of eosinophil-derived proteins, such as ECP, has also been observed. These findings indicate that eosinophils may contribute to tissue damage and intestinal inflammation in this disease. The relative importance of different chemotactic factors and the impact of steroid treatment on their effect in active ulcerative colitis are not known. We measured the eosinophil chemotactic activity in perfusion fluids from 11 patients with ulcerative colitis before and after steroid treatment and from 7 control patients. The effect of neutralizing antibodies to IL-5 and -8, RANTES, eotaxin, MCP-3, TNF-alpha, GM-CSF was investigated. The chemotactic activity was higher in perfusion fluids from patients than from controls (P = 0.0043). Anti-IL-5 (P = 0.005) and -TNF-alpha (P = 0.017) inhibited the activity in perfusion fluids obtained before treatment. Steroid treatment prevented the effect of all antibodies but had no significant effect on the chemotactic activity. The chemotactic activity correlated with the levels of eosinophil granule proteins in the perfusion fluids. In conclusion, in ulcerative colitis, eosinophils are attracted to the intestinal tissue by chemotactic factors, of which IL-5 and TNF-alpha may be the most prominent steroid-sensitive ones. The steroid-insensitive chemotactic activities remain unidentified.

The effect of folic acid supplementation on the risk for cancer or dysplasia in ulcerative colitis.

Lashner BA, Provencher KS, Seidner DL, Knesebeck A, Brzezinski A. USA

Gastroenterology (USA) 1997;112(1):29-32

Background and Aims: Two case-control studies have shown that folate may protect against neoplasia in ulcerative colitis. This historical cohort study was performed to better define this association. Methods: The records of 98 patients with ulcerative colitis who had disease proximal to the splenic flexure for at least 8 years were reviewed. Documented folate use of at least 6 months was deemed a positive exposure. Results: Of the patients, 29.6% developed neoplasia and 40.2% took folate supplements. The adjusted relative risk (RR) of neoplasia for patients taking folate was 0.72 (95% confidence interval (CI), 0.28-1.83). The dose of folate varied with the risk of neoplasia (RR, 0.54 for 1.0 mg folate; RR, 0.76 for 0.4 mg folate in a multivitamin compared with patients taking no folate). Folate use also varied with the degree of dysplasia (RR for cancer, 0.45; RR for high-grade dysplasia, 0.52; RR for low-grade dysplasia, 0.75 compared with patients with no dysplasia) (P = 0.08). Conclusions: Although not statistically significant, the RR for folate supplementation on the risk of neoplasia is < 1 and shows a dose-response effect, consistent with previous studies. Daily folate supplementation may protect against the development of neoplasia in ulcerative colitis.

Role of interleukin-12 in the induction of mucosal inflammation and abrogation of regulatory T cell function in chronic experimental colitis.

Liu Z, Geboes K, Heremans H, Overbergh L, Mathieu C, Rutgeerts P, Ceuppens JL. Laboratory of Experimental Immunology, University of Leuven, Belgium.

Eur J Immunol 2001 May;31(5):1550-60

IL-12 promotes Th1 cell differentiation and cell-mediated immunity. In the present study, the potential role of IL-12 was analyzed in an experimental colitis model in scid mice reconstituted with syngeneic CD45RBhighCD4+ T cells. Real-time reverse transcription-PCR studies demonstrated that IL-12 p40 mRNA in inflamed colon is induced shortly after T cell transfer and maintained at a stable level after week 4, at the time when wasting disease starts. Administration of anti-IL-12 on days 0,14, and 28 (early treatment) or on days 28, 42, and 56 (delayed treatment) after T cell transfer, effectively prevented or, respectively cured wasting disease and colitis in scid recipients. Anti-IL-12 treatment abrogated mucosal inflammation with significantly diminished leukocyte infiltration (CD4 cells, macrophages) and CD54 expression, and down-regulated proinflammatory cytokines IFN-gamma and IL-2. Of note, although splenic CD4+ T cells are unable to induce disease as a result of the presence of regulatory CD45RBlow cells, splenic CD4+ T cells, preactivated by IL-12 and anti-CD3 in vitro, were highly pathogenic in inducing severe mucosal inflammation, suggesting that IL-12 and anti-CD3 abrogated regulatory T cell function. These findings indicate that IL-12 is important for the induction of experimental colitis through effects on proinflammatory cytokine production and on regulatory T cell function.

Induction of nitric oxide synthase in colonic smooth muscle from patients with toxic megacolon.

Mourelle M, Casellas F, Guarner F, Salas A, Riveros-Moreno V, Moncada S, Malagelada J-R. Digestive System Research Unit, Hospital General Vall d'Hebron, 08035 Barcelona Spain

Gastroenterology (USA) 1995;109(5):1497-1502

Background and Aims: Colonic inflammation may lead to motility disturbances, including severe atony. Nitric oxide is released by inflamed tissue and induces smooth muscle relaxation. The aim of this study was to analyze NO generation pathways in colonic tissue from patients who had ulcerative colitis with or without toxic megacolon and in tumor-free samples from patients with colonic neoplasm. Methods: Enzymatic activity was determined by transformation of (14C)arginine to (14C)citrulline in mucosa and muscular layer samples. Immunostaining of tissue sections with antibody against inducible NO synthase was investigated. The effects of endotoxin on NO synthase activity was tested in muscle strips from human colon. Results: Ca2+-independent NO synthase was undetectable or very low in muscularis propria from tumor and colitis controls. In contrast, specimens from patients with toxic megacolon had high activity (< 0.05). Positive immunostaining for inducible NO synthase was found in muscular layers from patients with megacolon but not in tumor and colitis controls. Finally, endotoxin induced Ca2+-independent NO synthase activity in colonic muscle. Conclusions: Toxic megacolon is associated with the appearance of inducible NO synthase in the colonic muscularis propria. Local generation of excessive amounts of NO may be responsible for the colonic dilatation that is the hallmark of this syndrome.

Manipulation of the L-arginine-nitric oxide pathway in experimental colitis.

Neilly PJD, Kirk SJ, Gardiner KR, Anderson NH, Rowlands BJ. Department of Pathology, Queen's University of Belfast, Belfast United Kingdom.

Br J Surg (United Kingdom) 1995;82(9):1188-1191

The role of the L-arginine-nitric oxide pathway in the pathogenesis of colonic inflammation was assessed using L-arginine and its competitive analogue N(omega)-nitro-Larginine methyl ester (L-NAME) in a rat model of colitis. In the first study oral L-arginine 2 per cent (control: 3.4 per cent L-glycine) was administered with and without L-NAME 100 mg/l. Orally administered L-arginine increased colonic inflammation (P = 0.004) and decreased thymic weight (P = 0.0007). Addition of L-NAME reduced the colonic inflammation and prevented loss of body-weight (< 0.04). In the second study L-NAME was administered orally in concentrations of 100, 200 and 500 mg/l (control: no L-NAME). L-NAME 500 mg/l reduced colonic inflammation and increased thymic weight and body-weight (< 0.01). Thymic weight and body-weight correlated positively with the concentration of L-NAME administered orally (r(s) 0.3, P = 0.04). L-NAME 1 g/l was administered topically as an enema (control: suspension agent). Topical L-NAME reduced colonic inflammation and increased thymic weight (< 0.05). These results suggest that the L-arginine-nitric oxide pathway mediates colonic inflammation in this model.

Nutrition and gastrointestinal disease.

O'Keefe S.J.D. Gastrointestinal Clinic, Groote Schuur Hospital, Observatory 7925, Cape Town, South Africa.

Scand Journal Gastroenterol Suppl (Norway) 1996;31(220):52-59

Nutrition and intestinal function are intimately interrelated. The chief purpose of the gut is to digest and absorb nutrients in order to maintain life. Consequently, chronic gastrointestinal (GI) disease commonly results in malnutrition and increased morbidity and mortality. For example, studies have shown that 50-70% of adult patients with Crohn's disease were weight-depleted and 75% of adolescents growth-retarded. On the other hand, chronic malnutrition impairs digestive and absorptive function because food and nutrients are not only the major trophic factors to the gut but also provide the building blocks for digestive enzymes and absorptive cells. For example, recent studies of ours have shown that a weight loss of greater than 30% accompanying a variety of diseases was associated with a reduction in pancreatic enzyme secretion of over 80%, villus atrophy and impaired carbohydrate and fat absorption. Finally, specific nutrients can induce disease, for example, gluten-sensitive enteropathy, whilst dietary factors such as fibre, resistant starch, short-chain fatty acids, glutamine and fish oils may prevent gastrointestinal diseases such as diverticulitis, diversion colitis, ulcerative colitis, colonic adenomatosis and colonic carcinoma. The role of dietary antigens in the aetiology of Crohn's disease is controversial, but controlled studies have suggested that elemental diets may be as effective as corticosteroids in inducing a remission in patients with acute Crohn's disease. In conclusion, nutrition has both a supportive and therapeutic role in the management of chronic gastrointestinal diseases. With the development of modern techniques of nutritional support, the morbidity and mortality associated with chronic GI disease can be reduced. On the other hand, dietary manipulation may be used to treat or prevent specific GI disorders such as coeliac disease, functional bowel disease, Crohn's disease and colonic neoplasia. The future development of nutria-pharmaceuticals is particularly attractive in view of their low cost and wide safety margins.

Circulating antioxidants in ulcerative colitis and their relationship to disease severity and activity.

Ramakrishna BS, Varghese R, Jayakumar S, Mathan M, Balasubramanian KA. Dr. B.S. Ramakrishna, Dept. of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore 632004 India.

J Gastroenterol Hepatol (Australia) 1997;12(7):490-494

Oxygen free radicals produced by neutrophils are important in the pathogenesis of mucosal damage in ulcerative colitis. Vitamin A, vitamin E and cysteine in the plasma can scavenge free radicals. In the study, plasma levels of vitamin A, vitamin E, cysteine, cystine and protein-bound cysteine were measured in active ulcerative colitis before and immediately after treatment of the active disease, and correlated with disease severity, extent and activity. Plasma vitamin A and cysteine were significantly reduced in active ulcerative colitis compared with controls. Levels of vitamin E, cystine and protein-bound cysteine were not significantly altered in active ulcerative colitis. Vitamin A and cysteine concentrations returned to normal levels (< 0.05) within 2 weeks of treating active colitis. There were significant negative correlations between clinical severity and the plasma concentrations of vitamin A and cysteine. Plasma cysteine levels also correlated inversely to disease extent. Depletion of the circulating antioxidants, vitamin A and cysteine, in active ulcerative colitis is likely to be important in the pathophysiology of the disease.

The colonic epithelium in ulcerative colitis: an energy-deficiency disease?

Roediger WEW. Nuffield Dept. Surg., Radcliffe Infirm., Univ. Oxford United Kingdom.

Lancet (England) 1980;2(8197):712-715

Suspensions of colonocytes (isolated colonic epithelial cells) were prepared from mucosa of the descending colon from 6 patients with quiescent ulcerative colitis (UC), 4 with acute UC, and 7 control subjects. In each group metabolic performance was investigated by assessing utilization of n-butyrate, the main respiratory fuel of the colonic mucosa, as well as utilization of glucose and glutamine. In both acute and quiescent UC oxidation of butyrate to CO2 and ketones was significantly lower than in the control tissues, and the decrease correlated with the state of the disease. Enhanced glucose and glutamine oxidation compensated for decreased butyrate oxidation in UC, indicating that colonocytes in colitis were not metabolically degenerate cells. Failure of butyrate oxidation reflects a variable yet definite metabolic deficit in the mucosa in UC. Diminished oxidation of butyrate can explain the characteristic distribution of colitis along the colon, especially the frequency of UC in the distal colon. It is suggested that failure of fatty-acid (n-butyrate) oxidation in UC is an expression of an energy-deficiency disease of the colonic mucosa.

The role of marine fish oils in the treatment of ulcerative colitis.

Ross E. Department of Internal Medicine, Tufts University School of Medicine, Boston, MA 02111 U.S.A.

Nutr Rev (USA) 1993;51(2):47-49

Recent studies suggest that marine fish-oil supplements, which are rich in n-3 fatty acids, may reduce the inflammation associated with ulcerative colitis. Fish oils may exert their beneficial effects by shifting eicosanoid synthesis to less inflammatory species or by modulating tissue levels of certain cytokines.

Bone mineral density and calcium regulating hormones in patients with inflammatory bowel disease (Crohn's disease and ulcerative colitis).

Scharla SH, Minne HW, Lempert UG, Leidig G, Hauber M, Raedsch R, Ziegler R. Innere Medizin I, Universitatsklinik Heidelberg, Bergheimer Strasse 58, D-69115 Heidelberg Germany

Exp Clin Endocrinol (Germany) 1994;102(1):44-49

Inflammatory bowel disease (Crohn's disease and ulcerative colitis) is associated with decreased bone mineral density and increased risk of osteoporosis. However, the pathogenesis of this bone loss is not yet fully understood. In the present study we measured lumbar bone mineral density (by dual photon absorptiometry), serum levels of parathyroid hormone (PTH) and vitamin D metabolites, and serum markers of bone turnover (alkaline phosphatase and osteocalcin) in 15 patients with Crohn's disease and in 4 patients with ulcerative colitis. The median duration of the disease was 4 years and the median lifetime steroid dose was 10g of prednisone. We compared our results to a control group of 19 normal persons, who were matched for age and sex to the patients. We found that lumbar bone density was reduced by 11% in patients compared with control persons (Z-score -0.6 plus or minus 0.6 versus -0.1 plus or minus 0.8: < 0.05). In patients, the serum levels of PTH, 25-hydroxyvitamin D3, and calcitriol (1.25(OH)2D3) were significantly reduced compared with control persons. Serum alkaline phosphatase activity (AP) was significantly higher in the patients and was inversely related to lumbar bone density. Osteocalcin values were not different between patients and control persons. There was also no difference in serum levels of calcium between the two groups, whereas phosphorus levels were higher in patients. We conclude that malabsorption of calcium was not a primary cause of bone loss in our patients, because we did not find secondary hyperparathyroidism. Accordingly, we did not find a severe vitamin D deficiency, since 25-hydroxyvitamin D3 levels were within the normal range. Therefore, our results favor the hypothesis that glucocorticoid therapy and/or the inflammatory process itself caused changes in bone metabolism leading to a negative bone balance with secondary reduction of PTH and calcitriol levels.

Nutritional issues in pediatric inflammatory bowel disease.

Seidman E, LeLeiko N, Ament M, Berman W, Caplan D, Evans J, Kocoshis S, Lake A, Motil K, Sutphen J, Thomas D. Division of Gastroenterology, Hopital Ste-Justine, 3175 Cote Ste-Catherine Road, Montreal, Que. H3T 1C5 Canada.

J Pediatr Gastroenterol Nutr (USA) 1991; 12(4):424-438

Malnutrition characterized by weight loss, growth failure and micronutrient depletion are prominent features of inflammatory bowel disease (IBD) in the pediatric age group. Accurate evaluation of the patient's nutritional status and appropriate nutritional support, whether enteral or parenteral, constitute integral parts of the management of the growing child with IBD. Over the past two decades, a number of studies have supported the potential use of nutritional therapy to induce remission and to control disease activity in symptomatic Crohn's disease. More recently, preliminary studies on the use of dietary supplements of marine-oil-derived omega-3 fatty acids have also indicated a beneficial effect in IBD patients. In parallel with these clinical trials, scientific research has recently focused on the concept that specific dietary alterations can modulate the immune response. Components of the diet that may have particular relevance to mucosal immunity and the pathogenesis of IBD include polyunsaturated fatty acids, nucleotides, and amino acids such as glutamine and arginine. Future research in the interactions between specific nutrients and the immune system will likely increase our understanding of the causes of IBD, as well as enhance the development of novel nutritional therapies for IBD patients.

Nutrition in inflammatory bowel disease.

Steinhart AH, Greenberg GR. Canada

Curr Opinion Gastroenterol (USA) 1997;13(2):140-145

Nutrition is an important aspect of the inflammatory bowel diseases (IBDs), ulcerative colitis and Crohn's disease. Components of the diet and the nutritional status of an individual patient may impact on IBD, and the diseases themselves may in turn impact on nutritional status. In this review we highlight recent advances in the field of nutrition and IBD. A topic of particular interest over the past year is the effect of nutrients, particularly fish oils and glutamine, on gut inflammation and permeability, bacterial translocation, and cytokine profiles in humans and in experimental models of IBD. It appears that fish oil may be a useful therapeutic agent in the management of Crohn's disease. Over the past year, data from previous trials of enteral feeds for the treatment of Crohn's disease have been summarized in three meta-analyses, and further clinical experience with the long-term use of enteral feeds in pediatric patients has been published. Significant interest continues in the abnormalities of colonocyte metabolism in ulcerative colitis and the role of diminished short-chain fatty acid production or use in the pathogenesis of ulcerative colitis. Several additional reports on the use of topical short-chain fatty acid enemas for the treatment of distal ulcerative colitis have appeared in the literature.

Dietary supplementation of nucleotides and arginine promotes healing of small bowel ulcers in experimental ulcerative ileitis.

Sukumar P, Loo A, Magur E, Nandi J, Oler A, Levine RA. Dr. R.A. Levine, Division of Gastroenterology, University Hospital, 750 East Adams Street, Syracuse, NY 13210 U.S.A.

Dig Dis Sci (USA) 1997; 42(7):1530-1536

We previously showed that intravenous total parenteral nutrition supplemented with nucleosides and nucleotides (NS/NT) promoted ulcer healing in rats with indomethacin-induced ileitis. The present study evaluated whether dietary NT supplementation would similarly affect ulcer healing in this model. Female Lewis rats were randomized into either control or experimental groups receiving yeast RNA containing NT or arginine, glutamine, fish oil, guar gum, or a combination of yeast RNA + arginine diets. Ileitis was induced by two doses of indomethacin (7.5 mg/kg) administered subcutaneously 24 hr apart. Ulcer number and length were determined at 4, 8, and 14 days after induction of ileitis. Ileal villous and crypt length, crypt-villous ratio, and bromodeoxyuridine (BrdU) labeling were studied in the control and yeast RNA-supplemented diet groups. Ileal ulceration was present in all groups at 4 and 8 days and was almost healed by 14 days. Rats receiving yeast RNA, arginine, and yeast RNA + arginine diets showed a significant decrease in ulcer number (56%, 28%, and 34%, respectively) and length (67%, 41%, and 48%, respectively) compared to controls at 8 but not at 4 days. Glutamine, fish oil, and guar gum had no effect on ulcer healing at 4, 8, or 14 days. Among the histological parameters, a significant decrease in crypt length in the yeast RNA-supplemented group at 8 days suggested an acceleration of the healing process and restoration to a near-normal crypt-villous architecture. We conclude that the yeast RNA, arginine, and yeast RNA + arginine diets accelerated ulcer healing, as indicated by decreased ulcer number and length. We postulate that the underlying mechanism(s) contributing to ulcer healing may be related, in part, to increased cell proliferation.

Pattern of cytokine and adhesion molecule mRNA in hapten-induced relapsing colon inflammation in the rat.

Sun FF, Lai PS, Yue G, Yin K, Nagele RG, Tong DM, Krzesicki RF, Chin JE, Wong PY. Department of Cell Biology, School of Osteopathic Medicine, UMDNJ, Stratford, NJ 08084, U.S.A.

Inflammation 2001 Feb;25(1):33-45

We examined the mRNA expression of cytokines, chemokines, integrins, and selectins in colon lesions of rat colitis with a semi-quantitative RT-PCR assay. Rat colitis was induced by trinitrobenzene sulfonic acid (TNBS) in 50% ethanol. Within 24 h, an acute inflammation occurred with hyperemia, edema, necrosis and an intense infiltration of granulocytes in the mucosa. The lesion proceeded into a T-lymphocyte/monocyte-driven chronic inflammation for two weeks and healed in 6 weeks. An acute inflammation recurred at the same site when the recovered animals were systemically injected with TNBS. We isolated RNA from colon tissue at 24 h, 1, 2, 4, 6 weeks after TNBS treatment and from the relapsed animals. The mRNA for cytokines IL-1beta, IL-6, IL-10 and the chemokines CINC, MIP-1alpha, MCP-1 were significantly (< 0.05) elevated and persisted for 2 weeks, decreased in 6 weeks and increased again during relapse. IFN-gamma mRNA stayed at control levels initially, but increased dramatically in the second weeks of chronic inflammation as well as in relapse. The mRNA levels of adhesion molecules, ICAM-1, VCAM-1, the mucosal homing integrin beta7 as well as P- and E-selectin were greatly enhanced between 1 and 3 weeks. The data showed that the chronically inflamed tissue expresses a time-dependent changing pattern of TH1 cytokines and adhesion molecules that maintain the infiltration and activation of inflammatory cells and tissue injury.

Enhanced apoptosis in transformed human lung fibroblasts after exposure to sodium butyrate.

Thomas GL, Henley A, Rowland TC, Sahai A, Griffin M, Birckbichler PJ. Department of Urology, Univ. of Oklahoma Hlth. Sci. Center, 920 Stanton L. Young Blvd., Oklahoma City, OK 73190 U.S.A.

In Vitro Cell Dev Biol Anim (USA) 1996; 32(8):505-513

Simian virus-transformed human cells, WI-38 VA13A, showed a dose- dependent induction of apoptosis and reduction in cell numbers after exposure to sodium butyrate. Apoptosis was confirmed by ApopTag staining, isolation of apoptotic envelopes, and immunofluorescent staining with an antibody specific for apoptotic envelopes. Examination of the cell cultures by phase contrast and fluorescent microscopy revealed the presence of enlarged cells that displayed a more flattened morphology and morphological changes in the nucleus of cells exposed to sodium butyrate. Cell proliferation assays showed control and sodium butyrate cultures were synthesizing DNA and excluded any cytotoxic effects of sodium butyrate. Flow cytometry results indicated an increase in the number of aneuploid cells following sodium butyrate treatment. There was a decrease in the percentage of cells in G2/M in the diploid populations, but an increase in the percentage of cells in G2/M in aneuploid populations. This human in vitro model system suggests a mode of action for the therapeutic effects of sodium butyrate, which have been observed in the topical treatment of neoplastic cells and reversal of symptoms in ulcerative colitis: namely, the induction of apoptosis.

Nutritional assessment and disease activity for patients with inflammatory bowel disease.

Wasser TE, Reed JF, Moser K, Robson P, Faust L, Fink LL, Wunderler D. Research Department, The Lehigh Valley Hospital, Cedar Crest and I-78, Allentown, PA 18105-1556 U.S.A.

Can J Gastroenterol (Canada) 1995;9(3):131-136

Using the Harvard/Willett Semi-Quantitative Food Frequency Questionnaire (H/WSQFFQ), nutritional information was gathered on patients enrolled in an inflammatory bowel disease (IBD) registry. The registry lists 320 patients positive for either ulcerative colitis (n = 124) or Crohn's disease (n = 196). The sample was limited to those 19 to 84 years old (mean plus or minus SD 48.57plus or minus14.98), and comprised 136 males and 184 females. Using a battery of indices, quality of life, disease activity and general well-being were also assessed. Nutritional intake values from the Harvard-Willett data were compared with recommended dietary allowances (RDA) tables by sex age group (19 to 24 years, 25 to 50, 51 and older) to discover any intake deficiencies. Results showed that IBD patients were below RDA guidelines for vitamin E, calcium, magnesium, zinc iodine and selenium. Females were below RDA guildelines for iron while men were below for vitamin B6. There were also some deficiencies according to age in males and two nutrient deficiencies were seen by age group in women. There were no deficiencies by sex or age for vitamins A, C, D and niacin. There were no observed nutrient intake differences between ulcerative colitis and Crohn's disease groups. Patients receiving vitamin or mineral supplementation showed significant decreases in quality of life, regardless of diagnosis (Crohn's disease or ulcerative colitis) group. The H/WSQFFQ is a useful tool for assessment of the nutritional status of the IBD patient because it not only provides valuable measurement data to the clinician, but also adds to patient awareness about nutritional problems associated with IBD.

Special issues in nutritional therapy of inflammatory bowel disease.

Williams CN. CRC, Dalhousie University, 5849 University Avenue, Halifax, NS B3H 4H7 Canada

Can J Gastroenterol (Canada) 1993;7(2):196-199

There are many issues and controversies concerning nutrition in inflammatory bowel disease (IBD). Most authorities now accept that total parenteral nutrition (TPN) is useful, both as primary and adjunct therapy in the management of patients with Crohn's disease, but only useful as adjunct therapy in patients with acute flare-ups of ulcerative colitis. In both, there is a role for TPN in preparing patients for imminent surgery. In comparison with TPN, defined formula (elemental diet) therapy has less complications, is easier to monitor, is less costly, and gives equivalent results. Several controlled trials have shown that elemental diet therapy is as useful as prednisone in inducing remission in patients with active Crohn's disease. Elemental diets have been compared with polymeric diets in patients with Crohn's disease, and have been shown to be effective; recently a semi-elemental diet has also been shown to be as effective as elemental diet, but with a conferred benefit of maintaining essential fatty acid levels. Elemental diets do not appear to be effective in closing fistulas. If the problems of palatability and, in some patients, nausea, vomiting, abdominal cramps and diarrhea persist, these can be overcome to some extent by flavour changes, chilling, gradual introduction and counselling or nasogastric tube feeding. Recently, fish oils have been used in patients with IBD. There is suggestive evidence that they are of benefit in patients with ulcerative colitis but not in Crohn's disease. There is a suggestion that fish oils have a steroid-sparing effect which, if confirmed, will be of great potential benefit to patients with ulcerative colitis.

Aslan A.; Triadafilopoulos G.
Gastroenterology Section, Martinez VA Medical Center, 150 Muir Road, Martinez, CA 94553 USA
Am. J. Gastroenterol. (USA), 1992, 87/4 (432-437)

Arachidonic acid metabolites formed by both the cyclooxygenase and lipoxygenase pathways may contribute to the clinical diarrhea and colitis of inflammatory bowel disease. Patients with active ulcerative colitis have increased levels of leukotriene B4 in their rectal mucosa, and these levels tend to correlate with severity of the disease. In this study, we evaluated the efficacy of ingestion of fish oil n-3-omega-fatty acids, inhibitors of leukotriene synthesis, in the treatment of ulcerative colitis. Eleven patients with ulcerative colitis of mild to moderate severity were studied in a 8-month, double-blind, placebo-controlled, crossover trial of dietary supplementation with fish oil, which provided about 4.2 g of omega-3- fatty acids per day. A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mucosal leukotriene B4 production was measured by radioimmunoassay. Mean disease activity index declined 56% for patients receiving fish oil and 4% for patients on placebo (p < 0.05). There were no statistically significant differences in histopathologic scores or colonic mucosal leukotriene B4 levels. All patients tolerated fish oil ingestion and showed no alteration in routine blood studies. No patient worsened; anti-inflammatory drugs could be reduced or eliminated in eight patients (72%) while receiving fish oil. We conclude that fish oil dietary supplementation results in clinical improvement of active mild to moderate ulcerative colitis but is not associated with significant reduction in mucosal leukotriene B4 production, compared with placebo therapy. Further studies are needed to elucidate the mechanism of action and optimal dose and duration of fish oil supplementation in ulcerative colitis.

Simopoulos A.P.
The Center for Genetics, Nutrition and Health, 2001 S Street, NW, Washington, DC 20009 USA
Am. J. Clin. Nutr. (USA), 1991, 54/3 (438-463)

Several sources of information suggest that man evolved on a diet with a ratio of omega6 to omega3 fatty acids of similar 1 whereas today this ratio is similar 10:1 to 20-25:1, indicating that Western diets are deficient in omega3 fatty acids compared with the diet on which humans evolved and their genetic patterns were established. Omega-3 fatty acids increase bleeding time; decrease platelet aggregation, blood viscosity, and fibrinogen; and increase erythrocyte deformability, thus decreasing the tendency to thrombus formation. In no clinical trial, including coronary artery graft surgery, has there been any evidence of increased blood loss due to ingestion of omega3 fatty acids. Many studies show that the effects of omega3 fatty acids on serum lipids depend on the type of patient and whether the amount of saturated fatty acids in the diet is held constant. In patients with hyperlipidemia, omega3 fatty acids decrease low-density-lipoprotein (LDL) cholesterol if the saturated fatty acid content is decreased, otherwise there is a slight increase, but at high doses (32 g) they lower LDL cholesterol; furthermore, they consistently lower serum triglycerides in normal subjects and in patients with hypertriglyceridemia whereas the effect on high-density lipoprotein (HDL) varies from no effect to slight increases. The discrepancies between animal and human studies most likely are due to differences between animal and human metabolism. In clinical trials eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oils along with antirheumatic drugs improve joint pain in patients with rheumatoid arthritis; have a beneficial effect in patients with ulcerative colitis; and in combination with drugs, improve the skin lesions, lower the hyperlipidemia from etretinates, and decrease the toxicity of cyclosporin in patients with psoriasis. In various animal models omega3 fatty acids decrease the number and size of tumors and increase the time elapsed before appearance of tumors. Studies with nonhuman primates and human newborns indicate that DHA is essential for the normal functional development of the retina and brain, particularly in premature infants. Because omega3 fatty acids are essential in growth and development throughout the life cycle, they should be included in the diets of all humans. Omega-3 and omega6 fatty acids are not interconvertible in the human body and are important components of practically all cell membranes. Whereas cellular proteins are genetically determined, the polyunsaturated fatty acid (PUFA) composition of cell membranes is to a great extent dependent on the dietary intake. Therefore appropriate amounts of dietary omega6 and omega3 fatty acids need to be considered in making dietary recommendations, and these two classes of PUFAs should be distinguished because they are metabolically and functionally distinct and have opposing physiological functions. Their balance is important for homeostasis and normal development. Canada is the first country to provide separate dietary recommendations for omega6 and omega3 fatty acids.

O'Morain C.A.
Department of Gastroenterology, Meath/Adelaide Hospitals, Peter Street, Dublin 8 Ireland
Scand. J. Gastroenterol. Suppl. (Norway), 1990, 25/172 (29-34)

The aetiology of inflammatory bowel disease (IBD) remains unknown, and many methods of treatment have been advocated. Patients with IBD are often nutritionally deficient and in negative nitrogen balance. The cause is multifactorial and includes decreased intake and absorption due to previous resection or mucosal involvement or increased exudation. General recommendations of vitamin and mineral supplements are usually made for these patients. Diet may have a more fundamental role in the aetiology and treatment of Crohn's disease, although this is not certain. Several controlled studies have confirmed that an elemental diet is as effective as steroids in inducing a remission in patients with acute Crohn's disease. Bacteria have also been implicated in the aetiology of Crohn's disease. Dietary measures may alter the intestinal flora and could result in a decrease of toxin production, which has been shown to correlate with clinical improvement. Although elemental diets are not effective in the treatment of ulcerative colitis, dietary measures may still be important. Preliminary studies suggest that eicosapentaenoic acid, which inhibits the production of mediators of inflammation by competing with enzymes in the arachidonic acid pathway, may be effective. Recent findings of increased faecal bile acids in patients with long-standing ulcerative colitis who developed dysplasia or carcinoma suggest that dietary measures may counteract these developments. It does appear that nutritional therapy in patients with IBD has both a primary and adjunctive role.

Jenkins H.R.; Pincott J.R.; Soothill J.F.; et al.
Department of Gastroenterology, The Hospital for Sick Children, London United Kingdom
Arch. Dis. Child. (England), 1984, 59/4 (326-329)

Forty six children presented with colitis between 1977 and 1981, and all 8 of those below the age of 2 years had food allergic colitis which resolved completely after exclusion of certain foods. In most of the 8 the onset was soon after starting foods other than breast milk. The most common offending food was cows' milk protein, but soya (3 cases) and beef (1 case) were also implicated. A history of allergy in the child or family was common as were blood eosinophilia, high concentrations of serum IgE, and positive IgE antibodies. Colonoscopic appearances were distinctive and biopsies showed a noticeable increase in eosinophils and IgE-containing cells in the lamina propria. We suggest that food allergy is the major cause of colitis in infancy and that an exclusion diet is the treatment of choice.

Cosnes J.; Tello H.; Le Quintrec M.; et al.
Service d'Hepato Gastroenterologie, Hopital Rothschild, F-75571 Paris Cedex 12 France
Gastroenterol. Clin. Biol. (France), 1983, 7/12 (1003-1009)

In order to assess the effectiveness and potential limitations of continuous enteral nutrition (CEN) to correct denutrition related to underlying digestive diseases, 10 nutritional criteria were measured weekly in 92 undernourished patients fed with CEN for a 3-7 week period. All the patients received a standard non-elemental diet providing a mean daily energy intake of 52.8 kcal/kg BW (36.5 kcal/kg BW by tube feeding and 16.3 kcal/kg BW orally). The influence of preexisting intestinal malabsorption, hypercatabolic status, and post-radiation or inflammatory bowel disease was studied by an a posteriori classification of patients in one of the six following groups: I (no limiting factor), II (malabsorption), III (catabolic disease), IV (catabolic disease and malabsorption), V (colitis), VI (enteritis). During CEN, 8 patients had transient and one had persistent vomiting while 3 developed bronchopneumonia. Gains in body weight, triceps skinfold, midarm muscle circumference, creatinine-height index, urinary sodium and serum transferrin were significant as early as the 2nd week of CEN. Serum albumin and cholesterol, hemoglobin, and total count of lymphocytes were not significantly affected. Sixty-five patients (71 per cent) had an objective nutritional improvement and mean spontaneous oral intake increased from 17.8 to 28.7 kcal/kg BW per day. Significant increase of oral intake and objective nutritional improvement were observed in each group, but a longer period of CEN was necessary to achieve this result in groups II, IV and VI. These results a) confirm that CEN is an effective and well tolerated nutritional treatment in gastrointestinal patients, b) describe the kinetics of nutritional improvement during CEN, and c) show that, in the alimentary conditions of this study, malabsorption, hypercatabolic disease or inflammatory enteropathy are not a contra-indication to the use of CEN. In chronic denutrition CEN must be administered during at least 3 weeks and prolonged until nutritional autonomy is obtained.

Wensinck F.; Custers-Van Lieshout L.M.C.; Poppelaars-Kustermans P.A.J.; Schroder A.M.
Dept. Med. Microbiol., Erasmus Univ., Rotterdam Netherlands
J. Hyg. (England), 1981, 87/1 (1-12)

The faecal flora of patients with Crohn's disease was compared with that of healthy subjects. In patients with terminal ileitis, numbers of anaerobic gram-negative and coccoid rods (species of Eubacterium and Peptostreptococcus) were higher than in the controls whereas anaerobic gram-positive rods and cocci and aerobes occurred in normal numbers. The composition of the flora was neither influenced by duration of the disease nor by ileocaecal resection. In healthy subjects and patients, a chemically defined diet induced only slight changes in the flora. Thus, the flora in terminal ileitis although stable was permanently abnormal. In patients with Crohn's colitis, abnormally low numbers of anaerobes were found in patients with severe, bloody diarrhoea while aerobic counts were normal. The flora in patients with mild colitis was similar to that in terminal ileitis. It is suggested that the abnormal flora composition might be an expression of the genetic predisposition to Crohn's disease.

Axelsson C.; Jarnum S.
Div. Gastroenterol., Med. Dept. P, Rigshosp., Univ. Copenhagen Denmark
Infusionsther. Klin. Ernahr. (Switzerland), 1977, 4/6 (313-318)

During a 4-year period 59 patients were treated with an elemental diet (Vivasorb(Reg.trademark)) for 1-6 weeks. The great majority (41 patients) were suffering from chronic inflammatory bowel disease. The indication for treatment was insufficient remission on prednisone 10-60 mg daily for 1-4 weeks or no remission after a high dose of prednisone (6O-120 mg) for 1-4 weeks. Remission was obtained in 14 patients on elemental diet and a constant or decreasing dose of prednisone and in another 6 on elemental diet and a high dose of prednisone. Thus, a total of 2O patients (50%) remitted. This includes 12 out of 24 with ulcerative colitis, and 8 out of 17 with Crohn's disease. It was not possible to demonstrate significant differences between the groups having moderate and severe disease activity, or between those with topographically restricted and with extensive lesions. The remission was long. During this treatment of patients with chronic inflammatory bowel disease there occurred a significant reduction in faecal bulk, frequency of bowel movements, and the ESR (erythrocyte sedimentation rate). A number of parameters, including serum protein and albumin, remained greatly reduced. Moreover, there was a significant decrease in serum urea and in the renal excretion of urea, due to the low nitrogen content of Vivasorb(Reg.trademark). Treatment of patients with intestinal fistulae (13 patients), the short bowel syndrome (6 patients), intractable diarrhoea (4 patients), recurrent pancreatitis (2 patients) and hyperlipaemia (2 patients) gave good results in several, but far from all cases. In particular, no effect was obtained in patients having the short bowel syndrome.

Goschke H.; Buess H.; Gyr K.; et al.
Dept. Inn. Med., Univ., Basel Switzerland
Schweiz.Med.Wschr. (Switzerland), 1977, 107/2 (43-49)

21 patients with gastroenterological disease and indication for the use of intravenous nutrition received an elemental diet (ED) for 5-44 days. In 6 out of 8 patients with exacerbation of Crohn's disease remissions were achieved, apart from 3 persistent fistulas. In 5 out of 9 cases with various primary diseases and postoperative intestinal fistulas, spontaneous healing was observed. Furthermore, 2 patients with ulcerative colitis, 1 with radiation enteritis and 1 with pancreatitis were treated with ED. On ED, hemoglobin increased from 11.3 + or - 0.4 (m + or - SEM) to 12.0 + or - 0.5 g% (p <0.01) and serum albumin from 2.7 + or - 0.1 to 3.4 + or - 0.1 g% (p <0.001). Nitrogen requirements were studied in 11 patients receiving various quantities of ED. Nitrogen balance was found to be in equilibrium or positive in 7 patients, and negative in 4. In one patient with severe ulcerative colitis, fecal nitrogen losses were higher than urinary nitrogen losses. The unpleasant taste of ED resulting from free amino acids limited the ED supply in 3 patients and led to premature ending of ED administration in 3 other patients. In such cases ED may be given by nasogastric tube feeding. From the results presented it appears that ED is indicated in Crohn's disease and intestinal fistulas. However, the results obtained require confirmation by further observations and comparison with an intravenously fed control group.

Falchuk K.R.; Falchuk Z.M.
Dept. Med., Massachusetts Gen. Hosp., Peter Bent Brigham Hosp., Boston, Mass. USA
Gastroenterology (USA), 1975, 69/2 (503-506)

A patient with selective immunoglobulin A deficiency, severe ulcerative colitis, and malabsorption had a flat jejunal mucosa demonstrated by peroral biopsy. Treatment at different times with a gluten free diet for the jejunal lesion and corticosteroids for the ulcerative colitis, led to improvement of the malabsorption. A great jejunal biopsy demonstrated histological improvement of the jejunal mucosa, even though the colitis remained active. The occurrence of immunoglobulin A deficiency in a patient with ulcerative colitis and gluten sensitive enteropathy is uncommon.

Ito T.
I Dept. Int. Med., Hirosaki Univ. Sch. Med., Hirosaki Japan
Hirosaki Med.J. (Japan), 1974, 26/2 (167-186)

A comparative study of the absorption of various kinds of fatty acids and corresponding triglycerides and a study of MCT metabolism in experimental animals is presented. Time lapse absorption of MCT and LCT was studied in fasted albino rats by giving orally sup 1sup 4C labeled fatty acid preparations. Octanoic acids were mostly absorbed within an hr but only 32% of palmitate. The absorption of sup 1sup 4C labeled glycerol trioctanoate was studied. Small intestines of the dog were ligated and segmented into 3 parts (upper, middle and lower). Of the 3 segments, the middle showed the fastest absorption of glycerol trioctanoate 1 sup 1sup 4C. Experiments in dogs with indwelling cannulas in the thoracic ducts showed that only 5.21 x 10sup -sup 2 muCi of administered glycerol trioctanoate 1 sup 1sup 4C was transported to the lymphatics in 120 min. The radioactivity in the lipids of albino rat liver was studied 60 and 120 min after an oral administration of glycerol trioctanoate 1 sup 1sup 4C. The radioactivity of the lipid fraction was 1.3% of all activity that was absorbed. Nearly 54.1% of the radioactivity of lipids from liver slices was detected in phospholipids and 36.8% in triglycerides but in free fatty acids and cholesterol esters the activity was extremely low. The radioactivity of administered glycerol was detected in the form of sup 1sup 4COsub 2 as early as 15 min after ingestion and this activity increased abruptly after 30 min and in 75 min it reached 21.3% of the administered dose and 28% of the total absorbed glycerol. Clinical study was performed to evaluate MCT therapy in 10 patients, 7 of them with postoperative malabsorption syndrome, one with liver cirrhosis, one with pancreatic cyst and one with postoperative ulcerative colitis. After a control period, 150 g of MCT was added daily to the diet of the patients. Because of the untoward effects, the MCT regimen was discontinued in 3 cases. The other 7 patients treated for more than a mth showed an increase in body weight of over one kilogram on average. Abnormally low serum cholesterol and albumin in a patient attained a normal range after one month of MCT administration. sup 1sup 3sup 1I triolein test improved and the frequency of bowel movements decreased in all patients. To achieve clinical effectiveness, MCT was continuously administered for at least a mth. In patients with malabsorption syndrome, there was an increase in body weight, serum cholesterol and serum albumin, a decrease in frequency of bowel movements and an improvement in the nature of the stool.

Jarnum S.
Med. Afd. P, Gastroenterol. Afsnit, Rigshosp., Kobenhavn Denmark
Ugeskr.Laeg. (Denmark), 1974, 136/17 (912-920)

Crohn's disease attracts increasing interest on account of its many clinical and pathophysiological aspects and because it seems to be becoming more frequent. Based on case material of 179 patients with Crohn's disease treated in hospital over a 10 yr period, certain epidemiological, clinical and pathophysiological features are discussed. Diagnostic accuracy is considered high. Thus the small intestine was involved in approximately 90%. However, the case material is selected and, therefore, less suited for an epidemiological study. One third was transferred from other hospitals, one fourth lived in Copenhagen, one third in Jutland. Copenhagen citizens in the case material represented a 'minimal' prevalence of 7.8 per 100,000 inhabitants in Copenhagen City, and the total case material a prevalence of 3.6 per 100,000 in the whole country. Owing to selection the true prevalence must be considerably higher. There were 50% more women than men. The pathophysiological characteristics of Crohn's disease are largely due to its liability to involve the ileum. Enterogenous vitamin Bsub 1sub 2 malabsorption occurred in 67% of 118 patients studied. It was also present in 11% of 70 patients with ulcerative colitis. Extensive intestinal resection is another, less frequent consequence of Crohn's disease. Studies in 24 patients subjected to extenseive but intestinal resection (75-270 cm) showed Bsub 1sub 2 malabsorption to occur only after ileal resection, whereas decreased serum folic acid developed mainly following jejunal resection. The serum protein pattern shows a characteristic bun nonspecific change. Albumin and often transferrin are decreased, orosomucoid increased. Immunoglobulin levels are within normal range, but higher in patients who respond favourably to medical treatment than in patients who do not. Intestinal plasma protein loss is almost consistently present. Treatment of Crohn's disease should be a combined and harmonized surgical medical undertaking. Resection is now preferred to 'by pass' interventions. Medical treatment comprises specific and individualized treatment. Specific treatment aiming at suppression of the inflammatory process is possible with salicylazosulfapyridine which is effective in mild and moderate cases, glucocorticoids which may have a dramatic effect in severe cases without obstruction, and, possibly, immunosuppressive agents, the value of which is still disputable. Individualized medical treatment covers a wide range of therapeutic measures: vitamin substitution (especially vitamin Bsub 1sub 2), electrolytes, bile acid binding resin to counteract cholegenic diarrhoea, dietary fat restriction (40 g fat per day) in the short bowel syndrome, symptomatic therapy with analgetic, spasm relieving and constipating drugs. Complete parenteral nutrition or treatment with 'elementary diet' may be beneficial in selected, severe cases, in particular when intestinal fistulas are present.

Tasev T.; Nedkova Bratanova N.; Nikolov N.; et al.
Kat. Gastroenterol. Dietet., ISUL, Sofia Bulgaria
Vatr.Bolesti (Sofia) (Bulgaria), 1973, 12/2 (24-31)

The results are reported from simultaneous clinical, morphological and enzymological examinations of 105 patients with different gastrointestinal diseases. The quantitative determination of lactase, maltase and invertase in homogenate of jejunal mucous membrane was carried out by the Dahlquist method. A decrease of lactase was found in 65.45% of the patients with non specific chronic enteritis, of maltase on 56% and invertase in 43.9%. In patients with gastric resection the figures for these 3 examinations were 45.4%, 25% and 33.3%; and in patients with ulcerative colitis in 55.5%, 57.14% and 25% resp. Comparison of the data after disaccharide loading and the quantitative enzyme determination showed a certain parallelism in 2/3 of the cases. No correlation was established between the morphological investigations and enzyme values. The excluding of non tolerated disaccharides from the diet for a relatively longer time led to clinical improvement and restoration of jejunal mucous membrane with the exception of lactase, the disaccharide content was elevated.

Breuer R.I.; Soergel K.H.; Lashner B.A.; Christ M.L.; Hanauer S.B.; Vanagunas A.; Harig J.M.; Keshavarzian A.; Robinson M.; Sellin J.H.; Weinberg D.; Vidican D.E.; Flemal K.L.; Rademaker A.W.
Dr. R.I. Breuer, Evanston Hospital, Special GH Laboratory, 2650 Ridge Avenue, Evanston, IL 60201 USA
Gut (United Kingdom), 1997, 40/4 (485-491)

Background - Short chain fatty acid (SCFA) deficiency is associated with colitis in animals and humans, and the mucosal metabolism of these compounds is decreased in ulcerative colitis. Aims - To assess the efficacy of topical SCFA treatment in ulcerative colitis.

Patients and Methods - 103 patients with distal ulcerative colitis were entered into a six week, double-blind, placebo controlled trial of rectal SCFA twice daily; patients who were unchanged on placebo were offered SCFA in an open-label extension trial.

Results - Of the 91 patients completing the trial, more patients in the SCFA treated than in the placebo treated group improved (33% v 20%, p = 0.14, NS). Those on SCFA also had larger, but statistically non-significant, reductions in every component of their clinical and histological activity scores. In patients with a relatively short current episode of colitis (<6 months, n = 42), more responded to SCFA than to placebo (48% v 18%, p = 0.03). These patients also had larger, but statistically non-significant, decreases in their clinical activity index (p = 0.08 v placebo). Every patient who improved used at least five of six of the prescribed rectal SCFA irrigations, whereas only 37% who did not improve were as compliant. In the open-label extension trial, 65% improved on SCFA; these patients also had significant reductions (p < 0.02) in their clinical and histological activity scores.

Conclusions - Although SCFA enemas were not of therapeutic value in this controlled trial, the results suggest efficacy in subsets of patients with distal ulcerative colitis including those with short active episodes. Prolonged contact with rectal mucosa seems to be necessary for therapeutic benefit.

Williams C.N.
CRC, Dalhousie University, 5849 University Avenue, Halifax, NS B3H 4H7 Canada
Can. J. Gastroenterol. (Canada), 1993, 7/2 (196-199)

There are many issues and controversies concerning nutrition in inflammatory bowel disease (IBD). Most authorities now accept that total parenteral nutrition (TPN) is useful, both as primary and adjunct therapy in the management of patients with Crohn's disease, but only useful as adjunct therapy in patients with acute flare-ups of ulcerative colitis. In both, there is a role for TPN in preparing patients for imminent surgery. In comparison with TPN, defined formula (elemental diet) therapy has less complications, is easier to monitor, is less costly, and gives equivalent results. Several controlled trials have shown that elemental diet therapy is as useful as prednisone in inducing remission in patients with active Crohn's disease. Elemental diets have been compared with polymeric diets in patients with Crohn's disease, and have been shown to be effective; recently a semi-elemental diet has also been shown to be as effective as elemental diet, but with a conferred benefit of maintaining essential fatty acid levels. Elemental diets do not appear to be effective in closing fistulas. If the problems of palatability and, in some patients, nausea, vomiting, abdominal cramps and diarrhea persist, these can be overcome to some extent by flavour changes, chilling, gradual introduction and counselling or nasogastric tube feeding. Recently, fish oils have been used in patients with IBD. There is suggestive evidence that they are of benefit in patients with ulcerative colitis but not in Crohn's disease. There is a suggestion that fish oils have a steroid-sparing effect which, if confirmed, will be of great potential benefit to patients with ulcerative colitis.

Greenfield S.M.; Green A.T.; Teare J.P.; Jenkins A.P.; Punchard N.A.; Ainley C.C.; Thompson R.P.H.
Gastrointestinal Laboratory, The Rayne Institute, St Thomas' Hospital, London SE1 7EH United Kingdom
Aliment. Pharmacol. Ther. (United Kingdom), 1993, 7/2 (159-166)

In a placebo-controlled study, 43 patients with stable ulcerative colitis were randomized to receive either MaxEPA (n = 16), super evening primrose oil (n = 19), or olive oil as placebo (n = 8) for 6 months, in addition to their usual treatment. Treatment with MaxEPA increased red-cell membrane concentrations of eicospentaenoic acid (EPA) at 3 months by three-fold and at 6 months by four-fold (both P < 0.01), and doubled docosahexaenoic acid (DHA) levels at 6 months (P < 0.05). Treatment with super evening primrose oil increased red-cell membrane concentrations of dihomogamma-linolenic acid (DGLA) by 40% at 6 months (P < 0.05), whilst treatment with placebo reduced levels of DGLA and DHA at 6 months (both P < 0.05). Clinical outcome was assessed by patient diary cards, sigmoidoscopy and histology of rectal biopsy specimens. Super evening primrose oil significantly improved stool consistency compared to MaxEPA and placebo at 6 months, and this difference was maintained 3 months after treatment was discontinued (P < 0.05). There was however, no difference in stool frequency, rectal bleeding, disease relapse, sigmoidoscopic appearance or rectal histology in the three treatment groups. Despite manipulation of cell-membrane fatty acids, fish oils do not exert a therapeutic effect in ulcerative colitis, while evening primrose oil may be of some benefit.

Hawthorne A.B.; Daneshmend T.K.; Hawkey C.J.a; Belluzzi A.; Everitt S.J.; Holmes G.K.T.; Malkinson C.; Shaheen M.Z.; Willars J.E.
Department of Therapeutics, University Hospital, Nottingham NG7 2UH United Kingdom
Gut (United Kingdom), 1992, 33/7 (922-928)

The effect of fish oil on the course of ulcerative colitis was investigated in a randomised blinded controlled study. Eighty seven patients received supplements of 20 ml HiEPA fish oil as triglyceride (4.5 g of eicosapentaenoic acid) or olive oil placebo daily for one year. The oils were given in addition to standard drug therapy and trial entry was stratified for disease activity. Fish oil significantly increased the eicosapentanoic acid content of rectal mucosa to 3.2% of total fatty acids at six months, compared with 0.63% for patients on olive oil. This was associated with increased synthesis of leukotriene B5, and 53% suppression of leukotriene B4 synthesis by ionophore-stimulated neutrophils. Leukotriene B4 suppression persisted for at least two months after treatment was stopped. Treatment with fish oil resulted in measurable, but only limited clinical benefit. For patients entering the trial in relapse (n = 53), there was a significant reduction in corticosteroid requirement after one and two months treatment. There was a trend towards achieving remission (off corticosteroids) faster in the patients on fish oil, although differences were not significant. For patients in remission at trial entry or during the trial (n = 69), there was no significant difference in the rate of relapse by log rank analysis. We conclude that fish oil supplementation produces a modest corticosteroid sparing effect in active disease, but there is no benefit in maintenance therapy.

Hillier K.; Jewell R.; Dorrell L.; Smith C.L.
Clinical Pharmacology Group, Faculty of Medicine, University of Southampton, Southampton SO9 3TU United Kingdom
Gut (United Kingdom), 1991, 32/10 (1151-1155)

The incorporation of the fatty acids in fish and olive oil into the colonic mucosa of patients with inflammatory bowel disease was examined during 12 weeks' dietary supplementation with the oils, and the influence on colonic mucosal prostaglandin and thromboxane generation was measured. With a dietary supplement of 18 g fish oil daily, concentrations of the major polyunsaturated fatty acids in fish oil, eicosapentaenoic acid and docosahexaenoic acid, were significantly raised in mucosal lipids. The first time these were measured, after three weeks' supplementation, the mean increases in eicosapentaenoic and docosahexaenoic acid were seven fold and 1.5 fold respectively, and these increases were maintained during the 12 week study. Arachidonic acid values fell throughout the study and this reduction was significant at 12 weeks. Mucosal prostaglandin E2 (PGE2), thromboxane B2, and 6-keto prostaglandin F(1alpha) synthesis were suppressed, and this reached significance (p < 0.05) at three and 12 weeks for PGE2 and at 12 weeks for thromboxane B2. The predominant fatty acid in olive oil is oleic acid. Supplementation with 18 g/day resulted in a significant increase in oleic acid in colonic mucosa at 12 weeks (p < 0.05) and a fall in stearic acid and docosahexaenoic acid; there was no significant change in eicosanoid synthesis. It is concluded that colonic lipids and prostaglandin and thromboxane synthesis can be readily altered by dietary supplementation with fish oil. The extent of incorporation of the fatty acids present in oils is dependent upon the individual fatty acid.

Krizek V.; Sadilek L.
Vyzkumny Ustav Balneologicky, Marianske Lazne Czech Republic
Fysiatr. Revmatol. Vestn. (Czech Republic), 1993, 71/4 (195-212)

1. Carlsbad mineral water is a hydrogencarbonate-sulphur containing thermal water with a mineralization of cca 6.4 g.l-1. It is drunk at the springs in the spa and is bottled under the name 'Mlynsky pramen' (Mill spring).

2. 28-day controlled clinical trial comprising two weeks of drinking Carlsbad water was to provide new information on the suitability of this water in nephrourological indication.

3. The trial comprised 16 experimental subjects, mostly suffering from urolithiasis, four suffered from gout. During the first and fourth week the subjects drank 1.5 litres of ordinary drinking water, during the second and third week the same amount of Carlsbad water. The standard diet which was the same every week made it possible to compare the excretion of minerals and other substances during individual periods in the course of the investigation.

4. Drinking of Carlsbad water induced desirable diuresis. The demand of a diuresis of more than 2 l.d-1 was met only by 52 to 55% of the daily amounts.

5. Drinking of Carlsbad water led to slight alkalization of the urine from pH 5.8 to 6.8 with a corresponding decline of titratable acid and ammonia in urine. Acid-base indicators in blood were not affected.

6. Calciuria rose by 4 to 7%, magnesiuria, on the other hand, declined slightly. The Ca/Mg quotient in urine rose insignificantly. The blood levels of calcium and magnesium declined slightly. It was not possible to confirm analogous effects to those described formerly by Stransky.

7. A 20% rise of natriuria was recorded and elevated inorganic sulphaturia by 45 to 57%. The urinary potassium excretion increased slightly. The chloride excretion, on the other hand, declined by 8.5%. Serum electrolytes did not display major changes.

8. The tolerance of the Carlsbad water drinking cure - 3 times 0.5 l - was good. The water had a minor purgative effect. The daily frequency of bowel movements increased by 36 to 60% and there was a higher proportion of loose but not diarrhoeal stools.

9. Uricaemia declined by 17% and uricuria by 13 to 16%. The uric acid clearance declined by 7 to 11%. In the four patients suffering from gout analogous effects were recorded as in subjects without gout. No uricosuric effect was found.

10. During the drinking cure in the investigated non-diabetic subjects the morning blood sugar and insulin level were not affected.

11. The Carlsbad water drinking cure is indicated in particular in urate and cystine urolithiasis. It will be useful to use the drinking cure more frequently to ensure primary and secondary prevention of oxalate lithiasis in gastroenterological patients with malabsorption syndromes, in conditions following intestinal bypasses, jejunostomies, similarly as in the prevention of urate lithiasis in ulcerative colitis, in particular after operations such as ileostomies, colectomies etc.

12. The Carlsbad water drinking cure, in particular larger amounts, must be indicated carefully in conditions where the ingestion of sodium or alkalization of urine are not desirable.

Ferraris L.; Karmeli F.; Eliakim R.; Klein J.; Fiocchi C.; Rachmilewitz D.
Department of Medicine, Hadassah University Hospital, Mount Scopus, PO Box 24035, Jerusalem 91240 Israel
Gut (United Kingdom), 1993, 34/5 (665-668)

Generation of platelet activating factor by intestinal mucosal epithelial cells and lamina propria mononuclear cells was evaluated to elucidate the possible role of this mediator in the pathogenesis of inflammatory bowel disease. Epithelial and lamina propria mononuclear cells were isolated from surgical specimens from control, Crohn's disease, and ulcerative colitis patients. Platelet activating factor was extracted from highly purified cell preparations with 80% ethanol after stimulation with and without 0.2 uM calcium ionophore A23187 and was measured by platelet aggregation assay. Both cell types generated platelet activating factor activity and this was generally comparable for epithelial and lamina propria cells. Basal and stimulated platelet activating factor activity of epithelial and lamina propria cells from ulcerative colitis but not Crohn's disease patients was appreciably higher than that of control. Stimulation with calcium ionophore increased appreciably platelet activating factor activity in lamina propria cells from all groups. In contrast, only epithelial cells from ulcerative colitis showed an appreciable increase after calcium ionophore induction. These results suggest that epithelial cells are important contributors to intestinal platelet activating factor generation under normal and inflammatory conditions and that epithelial cells actively play a part in the pathogenesis of ulcerative colitis.

Kirsner J.B.
Department of Medicine, University of Chicago, Chicago, IL USA
Dis. Mon. (USA), 1991, 37/11 (673-675)

Once regarded as medical curiosities, ulcerative colitis and Crohn's disease have achieved a remarkable change in status recently and today are among the more compelling of all human illnesses. The cause(s) of inflammatory bowel disease (IBD) are not known. Genetic, environmental, microbial, and immunologic factors are involved, but the precise mechanisms are obscure. The incidence of ulcerative colitis is relatively stable, while Crohn's disease continues to increase in frequency. In 10% to 15% of patients, it is hard to differentiate between ulcerative colitis and Crohn's colitis, however, problems with diagnosis usually resolve with time and repeated examinations. In part I of his two-part monograph on IBD, Dr. Kirsner addressed the nature and pathogenesis of the disease. Increased study of ulcerative colitis and Crohn's disease in recent years has generated new knowledge regarding their etiology. Part I focused on microbial, immunologic, and genetic mechanisms of, and the inflammatory process involved in the disease. In this part, Dr. Kirsner deals with the clinical features, course, and management of IBD, based on the author's 55 years of experience with these problems and supplemented by critical examination of the recent (1988-1990) literature. Particular attention is directed to the symptoms and physical findings of ulcerative colitis and Crohn's disease. The laboratory, radiologic, endoscopic, and pathologic features, and the many systemic complications. IBDs are mimicked by several enterocolonic infections and other conditions making differential diagnosis necessary. Inflammatory bowel disease in children and the elderly conforms to conventional clinical patterns modified by the health circumstances of the respective age groups. Because the cause of IBD has not been established, current medical therapy is facilitative and supportive rather than curative. The principles of medical treatment are approximately the same for ulcerative colitis and Crohn's disease. Treatment emphasizes a program rather than a drug and also considers the individuality of the therapeutic response. A clearer understanding of dietary and nutritional needs, including hyperalimentation and electrolyte and fluid balance, aids treatment. Antidiarrheal and antispasmodal preparation and sedatives are prescribed for symptom relief. The bowel inflammation is controlled with sulfasalazine or the newer 5-amino-salicylic acid (5-ASA) compounds, antibacterial drugs for complications of Crohn's disease and IBD, adrenocortical steroids, and the immunosuppressive compounds 6-mercaptopurine (6MP), azathioprine, and cyclosporine, as determined in each patient. The surgical procedures available for treatment of ulcerative colitis include total protocolectomy and ileostomy or ileoanal anastomosis. In Crohn's disease of the small bowel, the usual approach is intestinal resection and reanastomosis. Strictureplasty is possible in some instances of stenotic intestinal disease. For treatment of Crohn's colitis, procedures include total proctocolectomy, total colectomy with ileal anastomosis, and occasionally, segmental resection of the large intestine. Chronic IBD requires prolonged observation, periodic adjustments in therapy, and colonic and radiologic surveillance. The prognosis of ulcerative colitis and Crohn's disease is much improved over the years, but a cure has not yet been found reemphasizing the need for further investigation of these challenging diseases.

Harries A.D.; Brown R.; Heatley R.V.; et al.
Department of Gastroenterology, University Hospital of Wales, Cardiff United Kingdom
Gut (England), 1985, 26/11 (1197-1203)

Forty patients with Crohn's disease were divided into undernourished (18) and well nourished (22) groups depending on whether their midarm circumference was below or above 90% of the ideal standard. Plasma 25-(OH)D3 and the dihydroxylated metabolites, 24,25-(OH)sub 2D3 and 1,25-(OH)sub 2D3 were measured in the summer. Results were related to clinical and biochemical parameters and also compared with results from patients with ulcerative colitis and healthy subjects who served as controls. Plasma 25-(OH)D3 was reduced in the undernourished Crohn's group compared with the well nourished Crohn's group, who did not differ from the controls. Over 50% of the undernourished Crohn's group had evidence of secondary hyperparathyroidism and raised alkaline phosphatase concentrations, although concentrations of 1,25-(OH)sub 2D3 were normal. The low 25-(OH)D3 concentrations related to disease activity. It is suggested that undernourished Crohn's patients who have high levels of disease activity are at risk of vitamin D deficiency, and attempts should be made to improve their vitamin D nutrition.

Bellaiche G.; Le Pennec M.P.; Slama J.L.; Ley G.; Choudat L.; Giacomini T.; Godefroy Y.; Paugam B.
Service de Gastroenterologie, Ctr. Hosp. General Robert Ballanger, Boulevard Robert-Ballanger, 93602 Aulnay-Sous-Bois Cedex France
Annales de Gastroenterologie et d'Hepatologie (France), 1996, 32/1 (11-17)

The goal of this study was to evaluate the contribution of sigmoidoscopy with bioptic microbiology to the etiologic diagnosis of acute diarrhea in adults. Patients and methods. Sixty-five patients with acute diarrhea were included prospectively from February 1993 to November 1994. Ages ranged from 17 to 83 years. In each patient, two stool samples were cultured and three examined for parasites. Clostridium difficile toxin was looked for in the 18 patients who had taken antimicrobials before onset of the diarrhea. Sigmoidoscopy with collection of biopsy specimens for bacteriologic cultures was performed routinely. Results. A pathogenic organism was identified in 35 patients (54%). Eighteen patients (28%) had positive stool cultures. Clostridium difficile toxin was detected in six patients. Colonic biopsy cultures were positive in 26 patients (40%). Endoscopic findings established the diagnosis of pseudomembranous colitis with negative tests for C. difficile toxin in two patients, diverticulitis in one, ischemic colitis in two, and cryptogenic colitis in seven. Conclusions. Sigmoidoscopy ensured the diagnosis in over 72% of cases of acute diarrhea. This investigation complements stool cultures and should be done routinely in adults with severe acute diarrhea.

Patterson M.; Healy G.R.; Shabot J.M.
Gastroenterol. Div., Dept. Med., Univ. Texas Med. Branch, Galveston, Tex. 77550 USA
Gastroenterology (USA), 1980, 78/1 (136-141)

The diagnosis of amoebiasis presents problems, particularly if one relies on finding the organism. Thus, serologic tests are expedient. A gel diffusion precipitin test (GDP), commercially available, simple to perform, and inexpensive, was compared with the indirect hemagglutination test (IHA). 257 Patients' sera were tested; 14 had amoebic colitis, 21 had amoebic liver abscess, 63 had suspected amoebic liver abscess, and 46 had inflammatory bowel disease. GDP tests were positive in 85% of amoebic colitis and 95% of amoebic liver abscess patients; IHA was positive in 91% of amoebic colitis and 94% of abscess patients. Within 6 mo, GDP tests became negative in 66% of patients. IHA tests were observed positive up to 20 yr. The performance characteristics of diagnostic methods for amoebiasis, fecal examination, IHA and GDP, show serologic tests have superior sensitivity and predictive value in recognizing invasive disease.

Solomon G.E.
Mount Sinai Sch. Med., City Univ. New York, N.Y. 10029 USA
Mt.Sinai J.Med. (USA), 1976, 43/5 (602-624)

The currently available clinical and laboratory data (119 references) make it still premature to conclude that IBD represents an autoimmune process. None of the 6 definitive criteria for autoimmune disease have been well established for either chronic ulcerative colitis (CUC) or Crohn's disease (CD). Nevertheless, there is a good deal of available data which supports an autoimmune etiology. Virtually all of the ancillary findings which Sell labels as presumptive evidence for autoimmune disease have been demonstrated in IBD. These include: a morphologic picture consistent with known allergic reactions; the demonstration of antibody or a positive delayed skin reaction; a depression of complement during any stage of the disease; a beneficial effect from agents known to inhibit some portions of an allergic reaction (steroids, radiation, anti-metabolites, etc.); an association with other possible autoimmune diseases; identification of a reasonable experimental model in animals that mimics the human disease: an increased familial susceptibility to the same or other autoimmune disease; and an association between the disease state and specific HLA (human histocompatibility antigen) types (Sell, S; Immunol., Immunopathol., and Immunity, New York, 1972). A framework, consistent with the available data, in which these criteria are satisfied consists of a breakdown of colonic mucosal barriers, which might represent a distinct immunizing event in which the underlying enteric lymphatic tissue becomes exposed to coliform antigens. Following immunization, a latent period might ensue during which sensitized cells or antigen or both communicate with the systemic immune system, possibly via Peyer's patches. Clones of cells programmed to respond to the coliform antigen are produced, possibly in the thymus, and migrate to the lamina propria of the enteric tract. Subsequent exposure to coliform antigen or cross-reacting colonic antigens causes release of lymphotoxin from these sensitized lymphocytes resulting in local cytolysis. Damage to mucosal cells leads to the release of mucosal cell antigens and further compromises the mucosal barrier, allowing a self perpetuating reaction in which the inflammatory process leads to the release of those antigens which initiated the inflammation. These antigens, both bacterial and colonic, have been fairly well identified. The evidence for a transmissable agent may well represent a transfer of the sensitive state by cells from an affected individual to a normal individual, and the periods of remission which punctuate IBD may represent the temporary induction of tolerance by optimal concentration of antigen. Although these proposed mechanisms are purely speculative, they are useful in that they clearly point out those areas to which future research must be directed.

Fabia R.; Ar'Rajab A.; Johansson M.-L.; Willen R.; Andersson R.; Molin G. Bengmark S.
Dept. of Surgery, Lund University, S-221 85 Lund Sweden
Scand. J. Gastroenterol. (Norway), 1993, 28/2 (155-162)

The potential beneficial effect of exogenous administration of Lactobacillus on acetic acid-induced colitis was evaluated in the rat. Colitis was induced by instillation of 4% acetic acid for 15 sec in an exteriorized colonic segment. This produced uniform colitis with a threefold increase in myeloperoxidase (MPO) activity of the colonic tissue (an index of neutrophil infiltration) and a sixfold increase in plasma exudation into the lumen of the colon (mucosal permeability) as evaluated 4 days after acetic acid administration. Intracolonic administration of L. reuteri R2LC immediately after acetic acid administration, at a dose of 5 ml of 7 x 107 colony-forming units (CFU)/ml in two forms: either as pure bacterial suspension or as fermented oatmeal soup, prevented the development of colitis. Thus, the morphologic score, MPO activity, and mucosal permeability were almost normalized by Lactobacillus treatment. Initiating the treatment 24 h after acetic acid administration or using lower doses of 1 ml for 3 consecutive days resulted in a smaller protective effect. We conclude that exogenous administration of L. reuteri R2LC prevents the development of acetic acid-induced colitis in the rat.

Besterman H.S.; Mallinson C.N.; Modigliani R.; et al.
Dep. Med., R. Postgrad. Med. Sch., London W12 0HS United Kingdom
Scand. J. Gastroenterol. (Norway), 1983, 18/7 (845-852)

We have studied fasting levels and the response to a standard test breakfast of blood glucose and several gut hormones in 24 patients with ulcerative colitis, in 14 patients with Crohn's disease, and in 14 healthy control subjects. Patients with ulcerative colitis had significantly elevated fasting human pancreatic polypeptide (HPP) concentrations, and both basal and postprandial levels of gastrin, gastric inhibitory polypeptide (GIP), and motilin were greater than normal. In contrast, patients with Crohn's disease had normal gastrin levels but had increased fasting and postprandial levels of GIP and motilin and, in addition, of enteroglucagon, compared with controls. These patients also had greater than normal HPP concentrations 30 min after the breakfast. Normal levels of insulin, pancreatic glucagon, neurotensin, and vasoactive intestinal polypeptide were found in both groups of patients. Much remains to be known about the pathophysiology of these two debilitating diseases, and the abnormal release of gut hormones may be of importance.

Rutgeerts P.; Ghoos Y.; Vantrappen G.
Dept. Med., Univ. Hosp. St Rafael, 3000 Leuven Belgium
Eur. J. Clin. Invest. (England), 1982, 12/2 (135-143

The metabolism of cholic acid and chenodeoxycholic acid was studied in seventeen patients with non-operated Crohn's disease, eleven ileitis and six ileocolitis patients. The turnover of cholic acid was significantly increased in patients with ileitis (k = 2.0 + or - 1.13 dayssup -sup 1; P < 0.001) and ileocolitis (k = 0.91 + or - 0.47 dayssup -sup 1; P < 0.005) as compared to normals (k = 0.35 + or - 0.19 dayssup -sup 1). Although chenodeoxycholic acid was better preserved in the enterohepatic circulation than cholic acid its turnover was also significantly faster in ileitis (k = 0.81 + or - 0.56 dayssup -sup 1; P < 0.005) and ileocolitis patients (k = 0.62 + or - 0.18 dayssup -sup 1; P < 0.01) than in normals (k = 0.20 + or - 0.09 dayssup -sup 1). The fractional turnover of cholic acid was related to the length of ileal involvement (r = 0.761; P < 0.001; n = 17). Patients with Crohn's ileitis tended to preserve normal fasting total bile acid pools by increased synthesis of primary bile acids and efficient absorption of deoxycholic acid and ursodeoxycholic acid by the normal colon. Patients with active ileocolitis had decreased total fasting pool sizes (2.62 + or - 1.83 mmol; P < 0.001) as compared to normals (7.69 + or - 1.61 mmol). In these patients there was no increase in bile acid synthesis as compared to normals and secondary bile acids were absent frome bile. It is concluded that the colon has an important role in maintaining the fasting pool size to a normal level in the presence of an interrupted enterohepatic circulation of bile acids due to ileal disease.

Vantrappen G.; Ghoos Y.; Rutgeerts P.; Janssens J.
Lab. Gastrointest. Pathophysiol., Dept. Med. Res., Univ. Leuven Belgium
Gut (England), 1977, 18/9 (730-735)

The pool size and composition of bile acids were studied in 13 unoperated patients with uncomplicated Crohn's disease, 10 patients with ulcerative colitis, and 10 normal subjects. Many patients with Crohn's disease had in their bile a significantly increased amount of ursodeoxycholic acid. The bile acid pool size was significantly decreased and the ratio of glycine to taurine conjugates was significantly increased in the Crohn's disease patients. The reduction in bile acid pool size was related to the activity of the disease. The disorders of bile acid metabolism suggest that the intestinal involvement in Crohn's disease is much more extensive than can be demonstrated by careful radiological examinations.

Lenz K.
Med. Dept. P, Div. Gastroenterol., Rigshosp., Copenhagen Denmark
Scand.J.Gastroent. (Norway), 1976, 11/8 (769-775)

Bile acid and vitamin Bsub 1sub 2 malabsorption were evaluated in 34 cases of ulcerative colitis. Twenty four patients were non operated and 10 patients were colectomized. The postprandial duodenal bile acid concentration was abnormally low in 13 of 24 non operated cases and found to be correlated to the activity of the disease. Two of six patients subjected to colectomy had a reduced bile acid concentraion. Bile acid absorption was assessed by the cholyl glycine 1 sup 1sup 4C breath test combined with faecal analysis. The sup 1sup 4C excretion in breath was abnormally elevated in only one of the patients in the total material. The faecal sup 1sup 4C output was related to the disease activity in the non operated group. Patients colectomized for ulcerative colitis had an extremely high excretion of isotope in the ileal effluent, from 15 to 81 per cent of the dose given. The faecal sup 1sup 4C output was correlated with the duration of the ileostomy and the mass of ileal discharge. Vitamin Bsub 1sub 2 malabsorption was only present in five patients. It is concluded that patients with ulcerative colitis during the active phase of the disease have bile acid malabsorption, and patients colectomized for ulcerative colitis have an abnormal high bile acid deconjugation in the ileal effluent.

Grimes D.S.
Dept. Med., Withington Hosp., Manchester United Kingdom
Lancet (England), 1976, 1/7956 (395-397)

A diet high in refined carbohydrate is implicated in the aetiology ofsome diseases of the colon i.e., diverticular disease, irritable bowel syndrome, ulcerative colitis, non occlusive ischaemic colitis, and pseudomembranous colitis. It is suggested that spasm of the smooth muscle is the common pathogenetic mechanism in these colonic diseases. The strength of the spasm producing increased pressure in the colonic lumen or wall and the length of time for which the colon has been affected are believed to determine the type of disease resulting. A diet high in refined carbohydrate allows the intense muscle spasm to occur because the physical buffering effect of faecal bulk is considerably reduced.

Ellestad Sayed J.J.; Nelson R.A.; Adson M.A.; et al.
Dept. Ped., Univ. Manitoba, Winnipeg USA
Amer.J.Clin.Nutr. (USA), 1976, 29/12 (1333-1338)

To investigate further an apparent relationship between chroniculcerative and granulomatous colitis and pantothenic acid deficiency,colonic tissues obtained at the time of colectomy in 29 patients with these disorders were assayed for pantothenic acid and for coenzyme A (CoA) activity. For comparison, normal colonic tissues free of pathological lesions were obtained from 31 patients having colectomy for carcinoma or diverticulitis. Plasma, red blood cells, and colonic mucosa were assayed microbiologically for free and total pantothenic acid. The activity of CoA in colonic mucosa was determined by assaying the acetylation of sulfanilamide. Concentrations of free, bound and total pantothenic acid in blood and in colonic mucosa did not differ between the two groups of patients. Bound pantothenic acid increased linearly with total pantothenic acid. Colonic mucosa concentrated free pantothenic acid to about 50 times the level of blood, and pantothenic acid in red cells was similar to the concentration in plasma. Compared to normal gut mucosa, CoA activity was markedly low in mucosa from patients with chronic ulcerative or granulomatous disease despite the presence of normal amounts of free and bound pantothenic acid. A block in the conversion of bound pantothenic acid to CoA in diseased mucosa is suggested.

Murch S.H.; MacDonald T.T.; Walker-Smith J.A.; Levin M.; Lionetti P.; Klein N.J.
Dept. Paediatric Gastroenterology, St Bartholomew's Hospital, London EC1A 8BE United Kingdom
Lancet (United Kingdom), 1993, 341/8847 (711-714)

We have studied the distribution and nature of sulphated glycosaminoglycans (GAGs) within normal and inflamed intestine. There is increasing evidence that these negatively charged polysaccharides, which both regulate the ability of albumin to leave the vasculature and inhibit thrombosis, may be affected by inflammatory cells and their products. We obtained samples of freshly resected intestinal tissue from eight controls, eleven patients with Crohn's disease, and six with ulcerative colitis. Sulphated GAGs were detected by means of a gold-conjugated poly-L-lysine probe, and the tissue density of anionic sites was assessed semiquantitatively by means of a Lennox graticule. In normal intestine there was staining in the vascular endothelium and the subepithelial basal lamina and throughout the extracellular matrix of the lamina propria and submucosa. Tissue from the patients with inflammatory bowel disease showed inflammation macroscopically and on histology. There were profound abnormalities of extracellular matrix GAGs, limited to the mucosa in ulcerative colitis and greatest in the submucosa in Crohn's disease. There was also substantial loss of GAGs from the subepithelial basal lamina in both disorders and from the vascular endothelium in submucosa in Crohn's disease. The extent of local GAG disruption was associated with the distribution of macrophages immunoreactive for tumour necrosis factor alpha and the activation marker RM 3/1. We suggest that inflammatory disruption of vascular and connective tissue GAGs may be an important pathogenetic mechanism, contributing to the leakage of protein and fluid, thrombosis, and tissue remodelling seen in inflammatory bowel disease.

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Stone O.J.
18700 Main Street, Huntington Beach, CA 92646 USA
Med. Hypotheses (United Kingdom), 1990, 31/2 (99-103)

Shortly after the introduction of sulfa drugs, sulfapyridine was found tohave unique therapeutic properties, unrelated to antibacterial activity. Later, sulfones were found to share the same properties. The disorders initially improved were dermatitis herpetiformis, pyoderma gangrenosum, subcorneal pustular dermatosis, acrodermatitis continua, impetigo herpetiformis and ulcerative colitis. They were also sometimes helpful in many other disorders. They are effective in select disorders characterized by edema followed by granulocytic inflammation or edema followed by vesicle or bullae formation. The sulfones work in low doses in leprosy and their mode of action is not fully understood. Several pieces of experimental information are available. It is proposed that these drugs are entering or influencing the protein moiety of glycosaminoglycans and decreasing tissue viscosity. This decreased tissue viscosity prevents edema and dilution of tissue fluid and decreases acute inflammation and vesicle and bullae formation.

Symonds D.A.
Dept. Pathol., US Publ. Hlth Serv. Hosp., Baltimore, Md. USA
Arch. Pathol. Lab. Med. (USA), 1978, 102/3 (146-149)

The glycosaminoglycans from normal colonic mucosa and colons with avariety of inflammatory diseases, as well as benign and malignant neoplasms were analyzed. Normal colonic mucosa contains predominantly chondroitin sulfates and dermatan sulfate. Increases in the levels of hyaluronic acid and heparan sulfate, as well as substantial increases in the amount of total glycosaminoglycans were characteristic of invasive colonic adenocarcinoma. Lesser elevations in the amount of total glycosaminoglycans and hyaluronic acid and heparan sulfate were present in neonatal colonic mucosa, villous adenoma, ulcerative colitis, and mucosa adjacent to carcinoma. The degree of elevation was proportional to the dysplastic potential. Since dysplastic lesions have scant connective tissue, the epithelial component of colonic neoplasms may contribute to these neoplasm-related alterations in glycosaminoglycan composition.

Siegel J.
7410 Long Point Rd, Houston, Tex., 77055 USA
Ann. Allergy (USA), 1981, 47/2 (92-94)

That inflammatory bowel disease (IBD) is just another possible facet of allergy is shown by the alleviation of IBD following allergy testing and treatment. This is further borne out by the findings in a survey (questionnaire) of local members of the National Foundation of Ileitis and Colitis (NFIC) in which 70% of individuals with IBD listed other symptoms which were judged to be 'Possibly Allergic.'

Aitola P.T.; Soppi E.T.; Halonen P.J.; Laine S.T.; Matikainen M.J.
Dept. of Surgery, Tampere University Hospital, P.O. Box 2000, FIN-33521 Tampere Finland
Scand. J. Gastroenterol. (Norway), 1994, 29/7 (646-650)

Background: The levels of antibodies against cow's milk proteins inulcerative colitis (UC) were used to study whether mucosal inflammation leads to immune recognition, as a marker of enhanced permeability, of dietary proteins. A further purpose was to study the effect of proctocolectomy on the serum antibody levels against cow's milk proteins and their relation to biochemical and histologic liver abnormalities associated with ulcerative colitis.

Methods: Serum antibody levels against six cow's milk proteins, alpha-casein, alpha-lactalbumin (LA), beta-lactoglobulin A (LGA), beta-lactoglobulin B (LGB), bovine serum albumin (BSA), and whole milk powder (MP) were determined before and after (mean, 24 months) proctocolectomy in 125 patients with ulcerative colitis. Simultaneously, serum liver enzymes were analyzed. A liver biopsy specimen was also obtained at proctocolectomy.

Results: Before proctocolectomy IgA antibody levels were significantly increased against all antigens except BSA. Increased levels of IgM antibodies against LGA, LGB, and BSA were also detected. IgG antibodies were significantly increased only against LGA. After proctocolectomy IgA and IgM antibody levels decreased significantly (p < 0.05) against LGA, LGB, and LA, whereas IgG antibodies increased significantly (p < 0.01). In the patient group with abnormal liver histology (n = 9) the IgA antibodies to all cow's milk proteins were significantly higher (p < 0.02) than in the group with normal liver histology both before and after proctocolectomy. The IgA antibody levels showed a significant positive correlation with alanine amino-transferase and gamma-glutamyltransferase (r value from 0.460 to 0.721, p value from < 0.05 to < 0.01), but not with alkaline phosphatase.

Conclusions: These results suggest that the inflamed mucosa in UC allows the antigenic contents of the bowel to escape. Proctocolectomy alters the antibody levels against certain milk proteins, which may serve as a model to suggest that proctocolectomy, probably by eliminating inflammation, may have positive effects by reducing the foreign pathogenic antigen and immune complex load.

Paganelli R.; Pallone F.; Montano S.; et al.
Cattedra di Immunologia Clinica, Clinica Medica III, Policlinico Umberto I, I-00161 Roma Italy
Int. Arch. Allergy Appl. Immunol. (Switzerland), 1985, 78/1 (81-85)

We studied the class-specific antibody response to the cow's milk antigenbeta-lactoglobulin (beta-LG) in sera from patients with ulcerative colitis and Crohn's disease. IgG and IgM to beta-LG were significantly higher in patients when compared to healthy non-atopic controls, whereas IgA values were similar, and specific IgE absent in all groups. No correlation between IgG- and IgM-containing immune complexes was found with the corresponding isotype of antibody to beta-LG; however, IgM complexes correlated with serum total IgM in ulcerative colitis. In these patients, IgG antibodies were higher in active cases, whereas IgM increased in patients without signs of disease activity. Antibody titers did not correlate with disease duration or administration of antiinflammatory drugs. This pattern of anti-beta-LG reactivity suggests that the presence of intestinal lesions may be revealed by the selective increase of some antibody isotopes to orally administered antigens. Enhanced mucosal permeability may be studied by this type of serological analysis.

Prudden J.F.; Balassa L.L.
Dept. Surg., Coll. Phys. Surg., Columbia Univ., New York, N.Y. USA
Semin.Arthritis Rheum. (USA), 1974, 3/4 (287-321)

Catrix is a material with proven clinical safety and efficacy in thetreatment of important chronic inflammatory conditions. Among these entities the authors have had the most experience with osteoarthritis, psoriasis, anal and perianal conditions, and inflammatory bowel disease. The results in the rheumatic diseases, while still preliminary, are encouraging and deserve intensive further investigation. An expansion of these studies should provide important new information about the nature and treatment of many diseases for which there is no present nontoxic therapy of value.

Mielants H.; Veys E.M.
Department of Rheumatology, University of Ghent, B-9000 Ghent Belgium
J. Rheumatol. (Canada), 1985, 12/2 (287-293)

In an open study, sulfasalazine was given to 15 HLA-B27 positive patientswith asymmetrical pauciarticular arthritis and enthesopathies resistant tononsteroidal antiinflammatory drugs (NSAID). In 11 patients, long lasting remission of inflammatory and biological variables was obtained after 3 to 12 months of treatment. In the other 4 patients significant improvement of the clinical and biological variables was observed. In the 7 patients on whom ileocolonoscopy was performed, inflammatory signs were seen in the terminal ileum or ileococcal valve, suggestive of inflammatory bowel disease (IBD). It is generally accepted that sulfasalazine improves the intestinal symptoms of IBD; our study suggests that it is also beneficial in HLA-B27 related arthropathies resistant to NSAID. No significant adverse reactions were encountered. These findings are encouraging but have to be confirmed in a double blind controlled study.

Mielants H.; Veys E.M.; Cuvelier C.; et al.
Department of Rheumatology, University of Ghent, B-9000 Ghent Belgium
J. Rheumatol. (Canada), 1985, 12/2 (294-298)

Ileocolonoscopy and microscopic examination of ileum biopsies wereperformed on 35 patients with reactive arthritis, with asymmetricalpauciarticular arthritis and enthesopathies. Ileocolonoscopy was alsoperformed on 26 patients with ankylosing spondylitis (AS) and on 19 control patients with rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematosus and psoriatic arthritis. In the reactive group, ileocolonoscopy showed macroscopic inflammation in 16 cases and abnormal microscopic examination in all but 2 cases, even in patients without gastrointestinal disorders. In the 2 patients with sexually acquired disease, the gut was normal. In the AS group, inflammation was observed in the B27 negative and positive patients with peripheral joint involvement. Occasionally, ileal signs were seen in the HLA-B27 positive patients without peripheral joint involvement. None of the controls showed signs of gut inflammation. Ileocolonoscopy may be of value in detecting subclinical forms of bowel inflammation.

Ramakrishna B.S.; Varghese R.; Jayakumar S.; Mathan M.; Balasubramanian K.A.
Dr. B.S. Ramakrishna, Dept. of Gastrointestinal Sciences, Christian Medical College Hospital, Vellore 632004 India
Journal of Gastroenterology and Hepatology (Australia), 1997, 12/7 (490-494)

Oxygen free radicals produced by neutrophils are important in thepathogenesis of mucosal damage in ulcerative colitis. Vitamin A, vitamin E and cysteine in the plasma can scavenge free radicals. In the present study, plasma levels of vitamin A, vitamin E, cysteine, cystine and protein-bound cysteine were measured in active ulcerative colitis before and immediately after treatment of the active disease, and correlated with disease severity, extent and activity. Plasma vitamin A and cysteine were significantly reduced in active ulcerative colitis compared with controls. Levels of vitamin E, cystine and protein-bound cysteine were not significantly altered in active ulcerative colitis. Vitamin A and cysteine concentrations returned to normal levels (P< 0.05) within 2 weeks of treating active colitis. There were significant negative correlations between clinical severity and the plasma concentrations of vitamin A and cysteine. Plasma cysteine levels also correlated inversely to disease extent. Depletion of the circulating antioxidants, vitamin A and cysteine, in active ulcerative colitis is likely to be important in the pathophysiology of the disease.

Wasser T.E.; Reed J.F.; Moser K.; Robson P.; Faust L.; Fink L.L.; Wunderler D.
Research Department, The Lehigh Valley Hospital, Cedar Crest and I-78, Allentown, PA 18105-1556 USA
Canadian Journal of Gastroenterology (Canada), 1995, 9/3 (131-136)

Using the Harvard/Willett Semi-Quantitative Food Frequency Questionnaire (H/WSQFFQ), nutritional information was gathered on patients enrolled in an inflammatory bowel disease (IBD) registry. The registry lists 320 patients positive for either ulcerative colitis (n = 124) or Crohn's disease (n = 196). The sample was limited to those 19 to 84 years old (meanplus or minusSD 48.57plus or minus14.98), and comprised 136 males and 184 females. Using a battery of indices, quality of life, disease activity and general well-being were also assessed. Nutritional intake values from the Harvard-Willett data were compared with recommended dietary allowances (RDA) tables by sex age group (19 to 24 years, 25 to 50, 51 and older) to discover any intake deficiencies. Results showed that IBD patients were below RDA guidelines for vitamin E, calcium, magnesium, zinc iodine and selenium. Females were below RDA guildelines for iron while men were below for vitamin B6. There were also some deficiencies according to age in males and two nutrient deficiencies were seen by age group in women. There were no deficiencies by sex or age for vitamins A, C, D and niacin. There were no observed nutrient intake differences between ulcerative colitis and Crohn's disease groups. Patients receiving vitamin or mineral supplementation showed significant decreases in quality of life, regardless of diagnosis (Crohn's disease or ulcerative colitis) group. The H/WSQFFQ is a useful tool for assessment of the nutritional status of the IBD patient because it not only provides valuable measurement data to the clinician, but also adds to patient awareness about nutritional problems associated with IBD.

Cetiner S.; Gorgulu S.; Kaymakcioglu N.; Sen D.
Genel Cerrahi Anabilim Dali, GATA, 06018 Etlik, Ankara Turkey
Bulletin of Gulhane Military Medical Academy (Turkey), 1994, 36/4 (452-457)

One of mediators which have been implicated as the cause of tissue injury in ulcerative colitis is the free oxygen radicals. In this study, it is investigated to induce experimental ulcerative colitis in this group. Vitamin E was administered IP at the same time with, before, before and after Mitomycin C in groups 3, 4 and 5 respectively. In group 2 than group 1, it was observed significantly meaningful histopathological alterations in colonic mucosa and meaningful decrease superoxide dismutase (SOD) levels in plasma (p < 0.01). While meaningful histopathological alterations in colonic mucosa were observed in groups 3 and 5 than group 1 (p < 0.05), but it is not as severe as group 2 and there was not meaningful difference SOD levels in plasma (p < 0.05). In group 4, histopathological alterations in colonic mucosa which were not as severe as group 2, but more severe than groups 3 and 5 and meaningful decrease SOD levels in plasma were observed (p > 0.05). As a result, free oxygen radicals are effective in the pathogenesis of experimental ulcerative colitis. Vitamin E, an antioxidant agent, appears to be a good choice in the treatment of the experimental ulcerative colitis.

Lauritsen K.; Laursen L.S.; Bukhave K.; Rask-Madsen J.
Department of Medical Gastroenterology, Odense University Hospital, Odense, DK-5000 Odense C Denmark
Pharmacol. Toxicol. (Denmark), 1987, 61/4 (246-249)

To determine whether supplementation with the physiological radical scavenger, vitamin E, would modulate arachidonate metabolism in human inflammation, we performed equilibrium dialysis of rectum in eight patients with active ulcerative colitis confined to the rectum. The patients, all off drug treatment, were supplemented with 1920 IU/day of alpha-tocopherol and had rectal dialysis done at entry and after three and 14 days. Luminal concentrations of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), determined by radioimmunoassay in purified dialysates, were significantly raised compared to healthy controls. Supplements caused no change in these levels either at day 4 or 15, although serum-tocopherol showed a 3-fold increase. Also disease activity was unaffected. This failure of vitamin E supplementation to suppress the mucosal release of PGE2 and LTB4 in active inflammation does not encourage controlled trials of the effect of oral vitamin E in ulcerative colitis.

Krasinski S.D.; Russell R.M.; Furie B.C.; et al.
USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111 USA
Am. J. Clin. Nutr. (USA), 1985, 41/3 (639-643)

Vitamin K deficiency results in the appearance of abnormal prothrombin, deficient in gamma-carboxyglutamic acid, in the blood. The presence of abnormal prothrombin can be eliminated or lowered by the administration of vitamin K. Since the abnormal prothrombin antigen assay is approximately 1000-fold more sensitive than the prothrombin time for the diagnosis of vitamin K deficiency, this assay was used to evaluate patients with intestinal abnormalities. Vitamin K deficiency was found in 18 of 58 patients (31%) with chronic gastrointestinal disease and/or resection. All patients with vitamin K deficiency had either Crohn's disease involving the ileum or ulcerative colitis treated with sulfasalazine or antibiotics. Abnormal prothrombin levels returned toward normal in patients treated with vitamin K but not in patients who were not treated with vitamin K. The mean plasma vitamin E level in patients with vitamin K deficiency was significantly lower than in vitamin-K sufficient patients (p<0.01). We conclude that certain chronic forms of gastrointestinal disorders are associated with vitamin K deficiency.

Galvez J.; Cruz T.; Crespo E.; Ocete M.A.; Lorente M.D.; Sanchez de Medina E.; Zarzuelo A.
J. Galvez, Department of Pharmacology, School of Pharmacy, University of Granada, Poligono de Cartuja s/n, E-18071, Granada Spain
Planta Medica (Germany), 1997, 63/5 (409-414)

The effect of the flavonoid rutoside on acetic acidinduced rat colitis was studied. Rats were pretreated orally with different doses of the flavonoid (10, 25, and 100 mg/kg) 48, 24, and 1 hour prior to colitis induction and examined for colonic damage 24 hours later. Colonic inflammation was characterized by gross and microscopical injury, bowel wall thickening, abolition of fluid absorption, glutathione depletion, enhanced leukotriene B4 synthesis, and increased levels of myeloperoxidase and alkaline phosphatase activities. Rutoside treatment (25 and 100 mg/kg) reduced histologic injury and prevented the increase in alkaline phosphatase activity, but it had no effect on myeloperoxidase levels or leukotriene B4 synthesis. In addition, glutathione depletion was effectively counteracted at the dose of 25 mg/kg, whereas fluid absorption was achieved at the highest dose assayed. It is concluded that rutoside has an acute antiinflammatory activity in this model which may be related to a putative direct protective effect on intestinal cells, mainly enterocytes, in which the antioxidative properties of the flavonoid may play a role.

De Medina F.S.; Galvez L.-H.; Romero J.A.; Zarzuelo A.
F.S. De Medina, Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada Spain
Journal of Pharmacology and Experimental Therapeutics (USA), 1996, 278/2 (771-779)

Quercitrin was tested for acute and chronic anti-inflammatory activity in trinitrobenzenesulfonic acid-induced rat colitis. The inflammatory status was evaluated by myeloperoxidase, alkaline phosphatase and total glutathione levels, leukotriene B4 synthesis, in vivo colonic fluid absorption, macroscopical damage and occurrence of diarrhea and adhesions. Treatment with 1 or 5 mg/kg of quercitrin by the oral route reduced myeloperoxidase and alkaline phosphatase levels, preserved normal fluid absorption, counteracted glutathione depletion and ameliorated colonic damage at 2 days. Increasing or lowering the dose of the flavonoid resulted in marked loss of effect. The acute anti-inflammatory effect of quercitrin is unrelated to impairment of neutrophil function or lipoxygenase inhibition, and it may be caused by mucosal protection or enhancement of mucosal repair secondary to increased defense against oxidative insult and/or preservation of normal colonic absorptive function. When tested in chronic colitis (2 and 4 weeks), quercitrin treatment (1 or 5 mg/kg . day) decreased colonic damage score and the incidence of diarrhea, and normalized the colonic fluid transport. All other parameters were unaffected. The chronic effect of the flavonoid is apparently related to its action on colonic absorption, although it can be partly secondary to its acute beneficial effect.

Bokkenheuser V.
Department of Pathology, St. Luke's-Roosevelt Hospital Center, 1111 Amsterdam Avenue, New York, NY 10025 USA
Clin. Infect. Dis. (USA), 1993, 16/Suppl. 4 (S427-S434)

Anaerobic bacteria include the most pathogenic of microorganisms. Their primary function, however, is hardly to cause illness. They rarely are involved in epidemics or in clinically significant infections. Some organisms, e.g. lactobacilli, control the normal vaginal ecosystem, and the intestinal anaerobes probably are instrumental in restraining the growth of Clostridium difficile in human carriers. The main role of anaerobes appears to be the provision of catabolic enzymes for organic compounds that cannot be digested by enzymes of eukaryotic origin. They are needed for the catabolism of cholesterol, bile acids, and steroid hormones; they hydrolyze a number of flavonoid glycosides to anticarcinogens; and they detoxify certain carcinogens. Anaerobic enzymes are used industrially in the production of cheese; the conversion of starch to sweeteners; and the transformation of sawdust, wood chips, and waste paper to fuel. Indeed, the anaerobes may well be the gene bank on which future generations of eukaryotic organisms will rely to adapt successfully to an ever-changing world.

Fernandez-Banares F.; Mingorance M.D.; Esteve M.; Cabre E.; Lachica M.; Abad-Lacruz A.; Gil A.; Humbert P.; Boix J.; Gassull M.A.
Department of Gastroenterology, Hospital Universitari 'Germans Trias I Pujol', Carretera del Canyet 2/n, 08916 Badalona Spain
Am. J. Gastroenterol. (USA), 1990, 85/12 (1584-1589)

Serum levels of zinc, copper, and selenium, and alkaline phosphatase activity were prospectively studied in 29 patients with inflammatory bowel disease. Fifteen patients had extensive active colitis (active colitis group). Seven patients had active, and seven cases inactive small bowel or ileocecal Crohn's disease (small bowel disease group). Ninety-three healthy subjects acted as controls. Serum trace element levels were considered in relation to vitamin A and E levels, nutritional parameters, the activity of the disease, and the recent intake of steroids. The effect of total enteral nutrition on serum trace elements was studied in seven cases. Serum zinc levels were lower and serum copper levels higher in the active colitis group than in controls (p = 0.0007, and p = 0.02, respectively). More than 50% of patients with active colonic or small bowel disease showed zinc levels below the 15th percentile of the control group. Serum zinc levels correlated with plasma vitamin A in acute colitis (r = 0.67; p = 0.006), and with both serum albumin concentration (r = 0.76; p = 0.002) and disease activity score (r = -0.67, p = 0.009) in patients with small bowel disease. The copper:zinc ratio was higher in the active colitis group than in controls (p = 0.002). In spite of the increase in serum albumin levels and the decrease in disease activity, serum zinc levels remained low after total enteral nutrition. The implications of the abnormal trace element status in patients with inflammatory bowel disease are discussed.

Gee M.I.; Grace M.G.A.; Wensel R.H.; et al.
Department of Food and Nutrition, Faculty of Home Economics, University of Alberta, Edmonton, Alta. Canada
J. Am. Diet. Assoc. (USA), 1985, 85/12 (1591-1599)

Dietary intakes of two groups of gastrointestinal patients, one group with inflammatory bowel disese (IBD) - Crohn's disease or chronic ulcerative colitis - and the other with functional disorders (FD) - irritable bowel syndrome, nonulcer dyspepsia or gastroesophageal reflux disease, were assessed by means of 48-hour recalls. The relationships between dietary intake and anthropometric and biochemical measurements were examined. The IBD group had lower mean serum albumin and hemoglobin levels (p < .05); however, FD patients had less adequate diets. The mean energy intake of women with FD was significantly lower than that of women with IBD (p < .05) and was associated with inadequate or marginal intakes of many nutrients. Comparison of nutrient intakes between the IBD and FD groups revealed a significantly lower mean intake of folate, ascorbic acid, and vitamin A for women with FD than for women with IBD (p < .05). In general, women had poorer diets and a higher prevalence of abnormal biochemical parameters than men. One notable feature of the dietary pattern of the women was that they consumed less meat than the general population consumed. Increasing meat consumption would improve the intake of many nutrients, including protein and iron. The results of this study suggest that more attention should be given to the adequacy of dietary intakes of gastrointestinal patients in general and of women in particular.

Pirzer U, Schonhaar A, Fleischer B, Hermann E, Meyer zum Buschenfelde KH
First Department of Medicine, University of Mainz, Germany.
Lancet 1991 Nov 16;338(8777):1238-9

Intestinal T lymphocytes are normally unresponsive to microbial and recall antigens in vitro, whereas the same antigens induce strong immune responses in peripheral-blood-derived T cells. We obtained T lymphocytes from peripheral blood and from the non-inflamed and inflamed intestinal mucosa of 6 patients (3 male, 3 female; mean age 33 years) with Crohn's disease. The T cells were stimulated in vitro with a range of microbial antigens. Whereas T cells from normal mucosa were unresponsive, those from inflamed mucosa had a proliferative response comparable to that of the peripheral-blood-derived T cells. These findings suggest that physiologic unresponsiveness to luminal antigens is abrogated in the inflammatory lesions of Crohn's disease patients. Infiltrating T lymphocytes may therefore mediate chronic inflammation on encountering the many antigens present in the intestine.

Straub RH, Vogl D, Gross V, Lang B, Scholmerich J, Andus T
Department of Internal Medicine I, University Medical Center, Regensburg, Germany.
Am J Gastroenterol 1998 Nov;93(11):2197-202

OBJECTIVES: Dehydroepiandrosterone sulfate (DHEAS) and cortisol are multifunctional adrenal hormones with immunomodulating properties. DHEAS levels were found to be very low in chronic inflammatory diseases. This study aimed to shed more light on the interrelation between DHEAS and cortisol (and humoral markers of inflammation) in chronic inflammatory bowel disease.

METHODS: DHEAS and cortisol serum levels were measured by ELISA in the serum of 66 normal subjects, 115 patients with Crohn's disease (CD) and 64 patients with ulcerative colitis (UC). Humoral markers of inflammation and disease activity scores were assessed by standard techniques.

RESULTS: DHEAS was lower in patients with CD (p < 0.005) and UC (p < 0.005) than in controls, which was, in part, dependent on previous corticosteroid treatment (p < 0.01). In CD patients, z-normalized DHEAS was inversely correlated with blood sedimentation rate (p = 0.017). Z-normalized DHEAS was negatively correlated with interleukin-6 (IL-6) in the form of a trend (p = 0.068), and z-normalized DHEAS was significantly positively correlated with hemoglobin (p = 0.001) but not with the Crohn's disease activity index. Cortisol, however, was positively correlated with blood sedimentation rate (p = 0.034) and C-reactive protein (p = 0.006). In contrast, in UC patients no such correlation of z-normalized DHEAS or cortisol and parameters of humoral inflammatory activity or Rachmilewitz index exist.

CONCLUSIONS: DHEAS as a marker of inflammation was low in CD and UC. In CD patients, low DHEAS and high cortisol serum levels were associated with higher humoral inflammatory activity. With respect to humoral inflammatory activity in CD patients, DHEAS and cortisol seem to be inversely regulated, which may have an impact on several immune functions, such as IL-6 secretion.

Christl SU Eisner HD Dusel G Kasper H Scheppach W.
Dig Dis Sci (1996 Dec) 41(12):2477-81I

It has been shown that feces of patients with ulcerative colitis uniformly contain sulfate reducing bacteria. Sulfide produced by these bacteria interferes with butyrate-dependent energy metabolism of cultured colonocytes and may be involved in the pathogenesis of ulcerative colitis. Mucosal biopsies from the sigmoid rectum of 10 patients (no cancer, polyps, inflammatory bowel disease) were incubated with either NaCl, sodium hydrogen sulfide (1 mmol/L), a combination of both sodium hydrogen sulfide and butyrate (10 mmol/L), or butyrate. Mucosal proliferation was assessed by bromodeoxyuridine labeling of cells in S-phase. Compared to NaCl, sulfide increased the labeling of the entire crypt significantly, by 19% (p < 0.05). This effect was due to an expansion of the proliferative zone to the upper crypt (compartments 3-5), where the increase in proliferation was 54%. Sulfide-induced hyperproliferation was reversed when samples were coincubated with sulfide and butyrate. The study shows that sodium hydrogen sulfide induces mucosal hyperproliferation. Our data support a possible role of sulfide in the pathogenesis of UC and confirm the role of butyrate in the regulation of colonic proliferation and in the treatment of UC.

Motley RJ Crawley EO Evans C Rhodes J Compston JE.
Gut (1988 Oct) 29 (10):1332-6

The rate of spinal trabecular bone loss during one year was measured in 54 patients with inflammatory bowel disease. The mean change in spinal bone mineral content was -5.1 mg/ml K2HPO4, representing 3% of the initial bone mineral content. The rate of bone loss showed a significant negative correlation with body mass index (r = -0.276, p less than 0.05) but no other significant correlations were found with other clinical or biochemical indices, including the total amount of prednisolone taken during the course of the study. Eleven patients had bone loss greater than 15 mg/ml/year; these included four non steroid-treated patients, two of whom had disease confined to the large bowel. The results indicate rapid rates of bone loss in some patients with inflammatory bowel disease over the course of one year. Although steroid therapy and malnutrition are likely to be contributory factors in some patients, other as yet unidentified risk factors also operate. The rapid bone loss observed in some patients emphasises the need for effective prophylactic regimes.

Marcus R Butterfield G Holloway L Gilliland L Baylink DJ Hintz RL Sherman BM.
J Clin Endocrinol Metab (1990 Feb) 70(2):519-27

We evaluated the effects of recombinant human GH (rhGH) in 16 men and women more than 60 yr of age. After 10 days of dietary equilibration and control collections, subjects were randomly assigned to receive 0.03, 0.06, or 0.12 mg/kg rhGH by daily injection for 7 days. A brisk rise in circulating somatomedin-C (insulin-like growth factor-I) occurred in all subjects, and this rise was dose dependent. RhGH produced striking changes in nitrogen retention, sodium excretion, and the parathyroid-vitamin D axis. Twenty-four-hour urinary nitrogen excretion decreased from 8.00 +/- 0.33 to 5.01 +/- 0.33 g (P less than 0.001), and sodium excretion decreased from 45.9 +/- 2.96 to 21.2 +/- 3.48 mmol/day (P less than 0.001). Serum calcium concentrations did not change, but serum inorganic phosphorus levels of 1.08 +/- 0.04 mmol/L at baseline increased significantly after rhGH treatment to 1.33 +/- 0.04 mmol/L (P less than 0.001). Increases were also observed in circulating PTH (53.2 +/- 6 vs. 39.5 +/- 4.2 ng/L; P less than 0.01) and calcitriol (82.8 vs. 65.8 pmol/L; P less than 0.05). A rise in serum osteocalcin (10.3 +/- .86 vs. 8.0 +/- 0.5 micrograms/L; P less than 0.05) was accompanied by increased urinary excretion of hydroxyproline (628 +/- 63 vs. 406 +/- 44 mumol/day; P less than 0.01). Despite the reduction in sodium excretion, marked increases were observed in urinary calcium (6.04 +/- 0.97 vs. 3.27 +/- 0.40 mmol/day; P less than 0.01). rhGH significantly impaired oral glucose tolerance and reduced insulin sensitivity, but was otherwise well tolerated and produced no systematic changes in weight or blood pressure. The results of this study indicate that RhGH requires further study as a potential agent for attenuating or reversing the loss of muscle and bone in elderly people.

Almallah YZ, Richardson S, O'Hanrahan T, Mowat NA, Brunt PW, Sinclair TS, Ewen S, Heys SD, Eremin O
Department of Surgery, University of Aberdeen, United Kingdom.
Am J Gastroenterol 1998 May;93(5):804-9

OBJECTIVES: Recently, it has been postulated that patients with ulcerative colitis have altered natural cytotoxicity, in particular natural killer (NK) and lymphokine-activated killer (LAK) cell activities. These cellular mechanisms have been postulated to play an etiological role in the pathogenesis of the disease process. We have shown previously that the essential fatty acids (EFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) specifically inhibit natural cytotoxicity. Our aim was to evaluate the role of omega-3 EFA in the modulation of natural cytotoxicity and disease activity in patients with distal procto-colitis.

METHODS: In this pilot study patients were randomized into two groups. Each patient received either fish oil extract (EPA, 3.2 g, and DHA, 2.4 g) (n = 9) or sunflower oil (placebo) (n = 9) daily in a double-blind manner for 6 months. Monthly assessments of disease activity (clinical and sigmoidoscopic scores) and histological evaluation of mucosal biopsies were carried out. Also, the circulating levels and activities of NK and LAK cells, using flow cytometric analysis (CD16+ CD56+) and in vitro 51 chromium release assays (K562), respectively, were monitored.

RESULTS: After 6 months' supplementation with EFA, there was improvement in the clinical activity compared with pretreatment evaluation. There was significant reduction in the sigmoidoscopic and histological scores in the EFA group compared with the placebo group. Essential fatty acid supplementation for 6 months also induced significant reduction in the circulating numbers of CD16+ and CD56+ cells and the cytotoxic activity of NK cells, compared with the placebo group.

CONCLUSIONS: This pilot study has demonstrated that omega-3 fatty acids can suppress natural cytotoxicity and reduce disease activity in patients with distal procto-colitis. These findings suggest a therapeutic strategy for managing patients with inflammatory bowel disease.

Mascolo N, Izzo AA, Autore G, Maiello FM, Di Carlo G, Capasso F
Department of Experimental Pharmacology, University of Naples, Federico II, Naples, Italy.
J Pharmacol Exp Ther 1995 Jan;272(1):469-75

Eicosanoids and platelet-activating factor (PAF) production increases in experimental colitis. Both eicosanoids and PAF seem to arise from similar membrane phospholipids. To support both these suggestions we have investigated whether a fat-free diet, which should alter production of eicosanoids and PAF, affects experimental colitis. Essential fatty acid deficient (EFAD) rats were obtained by putting 4-week-old animals on a fat-free diet for 3 months. Experimental colitis was induced by a single intracolonic administration of 2 ml of 4% acetic acid. One to seven days later the animals were sacrificed and the colon removed to assess macroscopically and histologically intestinal damage. Eicosanoids and PAF levels were also measured in the mucosa scrapings by specific radioimmunoassay. The injury to the colon was more evident in control rats compared with EFAD rats. Besides colonic tissue of control rats showed a highly significant increase of PGE2, LTB4 and PAF, compared with levels in EFAD rats. Our results indicate that fat-free diet reduces tissue damage, and at the same time PGE2, LTB4 and PAF colonic content.

Simopoulos AP
Center for Genetics, Nutrition and Health, Washington, DC.
Am J Clin Nutr 1999 Sep;70(3 Suppl):560S-9S

Human beings evolved consuming a diet that contained about equal amounts of n-3 and n-6 essential fatty acids. Over the past 100-150 y there has been an enormous increase in the consumption of n-6 fatty acids due to the increased intake of vegetable oils from corn, sunflower seeds, safflower seeds, cottonseed, and soybeans. Today, in Western diets, the ratio of n-6 to n-3 fatty acids ranges from approximately 20-30:1 instead of the traditional range of 1-2:1. Studies indicate that a high intake of n-6 fatty acids shifts the physiologic state to one that is prothrombotic and proaggregatory, characterized by increases in blood viscosity, vasospasm, and vasoconstriction and decreases in bleeding time. n-3 Fatty acids, however, have antiinflammatory, antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory properties. These beneficial effects of n-3 fatty acids have been shown in the secondary prevention of coronary heart disease, hypertension, type 2 diabetes, and, in some patients with renal disease, rheumatoid arthritis, ulcerative colitis, Crohn disease, and chronic obstructive pulmonary disease. Most of the studies were carried out with fish oils [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. However, alpha-linolenic acid, found in green leafy vegetables, flaxseed, rapeseed, and walnuts, desaturates and elongates in the human body to EPA and DHA and by itself may have beneficial effects in health and in the control of chronic diseases.

Han PD, Burke A, Baldassano RN, Rombeau JL, Lichtenstein GR
University of Pennsylvania School of Medicine, Philadelphia, USA.
Gastroenterol Clin North Am 1999 Jun;28(2):423-43, ix

This article reviews the nutritional aspects of inflammatory bowel disease (IBD) including the mechanisms and manifestations of malnutrition and the efficacy of nutritional therapies. Nutrient deficiencies in patients with IBD occur via several mechanisms and may complicate the course of the disease. Nutritional status is assessed by clinical examination and the use of nutritional indices such as the Subjective Global Assessment of nutritional status. Nutritional intervention may improve outcome in certain individuals; however, because of the costs and complications of such therapy, careful selection is warranted, especially in patients presumed to need parenteral nutrition.

Nieto N, Fernandez MI, Torres MI, Rios A, Suarez MD, Gil A
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Granada, Spain.
Dig Dis Sci 1998 Dec;43(12):2676-87

The intrarectal administration of trinitrobenzene sulfonic acid in rats induces ulcerative colitis, which results in histological alterations of colonic mucosa, severe modification of the cellular antioxidant defense system, and enhanced production of inflammatory eicosanoids. This study evaluated the influence of different dietary fatty acids, i.e., monounsaturated, n-3, and n-3 + n-6 polyunsaturated fatty acids, on the recovery of the colonic mucosa histological pattern, the cellular antioxidant defense system of colon, and PGE2 and LTB4 colonic mucosa contents in a model of ulcerative colitis induced by intrarectal administration of trinitrobenzene sulfonic acid. Administration of dietary n-3 polyunsaturated fatty acids led to a minimum stenosis score, a higher histological recovery, lower colon alkaline phosphatase and gamma-glutamyltranspeptidase activities, and lower mucosal levels of PGE2 and LTB4 compared with the other two experimental groups. However, glutathione transferase, glutathione reductase, glutathione peroxidase, and catalase activities were lower in the group treated with n-3 polyunsaturated fatty acids than in the groups fed with either the monounsaturated or the n-6 + n-3 polyunsaturated enriched diet. We conclude that n-3 polyunsaturated fatty acids can be administered to prevent inflammation in ulcerative colitis, but they cause a decrease in the colonic antioxidant defense system, promoting oxidative injury at the site of inflammation.

Akisu M, Baka M, Coker I, Kultursay N, Huseyinov A
Department of Pediatrics, Ege University Medical School, Izmir, Turkey
makisu@hotmail.com
Biol Neonate 1998;74(1):31-8

Necrotizing entercolitis (NEC) is an important neonatal disease with a high mortality rate. Inflammatory mediators, such as mainly platelet-activating factor (PAF), leukotrienes (LT) and tumor necrosis factor play an important role in the genesis of NEC. Diets in omega-3 (n-3) fatty acids appear to have an antiinflammatory effect, which is thought to be due to decreased active prostaglandins and leukotrienes production after incorporation of these fatty acids into cell membrane phospholipids. We investigated the protective effect of fish oil (source of n-3 fatty acids) on hypoxia-induced model of NEC. Young mice were divided into three groups; group 1 mice were fed standard chow (n-3 fatty acids-free), group 2 was fed a chow supplemented by 10% fish oil for 4 weeks. Group 3 mice served as control. We examined the intestinal lesions by light microscopy and measured intestinal tissue PAF and LB4 levels in hypoxia-induced model of NEC. Significantly increased intestinal PAF and LTB4 levels were found in group 1 mice when compared to group 2 and group 3 mice. The histopathology of the intestinal lesions in group 1 animals was characteristic of ischemic injury. In the n-3 fatty acids-supplemented animals these lesions were milder. The present study shows that endogenously released PAF and LTB4 play an important role in mediating hypoxia-induced intestinal necrosis. The present study also suggests that dietary supplementation with n-3 fatty acids suppress intestinal PAF and LTB4 generation in hypoxia-induced bowel necrosis. The intestinal protective effect of n-3 fatty acids in an experimental model of NEC may open new insight into the treatment and prevention of NEC in neonates.

Hunter JO
Addenbrooke's Hospital, Gastroenterology Research Unit, Cambridge, UK.
Eur J Gastroenterol Hepatol 1998 Mar;10(3):235-7

During the past 20 years there has been growing interest in the importance of nutritional factors in the pathogenesis of inflammatory bowel disease. There are so far no definite links between ulcerative colitis and diet, but links with Crohn's disease have been studied by both epidemiologists and clinicians. Epidemiological studies, although retrospective, have suggested that patients with Crohn's disease eat more sugar and sweets that control individuals; however, when dietary sugar is restricted, there is little clinical benefit. The clinical approach to nutrition in Crohn's disease has been by the use of elemental diets, which will produce symptomatic and objective remission in up to 90% of compliant patients. Those who return to normal eating soon relapse but, in some studies, have enjoyed prolonged remission on exclusion diets. The foods excluded have been not sugar, but predominantly cereals, dairy products and yeast. Attention has now switched to the possible harmful role of fat in Crohn's disease. The efficacy of elemental feeds appears to depend not on the presentation of nitrogen but on the amount of long chain triglyceride present. Increases in recent years in the frequency of Crohn's disease in Japan have been correlated with increased dietary fat intake, and a recent study suggested that W-3 fatty acids, which are metabolized by immunomodulatory leukotrienes and prostaglandins, may have a beneficial role to play. The links between nutrition and Crohn's disease have now become strong and the role of fat may be the most exciting of all.

[Article in Spanish]
Jorquera Plaza F, Espinel Diez J, Olcoz Goni JL
Seccion de Digestivo, Hospital de Leon, Espana.
Nutr Hosp 1997 Nov-Dec;12(6):289-98

Malnutrition is a very common situation in patients inflammatory with intestinal disease (IID), which can be caused by a multitude of factors. It has been shown that nutritional support not only improves the nutritional condition of the patients, but in Crohn's disease it also has an effect on the activity of the disease, although this effect is smaller than that of steroids. Elemental diets are no more efficient than polymeric diets except under very special circumstances, but they are more expensive and patients tolerate them worse. A digestive pause is not recommended unless there is an absolute contraindication for the use of the digestive tract. Therefore, parenteral nutrition, which is more expensive and can cause serious complications, will be reserved for very specific indications. The use of fish oil supplements, either because it competes with arachidonic acid and prevents the initiation of the inflammatory cascade, or because it decreases the production of cytokines, has shown to be potentially useful in inflammatory intestinal disease, and this must be confirmed by further studies. Short chain fatty acids enemas have shown promising results in distal ulcerative colitis but the lack of homogeneity in the studies makes it necessary for these results to be consolidated in new studies. Nutritional support is especially interesting in children with inflammatory intestinal disease given that the growth retardation which is often seen in severe cases, can be controlled by adequate enteral or parenteral diets.