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Abstracts

Colitis (Ulcerative)

ABSTRACTS

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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.