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Life Extension Magazine April 2012


Production of bioactive substances by intestinal bacteria as a basis for explaining probiotic mechanisms: bacteriocins and conjugated linoleic acid.

The mechanisms by which intestinal bacteria achieve their associated health benefits can be complex and multifaceted. In this respect, the diverse microbial composition of the human gastrointestinal tract (GIT) provides an almost unlimited potential source of bioactive substances (pharmabiotics) which can directly or indirectly affect human health. Bacteriocins and fatty acids are just two examples of pharmabiotic substances which may contribute to probiotic functionality within the mammalian GIT. Bacteriocin production is believed to confer producing strains with a competitive advantage within complex microbial environments as a consequence of their associated antimicrobial activity. This has the potential to enable the establishment and prevalence of producing strains as well as directly inhibiting pathogens within the GIT. Consequently, these antimicrobial peptides and the associated intestinal producing strains may be exploited to beneficially influence microbial populations. Intestinal bacteria are also known to produce a diverse array of health-promoting fatty acids. Indeed, certain strains of intestinal bifidobacteria have been shown to produce conjugated linoleic acid (CLA), a fatty acid which has been associated with a variety of systemic health-promoting effects. Recently, the ability to modulate the fatty acid composition of the liver and adipose tissue of the host upon oral administration of CLA-producing bifidobacteria and lactobacilli was demonstrated in a murine model. Importantly, this implies a potential therapeutic role for probiotics in the treatment of certain metabolic and immunoinflammatory disorders. Such examples serve to highlight the potential contribution of pharmabiotic production to probiotic functionality in relation to human health maintenance.

Int J Food Microbiol. 2012 Jan 16;152(3):189-205

Probiotics and pharmabiotics: alternative medicine or an evidence-based alternative?

That commensal bacteria play an important role in human health is beyond doubt, and it is now widely accepted that humans function as super organisms, whose collective metabolic potential exceeds the sum of our individual eukaryotic and prokaryotic components. However, while it is has been established that the prokaryotic component of the human superorganism is amenable to manipulation by chemotherapeutic, dietary or microbial interventions, the significance of such alterations in terms of human health or well being is less well established. Prebiotics (non- digestible food ingredients that stimulate the growth and/or activity of bacteria in the digestive system) and probiotics (live microorganisms that when administered in adequate amounts, confer a health benefit on the host) are often bracketed among ‘alternative’ approaches to influencing human health, such as homeopathy, naturopathy, acupuncture and hypnotherapy. Others believe that prebiotics and probiotics have proven their effectiveness in properly conducted, clinically controlled human trials and therefore can be considered as evidence-based alternatives or adjuncts to conventional medicines. My journey from a position of total skepticism to ‘reluctant convert’ is the basis of this article, which should not be considered in any sense as a review of the literature but simply a personal account of this transition. While I am not bent on converting other doubters, I will recount some of the thought processes and evidence that has helped to form my current opinion.

Bioeng Bugs. 2010 Mar-Apr;1(2):79-84

The potential for probiotic manipulation of the gastrointestinal microbiome.

Multiple internal and external sites of the healthy human body are colonized by a diversity of symbiotic microbes. The microbial assemblages found in the intestine represent some of the most dense and diverse of these human-associated ecosystems. Unsurprisingly, the enteric microbiome, that is the totality of microbes, their combined genomes, and their interactions with the human body, has a profound impact on physiological aspects of mammalian function, not least, host immune response. Lack of early-life exposure to certain microbes, or shifts in the composition of the gastrointestinal microbiome have been linked to the development and progression of several intestinal and extra-intestinal diseases, including childhood asthma development and inflammatory bowel disease. Modulating microbial exposure through probiotic supplementation represents a long-held strategy towards ameliorating disease via intestinal microbial community restructuring. This field has experienced somewhat of a resurgence over the past few years, primarily due to the exponential increase in human microbiome studies and a growing appreciation of our dependence on resident microbiota to modulate human health. This review aims to review recent regulatory aspects related to probiotics in food. It also summarizes what is known to date with respect to human gastrointestinal microbiota - the niche which has been most extensively studied in the human system - and the evidence for probiotic supplementation as a viable therapeutic strategy for modulating this consortium.

Curr Opin Biotechnol. 2011 Nov 30

The colonic microflora and probiotic therapy in health and disease.

PURPOSE OF REVIEW: Host-microbe dialogue is involved not only in maintenance of mucosal homeostasis but also in the pathogenesis of several infectious, inflammatory, and neoplastic disorders of the gut. This has led to a resurgence of interest in the colonic microbiota in health and disease. Recent landmark findings are addressed here. RECENT FINDINGS: Reciprocal signalling between the immune system and the microbiota plays a pivotal role in linking alterations in gut microbiota with risk of metabolic disease in the host, notably insulin resistance, obesity, and chronic low-grade inflammation. Loss of ancestral indigenous organisms consequent upon a modern lifestyle may contribute to an increased frequency of various metabolic and immuno-allergic diseases. The potential to address this underpins the science of pharmabiotics. SUMMARY: Advances in understanding host-microbe interactions within the gut can inform rational probiotic or pharmabiotic selection criteria. In addition, the gut microbiota may be a repository for drug discovery as well as a therapeutic target.

Curr Opin Gastroenterol. 2011 Jan;27(1):61-5

Probiotics-host communication: Modulation of signaling pathways in the intestine.

The intestinal microbiota includes a diverse group of functional microorganisms, including candidate probiotics or viable microorganisms that benefit the host. Beneficial effects of probiotics include enhancing intestinal epithelial cell function, protecting against physiologic stress, modulating cytokine secretion profiles, influencing T lymphocyte populations, and enhancing antibody secretion. Probiotics have demonstrated significant potential as therapeutic options for a variety of diseases, but the mechanisms responsible for these effects remain to be fully elucidated. Accumulating evidence demonstrates that probiotics communicate with the host by modulating key signaling pathways, such as NFkB and MAPK, to either enhance or suppress activation and influence downstream pathways. Beneficial microbes can profoundly alter the physiology of the gastrointestinal tract, and understanding these mechanisms may result in new diagnostic and therapeutic strategies.

Gut Microbes. 2010 May-Jun;1(3):148-63

Mechanisms of probiotic action: Implications for therapeutic applications in inflammatory bowel diseases.

Probiotics are defined as nonpathogenic living microorganisms, including some commensal bacterial flora, which have beneficial effects on host health and disease prevention and/or treatment. Clinical trials have shown beneficial effects of probiotics on several human diseases, such as inflammatory bowel diseases (IBDs), which are among the most-studied diseases testing probiotics as a potential therapy. However, a significant question regarding clinical use of probiotics is the mechanism underlying the wide range of actions. Studies discussed in this review suggest 3 distinct cellular and molecular mechanisms for probiotic regulation in IBD therapy: 1) Probiotics block pathogenic bacterial effects by producing bactericidal substances and competing with pathogens and toxins for adherence to the intestinal epithelium; 2) Probiotics regulate immune responses by enhancing the innate immunity and modulating pathogen-induced inflammation via toll-like receptor-regulated signaling pathways; and 3) Probiotics regulate intestinal epithelial homeostasis by promoting intestinal epithelial cell survival, enhancing barrier function, and stimulating protective responses. Probiotics modulate host cell signaling pathways, including Akt, mitogen-activated protein kinases, and nuclear factor-kappaB to mediate these intestinal epithelial functions. It is hoped that developing a mechanistic understanding of probiotic action will provide the rationale to support the development of new hypothesis-driven studies to define the clinical efficacy in preventive, adjunctive, or alternative treatments for IBD.

Inflamm Bowel Dis. 2008 Nov;14(11):1585-96

Indications for the use of probiotics in gastrointestinal diseases.

Probiotics are live microbial organisms that are present in foods or dietary supplements and that confer health benefits to the host when ingested in sufficient quantities. Probiotics can be bacterial (e.g. Bifidobacteria spp. and Lactobacillus spp.) or yeasts (e.g. Saccharomyces boulardii). The administration of probiotics is often believed to be by and large beneficial for individuals with inflammatory or infectious diseases of the gastrointestinal tract. These positive effects are generally attributed to the ability of probiotics to regulate intestinal permeability, normalize host intestinal flora, improve gut immune barrier function, and equilibrate the balance between proinflammatory and anti-inflammatory cytokines. Of note, however, these claims are not always substantiated by findings from properly conducted clinical trials. Of particular importance, even when results from randomized controlled trials support the beneficial effects of a particular probiotic for a specific indication, the benefits achieved by the probiotic are generally not translatable to other probiotic formulations. This review discusses the gastrointestinal indications for probiotic use and describes the level of evidence that supports the use of specific probiotics for these indications. Several indications are addressed, including enteric infections, gastritis caused by Helicobacter pylori infection, necrotizing enterocolitis, inflammatory bowel diseases, and irritable bowel syndrome.

Dig Dis. 2011;29(6):574-87

Gut microbiota, probiotics, and vitamin D: interrelated exposures influencing allergy, asthma, and obesity?

Current evidence supports a role for gut colonization in promoting and maintaining a balanced immune response in early life. An altered or less diverse gut microbiota composition has been associated with atopic diseases, obesity, or both. Moreover, certain gut microbial strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. However, there has been no fully adequate longitudinal study of the relation between the neonatal gut microbiota and the development of allergic diseases (eg, atopic asthma) and obesity. The emergence of promising experimental studies has led to several clinical trials of probiotics (live bacteria given orally that allow for intestinal colonization) in human subjects. Probiotic trials thus far have failed to show a consistent preventive or therapeutic effect on asthma or obesity. Previous trials of probiotics have been limited by small sample size, short duration of follow-up, or lack of state-of-the art analyses of the gut microbiota. Finally, there is emerging evidence that the vitamin D pathway might be important in gut homeostasis and in signaling between the microbiota and the host. Given the complexity of the gut micriobiota, additional research is needed before we can confidently establish whether its manipulation in early life can prevent or treat asthma, obesity, or both.

J Allergy Clin Immunol. 2011 May;127(5):1087-94

Regulation of tight junction permeability by intestinal bacteria and dietary components.

The human intestinal epithelium is formed by a single layer of epithelial cells that separates the intestinal lumen from the underlying lamina propria. The space between these cells is sealed by tight junctions (TJ), which regulate the permeability of the intestinal barrier. TJ are complex protein structures comprised of transmembrane proteins, which interact with the actin cytoskeleton via plaque proteins. Signaling pathways involved in the assembly, disassembly, and maintenance of TJ are controlled by a number of signaling molecules, such as protein kinase C, mitogen-activated protein kinases, myosin light chain kinase, and Rho GTPases. The intestinal barrier is a complex environment exposed to many dietary components and many commensal bacteria. Studies have shown that the intestinal bacteria target various intracellular pathways, change the expression and distribution of TJ proteins, and thereby regulate intestinal barrier function. The presence of some commensal and probiotic strains leads to an increase in TJ proteins at the cell boundaries and in some cases prevents or reverses the adverse effects of pathogens. Various dietary components are also known to regulate epithelial permeability by modifying expression and localization of TJ proteins.

J Nutr. 2011 May;141(5):769-76

An intimate tête-à-tête - how probiotic lactobacilli communicate with the host.

Pharmaceutical agents are routinely used in the treatment of gastrointestinal disorders and their role as modulators of host cell responses is well characterized. In contrast, the understanding of the molecular mechanisms, which determine the role of probiotics, i.e. health-promoting bacteria, as host cell modulators is still in its infancy. Both in vitro and in vivo studies are just starting to reveal the capability of probiotic lactobacilli to modulate host cell-signaling networks and the associated influences on downstream regulatory pathways, including modulation of mucosal cytokine profiles that dictate host immune functions. The communication between probiotic lactobacilli and intestinal host cells is multifactorial and involves an integrative repertoire of receptors on the host side that recognize multiple effector molecules on the bacterial side, of which most have been found to be cell wall- or cell surface-associated compounds and proteins. This review describes the discovery of these bacterial effector molecules and their role in strain- and species-specific modulation of host signaling pathways. Unraveling the mechanisms responsible for probiotic-host interactions will progress this research field towards molecular science and will provide markers for probiotic product quality control as well as host-response efficacy. These developments can ultimately lead to a more dedicated, personalized application of probiotics with strong molecular and scientific support for health promotion.

Eur J Pharmacol. 2011 Sep;668 Suppl 1:S33-42

Microbes, intestinal inflammation and probiotics.

Inflammatory bowel disease (IBD) is known for causing disturbed homeostatic balance among the intestinal immune compartment, epithelium and microbiota. Owing to the emergence of IBD as a major cause of morbidity and mortality, great efforts have been put into understanding the sequence of intestinal inflammatory events. Intestinal macrophages and dendritic cells act in a synergistic fashion with intestinal epithelial cells and microbiota to initiate the triad that governs the intestinal immune responses (whether inflammatory or regulatory). In this review, we will discuss the interplay of intestinal epithelial cells, bacteria and the innate immune component. Moreover, whether or not genetic intervention of probiotic bacteria is a valid approach for attenuating/mitigating exaggerated inflammation and IBD will also be discussed.

Expert Rev Gastroenterol Hepatol. 2012 Feb;6(1):81-94

Probiotics in the treatment of human inflammatory bowel diseases: update 2011.

Crohn’s disease, ulcerative colitis, and pouchitis after ileal pouch anal anastomosis in ulcerative colitis patients are often refractory to standard therapy. Over the last decade, the rational to use probiotics and its beneficial efficacy in the treatment of chronic inflammatory bowel disease (IBD) is increasingly under scrutiny. Although it has become clear that intestinal epithelial-mucosal immune interactions and enteric bacteria play a critical role in the development of IBD, the substantial clinical efficacy of probiotics in these disorders is less evident. This review outlines the clinical studies regarding probiotics before October 2007. These studies formed the foundation of probiotic clinical trials in IBD, but they also indicated the need of larger and better-controlled studies than the past experimental approaches. Furthermore, this review also examines in-depth the probiotic clinical trials published between 2007 and December 2010, providing new insights into the role of probiotics for inducing and maintaining remission of IBD, and highlighting some of the breakthroughs, especially regarding induction of remission for ulcerative colitis.

J Clin Gastroenterol. 2011 Nov;45 Suppl:S139-44

Probiotics and prebiotics in primary care for colon cancer.

CONTEXT: Colon neoplasias are presently the third most common cancer type. Its treatment is still associated with high risk of complications, thus emphasizing the need to design new treatment strategies. The ingestion of probiotics and prebiotics, or the combination of both (symbiotics), represents a new therapeutic choice. In front of the importance among qualitative and quantitative balance in intestinal microbiota for human’s health and with the purpose to evaluate the application of probiotics and prebiotics, this study tries to approach the importance of these in both the prevention and treatment of colon cancer. EVIDENCE ACQUISITION: A study was conducted on scientific databases (Medline, Lilacs, PubMed, Ovid, SciELO), and a review was made of recent scientific articles in the literature, from 2003 to 2008. Additional informations were taken from sites in the internet. RESULTS: Studies point out the inverse relation between the consumption of probiotics and prebiotics in colon cancer diagnosis through various action mechanisms, including: immune response stimulation, reduction in inflammation, for directly inhibiting the formation of tumor cells and for converting pre-carcinogenic substances into carcinogenic ones. CONCLUSION: Through this literature review, it was possible to achieve positive answers as regards the use of probiotics and prebiotics in carcinogenesis, which can be adequately recommended.

Arq Gastroenterol. 2010 Jan-Mar;47(1):93-8

Probiotics Prevent the Development of 1,2-Dimethylhydrazine (DMH)-Induced Colonic Tumorigenesis through Suppressed Colonic Mucosa Cellular Proliferation and Increased Stimulation of Macrophages.

Probiotics modulate immunity and inhibit colon carcinogenesis in experimental models, but these effects largely depend on the bacterial strain, and the precise mechanisms are not well understood. Therefore, we studied the effect of Bifidobacterium longum and/or Lactobacillus gasseri on the development of 1,2-dimethylhydrazine (DMH)-induced colonic precancerous lesions and tumors in mice while delineating the possible mechanisms involved. The results suggest that dietary consumption of probiotics (B. longum and L. gasseri) resulted in a significant inhibition of DMH-induced aberrant crypt foci (ACF) formation in male ICR mice. Long-term (24 weeks) dietary consumption of probiotics resulted in a reduction of colon tumor multiplicity and the size of the tumors. Administration of B. longum and L. gasseri suppressed the rate of colonic mucosa cellular proliferation in a manner correlating with the inhibition of tumor induction by DMH. In addition, the phagocytic activity of peritoneal macrophages was significantly increased in the DMH-treated mice that were fed various doses of B. longum, but not with L. gasseri or combined probiotics (B. longum + L. gasseri). We also found that L. gasseri significantly increased the proliferation of RAW264.7 macrophage cells through an increase in S phase DNA synthesis, which was related to the up-regulation of proliferating cell nuclear antigen (PCNA) and cyclin A. Taken together, these results demonstrate the in vivo chemopreventive efficacy and the immune stimulating mechanisms of dietary probiotics against DMH-induced colonic tumorigenesis.

J Agric Food Chem. 2011 Dec 28;59(24):13337-45