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.     

Probiotics in infective diarrhoea and inflammatory bowel diseases

Bacteria are present throughout the gastrointestinal tract, but their pattern and concentration vary greatly. Probiotics are living organisms that supply beneficial health effects to the host. So far the beneficial effects of probiotics have been shown, almost exclusively, under poorly defined experimental conditions. There are little convincing data from well-designed, double-blind controlled trials supporting health-promoting effects. The use of probiotics to treat gastrointestinal infections has produced contrasting results. Apart from information on rotavirus infection in children, there is no convincing evidence from controlled studies on the efficacy of probiotics in the prevention or treatment of infective diarrhoea. However, experimental and clinical studies suggest that there are potential therapeutic roles for probiotics in the treatment of inflammatory bowel diseases. This review focuses on the available data concerning the mechanisms of action of probiotics, and on the results from clinical studies using probiotics to treat infective diarrhoea and inflammatory bowel disease.     

Probiotics and immunity

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, including the gastrointestinal tract. While this beneficial effect was originally thought to stem from improvements in the intestinal microbial balance, there is now substantial evidence that probiotics can also provide benefits by modulating immune functions. In animal models, probiotic supplementation is able to provide protection from spontaneous and chemically induced colitis by downregulating inflammatory cytokines or inducing regulatory mechanisms in a strain-specific manner. In animal models of allergen sensitization and murine models of asthma and allergic rhinitis, orally administered probiotics can strain-dependently decrease allergen-specific IgE production, in part by modulating systemic cytokine production. Certain probiotics have been shown to decrease airway hyperresponsiveness and inflammation by inducing regulatory mechanisms. Promising results have been obtained with probiotics in the treatment of human inflammatory diseases of the intestine and in the prevention and treatment of atopic eczema in neonates and infants. However, the findings are too variable to allow firm conclusions as to the effectiveness of specific probiotics in these conditions.     

Probiotics in gastroenterology: indications and future perspectives

Nowadays. there is a growing interest in probiotics as a safe way of changing the intestinal bacterial flora. Probiotics may have potential in several gastroenterological conditions, especially when the intestinal flora has been disturbed. Most scientific evidence is available for diarrhoea patients treated with Lactobacillus GG, Lactobacillus reuteri or Saccharomyces boulardii. Meta-analyses have shown an overall reduction in the risk of antibiotic-associated diarrhoea during treatment with probiotics, and benefits have also been demonstrated for patients with rota-virus-associated diarrhoea. Patients with inflammatory bowel disease, an inflammatory disorder characterized by a change in the intestinal flora, are another important target group for which probiotics may be beneficial. It has been claimed that in ulcerative colitis and Crohn disease patients, lactobacilli, S. boulardii and Escherichia coli reduce relapses. but most studies were not placebo-controlled. A reduction in relapses has also been demonstrated in pouchitis patients treated with a multispecies probiotic. Irritable bowel syndrome might be another clinical indication for probiotic therapy, but results of clinical trials performed in these patients are inconsistent. Additionally, probiotics may improve lactose absorption. Helicobacter pylori eradication and constipation. Finally, in animal models of colorectal cancer, treatment with probiotics reduces the prevalence of this disease, and in humans the amount of genotoxic substances in faeces has been reduced. In conclusion, the results of studies on the effects of probiotics in gastrointestinal conditions are encouraging. but well-designed placebo-controlled studies are warranted before recommendations for therapeutic or preventive use can be given. Many issues still have to be resolved, including optimal dose and duration of treatment, selection of and differences between the several available probiotic strains, and, importantly, their mechanisms of actions have to be elucidated.     

Effect of probiotic administration on the intestinal microbiota,current knowledge and potential applications

Although it is now known that the human body is colonized by a wide variety of microbial populations in different parts(such as the mouth, pharynx and respiratory system, the skin, the gastro- and urogenital tracts), many effects of the complex interactions between the human host and microbial symbionts are still not completely understood. The dysbiosis of the gastrointestinal tract microbiota is considered to be one of the most important contributing factors in the development of many gastrointestinal diseases such as inflammatory bowel disease, irritable bowel syndrome and colorectal cancer, as well as systemic diseases like obesity, diabetes, atherosclerosis and non-alcoholic fatty liver disease. Fecal microbial transplantations appear to be promising therapies for dysbiosis-associated diseases; however, probiotic microorganisms have been growing in popularity due to increasing numbers of studies proving that certain strains present health promoting properties, among them the beneficial balance of the intestinal microbiota. Inflammatory bowel diseases andobesity are the pathologies in which there are more studies showing this beneficial association using animal models and even in human clinical trials.In this review,the association of the human gut microbiota and human health will be discussed along with the benefits that probiotics can confer on this symbiotic activity and on the prevention or treatment of associated diseases.     

Mechanisms of action of probiotics: recent advances

The intestinal microbiota plays a fundamental role in maintaining immune homeostasis. In controlled clinical trials probiotic bacteria have demonstrated a benefit in treating gastrointestinal diseases, including infectious diarrhea in children, recurrent Clostridium difficile-induced infection, and some inflammatory bowel diseases. This evidence has led to the proof of principle that probiotic bacteria can be used as a therapeutic strategy to ameliorate human diseases. The precise mechanisms influencing the crosstalk between the microbe and the host remain unclear but there is growing evidence to suggest that the functioning of the immune system at both a systemic and a mucosal level can be modulated by bacteria in the gut. Recent compelling evidence has demonstrated that manipulating the microbiota can influence the host. Several new mechanisms by which probiotics exert their beneficial effects have been identified and it is now clear that significant differences exist between different probiotic bacterial species and strains; organisms need to be selected in a more rational manner to treat disease. Mechanisms contributing to altered immune function in vivo induced by probiotic bacteria may include modulation of the microbiota itself, improved barrier function with consequent reduction in immune exposure to microbiota, and direct effects of bacteria on different epithelial and immune cell types. These effects are discussed with an emphasis on those organisms that have been used to treat human inflammatory bowel diseases in controlled clinical trials.     

Probiotics and chronic disease

In today's climate, changed lifestyles and the increased use of antibiotics are significant factors that affect the preservation of a healthy intestinal microflora. The concept of probiotics is to restore and maintain a microflora advantageous to the human body. Probiotics are found in a number of fermented dairy products, infant formula, and dietary supplements. Basic research on probiotics has suggested several modes of action beneficial for the human body and clinical research has proven its preventive and curative features in different intestinal and extraintestinal diseases. Chronic diseases cause considerable disablement in patients and represent a substantial economic burden on healthcare resources. Research has demonstrated a crucial role of nutrition in the prevention of chronic disease. Thus, positive, strain-specific effects of probiotics have been shown in diarrheal diseases, inflammatory bowel diseases, irritable bowel syndrome, and Helicobacter pylori-induced gastritis, and in atopic diseases and in the prevention of cancer. As the majority of probiotics naturally inhabit the human intestinal microflora, their use has been regarded as very safe. However, in view of the range of potential benefits on health that might be achieved by the use of some probiotic bacteria, major and thorough evaluation is still necessary. In conclusion, probiotics act as an adjuvant in the prevention and treatment of a wide variety of chronic diseases.     

益生菌对肠易激综合征和炎症性肠病的作用

由于胃肠道微生物参与炎症性肠病（inflammatory bowel disease,IBD）的病理过程,而且最近研究表明微生物可能在肠易激综合征（irritable bowel syndrome,IBS）中扮演重要作用.本文重点关注益生菌在这两种疾病中的作用机制和疗效.胃肠道微生物的组成受多种因素调节,包括年龄、饮食和疾病状态.益生菌可能通过影响宿主的微生物菌群和提高黏膜的免疫调节作用发挥疗效.益生菌的口服耐受性较好.许多短期研究表明益生菌在IBS中有效,尽管只是在部分的特殊菌株和某些特定症状中有效.在IBD中,许多临床试验表明大量的益生菌在结肠袋炎和溃疡性结肠炎中有效,而对克罗恩病无明显疗效.显然,益生菌在IBS和IBD的治疗中能起到巨大的作用,但是,这些只是针对特殊的菌株.将来迫切需要进行高质量的临床研究和实验观察益菌对IBD和IBS的疗效.     

A Gastroenterologist's Guide to Probiotics

The enteric microbiota contribute to gastrointestinal health, and their disruption has been associated with many disease states. Some patients consume probiotic products in attempts to manipulate the intestinal microbiota for health benefit. It is important for gastroenterologists to improve their understanding of the mechanisms of probiotics and the evidence that support their use in practice. Clinical trials have assessed the therapeutic effects of probiotic agents for several disorders, including antibiotic- or Clostridium difficile-associated diarrhea, irritable bowel syndrome, and the inflammatory bowel diseases. Although probiotic research is a rapidly evolving field, there are sufficient data to justify a trial of probiotics for treatment or prevention of some of these conditions. However, the capacity of probiotics to modify disease symptoms is likely to be modest and varies among probiotic strains-not all probiotics are right for all diseases. The current review provides condition-specific rationale for using probiotic therapy and literature-based recommendations.     

Probiotics and Iletis

Probiotics have gained tremendous popularity amongst individuals searching for alternative and "natural" means to promote intestinal health. It has been suggested that the probiotic formulation VSL#3 promotes several aspects of intestinal health including attenuation of inflammatory bowel diseases (IBD). Although a definitive mechanism of action has not been clearly identified, it is generally accepted that probiotics suppress development of chronic inflammation by inhibiting activation of various inflammatory signaling pathways. This concept however needs to be revisited in light of a recent publication by Pagnini et al. showing that VSL#3 prevents development of ileitis through activation of NF-kB and production of the prototypical inflammatory cytokine TNFa.     

Probiotics in the management of gastrointestinal disease: analysis of the attitudes and prescribing practices of gastroenterologists and surgeons

OBJECTIVE: Probiotics are increasingly advocated in the management of various gastrointestinal disorders. The aim of this study was to investigate the current attitudes and prescribing practices of surgeons and gastroenterologists for probiotics in the treatment of gastrointestinal disorders. METHODS: A questionnaire was designed to look at the frequency of probiotic prescribing, types of probiotics used, indications for and duration of treatment and clinicians' experiences with probiotic use. A total of 220 questionnaires were mailed to consultant gastroenterologists and surgeons practicing in the UK. RESULTS: The overall response rate was 80.5%, of which 69.5% of respondents said they recommended or prescribed probiotic food supplements to their patients, including 53.4% of surgeons and 80.8% of gastroenterologists (P = 0.00013). The most popular probiotic supplements among surgeons were probiotic‐containing yoghurt and drinks (79.5% and 71.8%, respectively), whereas VSL#3 was more popular with gastroenterologists (83.3%). The most popular indications were irritable bowel syndrome (70.7% of prescribers) and pouchitis (67.5% of prescribers). Many respondents prescribed long‐term probiotics. Most consultants had been prescribing probiotics for a period of 1 to 5 years. CONCLUSION: Probiotics are popular among gastroenterologists and surgeons in the UK for the treatment of gastrointestinal disorders. Further evidence to support their routine use, by way of large, well‐designed randomized controlled trials, is necessary.     

Probiotics: history,definition, requirements and possible therapeutic applications

The ingestion of probiotics is associated with various beneficial effects on human health and modifies the physiological homeostasis of the intestinal flora. Probiotics are microorganisms with some particular characteristics: human origin, safety in human use, bile and acid resistance, survival in the intestine, at least temporary colonization of the human gut, adhesion to the mucosa and bacteriocine production. Thanks to these characteristics, probiotics block the invasion of human intestinal cells by the enteroinvasive bacteria. Furthermore, they should be able to stimulate and modulate the intestinal immune response, and to protect and stabilize the mucosal barrier. Finally, the efficacy of probiotics should be evident and documented with valid studies. All their properties should be maintained during processing and storage. Probiotics are usually used to protect the host from pathogens. With regard to this, they are useful in the prevention of antibiotic and traveler's diarrhea and they may play a role in the management of gastric Helicobacter pylori infection. Furthermore, their efficacy in the treatment of infectious diarrhea, in inflammatory bowel diseases, in pouchitis and in food allergy has been shown. Probiotics can improve the symptoms of irritable bowel syndrome and of lactose malabsorption. Finally, it has been suggested that such microorganisms may play a role in the prevention of carcinogenesis and of tumor growth.     

Probiotics and ileitis: Could augmentation of TNF/NFκB activity be the answer?

Probiotics have gained tremendous popularity amongst individuals searching for alternative and "natural" means to promote intestinal health. It has been suggested that the probiotic formulation VSL#3 promotes several aspects of intestinal health including attenuation of inflammatory bowel diseases (IBD). Although a definitive mechanism of action has not been clearly identified, it is generally accepted that probiotics suppress development of chronic inflammation by inhibiting activation of various inflammatory signaling pathways. This concept however needs to be revisited in light of a recent publication by Pagnini et al. showing that VSL#3 prevents development of ileitis through activation of NFκB and production of the prototypical inflammatory cytokine TNFα.     

Probiotics in the treatment of human inflammatory bowel diseases: update 2008

Probiotic research and clinical trials have been forging ahead over the last decade. Although much has been learnt in relation to probiotic intestinal epithelial-mucosal immune interactions, the evidence for substantial clinical efficacy of probiotics continues to progress much slower. This review outlines the probiotic clinical studies before 2005 that formed the foundation of probiotic clinical trials in inflammatory bowel disease and then examines indepth those inflammatory bowel disease probiotic clinical trials published after 2005 that are leading to new understanding of the role of probiotics in the induction and remission of inflammatory bowel disease in humans.     

Probiotics,irritable bowel syndrome,and inflammatory bowel disease

Opinion statement Probiotics are live, microbial food supplements that benefit the host animal by improving intestinal microbial balance. Their major role in preventing and treating gastrointestinal disease appears to be from their effect on the immune process, protection against abnormal invasive bacteria, and in the production of short-chain fatty acids from starch and non-starch polysaccharides. Probiotic microorganisms are administered in food supplements and yogurts. They are also now sold in the form of capsules and powders. There is great variation in the microorganisms in the various supplements. It is important to understand that all probiotic products are different. Some contain a single organism and others contain multiple organisms. Therapeutic results have been achieved with various probiotics in different diseases. In the treatment of inflammatory bowel diseases (IBD), success has been reported with Escherichia coli Nissle strain in ulcerative colitis, and with a multiple organism product, VSL#3 (VSL Pharmaceuticals, Fort Lauderdale, FL), in Crohn’s disease and pouchitis. Initial reports in irritable bowel syndrome (IBS) have resulted in encouraging results with the use of E. coli Nissle strain, and recently with multiple organism probiotic supplements. However, caution must still apply to the use of probiotics in IBD and IBS because the reports and the number of patients treated are limited.     

Rationale for probiotic treatment strategies in inflammatory bowel disease

Chronic inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are recurrent and aggressive inflammatory disorders that are most likely the result of an overly aggressive immune response to ubiquitous intestinal antigens in a genetically susceptible host. Despite decades of intense research, our knowledge of factors causing IBD remains incomplete and, therefore, conventional therapy to induce and maintain remission works in a symptomatic fashion, merely suppressing the immune response. Probiotic bacteria have long been known to confer health benefits, especially with regard to intestinal disorders. Although there is mounting evidence from in vitro and animal experiments supporting the use of probiotics in IBD, clinical trials have not provided definite evidence for the therapeutic effect of probiotic therapy in IBD to date. This is with the notable exception of pouchitis and the maintenance of remission in ulcerative colitis, whereas Crohn’s disease and active ulcerative colitis do not seem amenable to probiotic intervention. The next 5 years will see more trials targeting specific clinical settings using tailor-made probiotic combinations, taking into account our increasing knowledge of individual probiotic properties and the diversity of these microorganisms.     

Probiotics in inflammatory bowel disease: a critical review

Intestinal bacteria play a key role in inflammatory bowel disease. Probiotics attempt to modify disease by favourably altering bacterial composition, immune status, and inflammation. Until recently, probiotic therapy was considered 'folk' medicine, but there now is emerging interest on the part of the general public and scientific communities in the use of probiotics in human disease. This practical, evidence-based review examines probiotics as therapy for inflammatory bowel disease in humans. There are very few such published randomized clinical trials, but some data exist that possibly show an efficacy of probiotics as maintenance therapy in chronic relapsing pouchitis. Obstacles to providing probiotic therapy include selection of appropriate strains, poorly regulated probiotic quality standardization, processing and human biologic factors which impair probiotic viability, difficulty in maintaining new bacterial populations in the gut, and local product unavailability. Studies have focused on specific inflammatory bowel disease subgroups, limiting general applicability for the practitioner. Basic research highlights the importance of bacteria in these conditions, and the possibility that probiotics will modify physiological parameters. Well-designed, randomized clinical studies are still required to define the role of probiotics as therapeutic agents in inflammatory bowel disease.     

Developmental biology of gut-probiotic interaction

While our current knowledge of probiotic interaction in the developing gut remains poorly understood, emerging science is providing greater biological insight into their mechanism of action and therapeutic potential for human disease. Given their beneficial effects, probiotics remain promising agents in neonatal gastrointestinal disorders. Probiotics may restore or supply essential bacterial strains needed for gut maturation and homeostasis, particularly in hosts where this process has been disrupted. Here we highlight the unique characteristics of developing intestinal epithelia with a focus on gut development and colonization as well as the inflammatory propensity of immature epithelia. Additionally, we review potential mechanisms of beneficial probiotic interaction with immature intestinal epithelia including immunomodulation, upregulation of cytoprotective genes, prevention and regulation of apoptosis, and maintenance of barrier function. Improved knowledge of gut-probiotic interaction in developing epithelia will allow for a better understanding of how probiotics exert their beneficial effects and help guide their therapeutic use.     

Cyclopropane fatty acid synthase mutants of probiotic human-derived Lactobacillus reuteri are defective in TNF inhibition

Probiotics are live microorganisms that confer health benefits to the host when administered in adequate amounts. Many probiotic strains are now marketed to consumers and include organisms such as lactobacilli, streptococci, bifidobacteria, Escherichia coli Nissle 1917, and the yeast Saccharomyces cerevisiae strain, “Saccharomyces boulardii”. In general, probiotics are considered safe for human consumption based on previous clinical trials, epidemiological studies, and historical usage in fermented foods. A subset of these probiotics have been derived from commensal bacteria indigenous to Homo sapiens. One such indigenous Lactobacillus species, Lactobacillus reuteri, includes a variety of strains derived from human breast milk and the gastrointestinal tract. The mechanisms by which commensal-derived probiotics promote health and combat diseases are poorly understood. Possible mechanisms include improving nutrient absorption, pathogen exclusion, strengthening intestinal barrier function and regulation of the immune system. A better understanding of how probiotics influence health is critical to fully optimize the integrative physiology of commensal microbial communities and mammalian hosts.     

Developmental biology of gut-probiotic interaction

While our current knowledge of probiotic interaction in the developing gut remains poorly understood, emerging science is providing greater biological insight into their mechanism of action and therapeutic potential for human disease. Given their beneficial effects, probiotics remain promising agents in neonatal gastrointestinal disorders. Probiotics may restore or supply essential bacterial strains needed for gut maturation and homeostasis, particularly in hosts where this process has been disrupted. Here we highlight the unique characteristics of developing intestinal epithelia with a focus on gut development and colonization as well as the inflammatory propensity of immature epithelia. Additionally, we review potential mechanisms of beneficial probiotic interaction with immature intestinal epithelia including immunomodulation, upregulation of cytoprotective genes, prevention and regulation of apoptosis and maintenance of barrier function. Improved knowledge of gut-probiotic interaction in developing epithelia will allow for a better understanding of how probiotics exert their beneficial effects and help guide their therapeutic use.