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.     

Probiotics and gastrointestinal diseases

There is increasing evidence indicating health benefits by consumption of foods containing microorganisms, i.e. probiotics. A number of clinical trials have been performed to evaluate the effects in the prevention and treatment of gastrointestinal diseases caused by pathogenic microorganisms or by disturbances in the normal microflora. Gastrointestinal infections caused by Helicobacter pylori, traveller's diarrhoea, rotavirus diarrhoea, antibiotic-associated diarrhoea (AAD) and Clostridium difficile-induced diarrhoea are conditions that have been studied. There are also studies performed on the preventive effect of probiotics on radiation-induced diarrhoea and diarrhoea in tube-fed patients. Inflammatory bowel disease and irritable bowel syndrome, two idiopathic conditions where alterations in the normal microflora have been implicated as responsible for initiation, are two further areas where the use of probiotics has been regarded as promising. The results from clinical studies have not been conclusive in that the effects of probiotics have been strain-dependent and different study designs have been used. Treatment of acute diarrhoea in children and prevention of AAD are the two most justified areas for the application of probiotics.     

Gut microbiota and inflammatory bowel disease

Bacteria play an important role in the pathogenesis of inflammatory bowel disease (IBD), its complications and its symptoms. Antibiotics can decrease tissue invasion and eliminate aggressive bacterial species. They are used in IBD to treat infective complications and for altering bacterial flora, which may result in specific anti-inflammatory effects. In addition, suppression of bacterial metabolic activities or direct effects of antibiotics on intestinal structures and functions may result in symptoms which cannot be differentiated from symptoms caused by inflammation. Although current clinical trials do not fulfill criteria of evidence-based treatment, a few placebo- or standard treatment-controlled studies suggest that metronidazole and ciprofloxacin are effective in Crohn's colitis and ileocolitis, perianal fistulae and pouchitis. Administration of probiotics, prebiotics and synbiotics can restore a predominance of beneficial species. However, beneficial effects of probiotics in IBD are modest, strain-specific and limited to certain manifestations of disease and duration of use of the probiotic. For probiotics there is reasonable evidence of efficacy in relapse prevention in chronic pouchitis and ulcerative colitis, and suggestive evidence for postoperative prevention in pouchitis. Therapeutic manipulation of the intestinal flora offers considerable promise for treating IBD, but must be supported by large controlled therapeutic trials before widespread clinical acceptance. These agents may become a component of treating IBD in combination with traditional anti-inflammatory and immunosuppressive agents. Probiotic strategies, based on metagenomic or metabonomic analyses, and new classes of probiotics might play an important role in the future management of IBD.     

Current level of consensus on probiotic science--report of an expert meeting--London, 23 November 2009

The present paper summarizes the consensus views of a group of 9 European clinicians and scientists on the current state of scientific knowledge on probiotics, covering those areas where there is substantial evidence for beneficial effects and those where the evidence base is poor or inconsistent. There was general agreement that probiotic effects were species and often strain specific. The experts agreed that some probiotics were effective in reducing the incidence and duration of rotavirus diarrhoea in infants, antibiotic-associated diarrhoea in adults and, for certain probiotics, Clostridium difficile infections. Some probiotics are associated with symptomatic improvements in irritable bowel syndrome and alleviation of digestive discomfort. Probiotics can reduce the frequency and severity of necrotizing enterocolitis in premature infants and have been shown to regulate intestinal immunity. Several other clinical effects of probiotics, including their role in inflammatory bowel disease, atopic dermatitis, respiratory or genito-urinary infections or H.pylori adjuvant treatment were thought promising but inconsistent.     

Current level of consensus on probiotic science-Report of an expert meeting- London, 23 November 2009

The present paper summarizes the consensus views of a group of 9 European clinicians and scientists on the current state of scientific knowledge on probiotics, covering those areas where there is substantial evidence for beneficial effects and those where the evidence base is poor or inconsistent. There was general agreement that probiotic effects were species and often strain specific. The experts agreed that some probiotics were effective in reducing the incidence and duration of rotavirus diarrhoea in infants, antibiotic-associated diarrhoea in adults and, for certain probiotics, Clostridium difficile infections. Some probiotics are associated with symptomatic improvements in irritable bowel syndrome and alleviation of digestive discomfort. Probiotics can reduce the frequency and severity of necrotizing enterocolitis in premature infants and have been shown to regulate intestinal immunity. Several other clinical effects of probiotics, including their role in inflammatory bowel disease, atopic dermatitis, respiratory or genito-urinary infections or H.pylori adjuvant treatment were thought promising but inconsistent.     

Probiotics for the Treatment of Inflammatory Bowel Disease

Probiotics are organisms which provide a desired and beneficial effect on human health. With recent evidence implicating a disruption in the balance of the gastrointestinal microbiome and intestinal immunity as a potential trigger for inflammatory bowel disease (IBD), there has been growing interest in using probiotics as an adjunct to standard anti-inflammatory and immune suppressing therapy. Animal models describe potential and plausible mechanisms of action for probiotics to counter inflammation of colonic mucosa. Although there are insufficient data to recommend probiotics in ulcerative colitis or Crohn's disease, good evidence supports the use of specific probiotics for maintenance of remission in pouchitis. Although there are limited regulatory standards for the agents, probiotics are relatively safe with minimal reported side effects or contraindications. More rigorous studies need to be published supporting efficacy and safety of these agents before they become a mainstay of IBD medical treatment.     

Probiotics, antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in humans

Probiotics are living organisms which, when ingested, have a beneficial therapeutic effect. Examples are bacteria, especially Lactobacillus rhamnosus GG, and the yeast Saccharomyces boulardii. Controlled trials indicate a benefit of both of these in the prevention of antibiotic-associated diarrhoea. Other less effective probiotics are Lactinex, Enterococcus faecium and bifidobacteria. In the difficult clinical problem of recurrent Clostridium difficile disease, S. boulardii as an adjunct to antibiotics has shown benefit in controlled trials. There is, however, less convincing evidence for the efficacy of Lactobacillus GG in this disease. Additional controlled trials and safety studies are needed before there can be a widespread endorsement of probiotics for these two conditions.     

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.     

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 to enhance anti-infective defences in the gastrointestinal tract

Several clinical studies have demonstrated the therapeutic and/or prophylactic efficacy of specific probiotics against acute viral gastroenteritis and antibiotic-associated diarrhoea (including Clostridium difficile infection). Emerging evidence also suggests beneficial effects against Helicobacter pylori infection. The evidence of efficacy against traveller's diarrhoea remains, however, inconclusive. The precise mechanisms by which probiotics potentiate host gastrointestinal defences and mediate protection are not fully known. There is evidence to suggest, however, that probiotics might contribute to host defence by reinforcing non-immunological defences and stimulating both specific and non-specific host immune responses. Little is known about the relative importance of the probiotic-stimulated mechanisms in host protection. This review summarises the evidence for the anti-infective effects of probiotics and discusses the effect of orally delivered probiotics on non-immunological and immunological defence mechanisms in the host, especially in the gastrointestinal tract.     

Probiotic drug therapy with E. coli strain Nissle 1917 (EcN): results of a prospective study of the records of 3,807 patients

INTRODUCTION: Living microorganisms that enter the gut in an active state and exert a positive influence on the host are called probiotics. Numerous experimental and clinical studies were performed recently and confirm both the efficacy and modes of action of probiotic drugs. PATIENTS AND METHODS: In a post-marketing-surveillance study with the probiotic Escherichia Coli strain Nissle 1917 (EcN) data on the range of indications as well as on efficacy and tolerance were gathered prospectively in 446 centres. The intended treatment duration was limited to a maximum of 12 weeks. RESULTS: EcN was used in 3,807 patients with more than 20 different indications, n = 3,511 of whom had gastrointestinal complaints: Among others, 1,067 patients presented with chronically recurring (n = 728) or protracted diarrhoea (n = 339), 415 with inflammatory bowel disease, 679 with irritable bowel syndrome, and 253 with chronic constipation. The overall efficacy was assessed as good to very good by an average of 81.4 % of the therapists. The stool frequency and consistency as well as the symptoms of meteorism and abdominal pain were improved in very many patients. Suspected cases of side effects were documented in only 2.8 % of the patients. CONCLUSION: EcN is frequently used in practice for the treatment of various, mostly gastrointestinal, complaints and is well tolerated.     

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.     

Antibiotics and probiotics in treatment of inflammatory bowel disease

Many experimental and clinical observations suggest that intestinal microflora plays a potential role in the pathogenesis of inflammatory bowel disease (IBD). Manipulation of the luminal content using antibiotics or probiotics represents a potentially effective therapeutic option. The available studies do not support the use of antibiotics in ulcerative colitis (UC). Antibiotics are effective in treating septic complications of Crohn's disease (CD) but their use as a primary therapy is more controversial, although this approach is frequently and successfully adopted in clinical practice. There is evidence that probiotic therapy may be effective in the prevention and treatment of mild to moderate UC. In contrast, a lack of successful study data at present precludes the widespread use of probiotics in the treatment of CD. Both antibiotics and probiotics appear to play a beneficial role in the treatment and prevention of pouchitis and further trials are warranted to fully quantify their clinical efficacy.     

Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics

Crohn's disease, ulcerative colitis, and pouchitis are caused by overly aggressive immune responses to a subset of commensal (nonpathogenic) enteric bacteria in genetically predisposed individuals. Clinical and experimental studies suggest that the relative balance of aggressive and protective bacterial species is altered in these disorders. Antibiotics can selectively decrease tissue invasion and eliminate aggressive bacterial species or globally decrease luminal and mucosal bacterial concentrations, depending on their spectrum of activity. Alternatively, administration of beneficial bacterial species (probiotics), poorly absorbed dietary oligosaccharides (prebiotics), or combined probiotics and prebiotics (synbiotics) can restore a predominance of beneficial Lactobacillus and Bifidobacterium species. Current clinical trials do not fulfill evidence-based criteria for using these agents in inflammatory bowel diseases (IBD), but multiple nonrigorous studies and widespread clinical experience suggest that metronidazole and/or ciprofloxacin can treat Crohn's colitis and ileocolitis (but not isolated ileal disease), perianal fistulae and pouchitis, whereas selected probiotic preparations prevent relapse of quiescent ulcerative colitis and relapsing pouchitis. These physiologic approaches offer considerable promise for treating IBD, but must be supported by rigorous controlled therapeutic trials that consider clinical disease before their widespread clinical acceptance. These agents likely will become an integral component of treating IBD in combination with traditional anti-inflammatory and immunosuppressive agents.     

Are probiotics a feasible intervention for prevention of diarrhoea in the developing world?

With more than 1.4 million of the 9 million child deaths being attributed to diarrhoea in 2008 and 49% of them occurring in five countries namely, India, Nigeria, Democratic Republic of the Congo, Pakistan and China, there is an urgent need for intervention to prevent and control diarrhoeal diseases. Of the various interventions, probiotics offer immense potential. The past decade has witnessed the validation of their utility for the prevention, treatment and management of a variety of infective and non infective disorders. The most investigated field continues to remain infectious diarrhoea and compelling evidence comes from randomized placebo controlled trials. While results from these studies are encouraging most of them reflect the outcomes of the developed world. Developing countries like India continue to struggle with nutritional and health challenges and bear the greatest burden of diarrhoea. A paucity of data from the developing countries limits the definite recommendation of probiotics. In these countries curd, often confused for a probiotic, is practiced as an integral part of the culture. While the nutritional benefits of these products cannot be understated, it is still uncertain whether these products can be classified as a probiotic. The emergence of probiotic foods which are scientifically validated for their efficacy and impart defined health benefits offer an excellent opportunity to improve public health. A recent randomized controlled trial conducted by the National Institute of Cholera and Enteric Diseases in Kolkata, India demonstrated a protective efficacy of 14% in preventing diarrhoea among children who received a probiotic. For the developing world however the vision for probiotics would mean a fundamental change in perception and developing a well planned strategy to allow interventions like probiotics to permeate to impoverished settings, where the assault of micro organisms is on a daily basis. This would mean that probiotics are ingrained into the public health system without being seen as a medicine.     

The role of endogenous bacterial flora: bystander or the necessary prerequisite?

Abundant experimental and clinical data incriminate microbial factors in the pathogenesis of inflammatory bowel diseases. Commensal bacteria, and their products, provide the constant antigenic stimulus to disequilibrate the mucosal immune system towards an overly aggressive response in a genetically susceptible host with reduced tolerance towards the autologous flora. Not all bacteria have equal proinflammatory capabilities. Some may be even beneficial as demonstrated by the anti-inflammatory effects of so-called probiotics. Further investigations are needed to translate the clear experimental and clinical evidence into benefit for the patients.     

What is the evidence for the use of probiotics in functional disorders?

A rationale for the use of probiotics for a number of functional gastrointestinal symptoms and syndromes can be developed, and an experimental basis for their use continues to emerge, but data from well-conducted clinical trials of probiotics in this area remain scarce. Irritable bowel syndrome (IBS) has attracted the most attention; recent revelations regarding the potential pathogenic roles of the enteric flora and immune activation have led to reawakened interest in bacteriotherapy for this common and challenging disorder. Some recent randomized, controlled studies attest to the efficacy of some probiotics in alleviating individual IBS symptoms, and selected strains have a more global impact. Evidence for long-term efficacy is also beginning to emerge, though more studies are needed in this regard. In other functional syndromes, data are far from adequate to make recommendations, but there is evidence for efficacy of probiotics in treating individual symptoms such as diarrhea, constipation, and bloating. The interpretation of much of the literature in this area is complicated by lack of quality control, use of many different species and strains, and, above all, significant deficiencies in trial methodology.     

Bugs and irritable bowel syndrome: The good,the bad and the ugly

Recently, there has been strong interest in the therapeutic potential of probiotics for irritable bowel syndrome (IBS). At the same time, there is a rapidly growing body of evidence to support an etiological role for gastrointestinal infection and the associated immune activation in the development of post‐infectious IBS. In a more controversial area, small intestinal bacterial overgrowth has been associated with a subset of patients with IBS; the issue of whether it is appropriate to treat a subset of IBS patients with antibiotics and probiotics is currently a matter for debate. Thus, it appears that the gastrointestinal microbial flora may exert beneficial effects for symptoms of IBS under some circumstances, while in other situations gut microbes could give rise to symptoms of IBS. How do we make sense of the apparently diverse roles that ‘bugs’ may play in IBS? To address this question, we have conducted an in‐depth review, attempting where possible to draw lessons from Asian studies.     

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.     

Etiology and pathophysiology of inflammatory bowel disease--environmental factors

Environmental factors play an important role in the pathophysiology of inflammatory bowel disease. There is a strong and consistent association between smoking and Crohn's disease, and between nonsmoking and ulcerative colitis. Despite extensive research, the exact pathophysiological mechanisms for these associations remain unclear. In spite of this, some clinical trials with nicotine-patches showed beneficial effects for the treatment of ulcerative colitis. Associations of Crohn's disease and ulcerative colitis with other environmental factors are weaker like the association with use of oral contraceptives or those less well investigated such as the association with childhood hygiene. Most studies suggesting a potential pathogenetic role of Mycobacterium paratuberculosis or an effect of tuberculostatic therapy in Crohn's disease could not be reproduced by others. Perinatal or childhood infections by viruses like measles are heavily debated, but not proven to be causal for inflammatory bowel disease. Coagulation disorders have been described as protecting from inflammatory bowel disease, suggesting hypercoagulability to be a pathogenetic factor. Some studies described that appendectomy may prevent the onset of ulcerative colitis in man and mice. Other environmental factors such as hydrogen sulfide, tonsillectomy, diet, blood transfusions, and Listeria also require confirmation. There are, however, convincing data from genetic animal models and twin studies that environmental factors as the intestinal bacterial flora interact with susceptible hosts to cause inflammatory bowel disease. Inflammatory bowel diseases have multifactorial etiologies, which require a differentiated approach for treatment and prevention.