Mechanisms of action of probiotics in intestinal diseases. ScientificWorldJournal 7:31–46

Abstract

Intestinal microbiota is a positive health asset that exerts a conditioning effect on intestinal homeostasis. Resident bacteria deliver regulatory signals to the epithelium and instruct mucosal immune responses. Recent research has revealed a potential therapeutic role for the manipulation of the microbiota and exploitation of host-microbial signalling pathways in the maintenance of human health and treatment of various mucosal disorders. A variety of pharmabiotic strategies, such as the use of specific members of the microbiota, their surface components, or metabolites, as well as genetically modified commensal bacteria, are being investigated for their ability to enhance the beneficial components of the microbiota. It is clear that engagement with host cells is central to pharmabiotic action, and several strain-specific mechanisms of action have been elucidated. However, the molecular details underpinning these mechanisms remain almost entirely unknown. Understanding how pharmabiotics exert their beneficial effects is critical for the establishment of definitive selection criteria for certain pharmabiotic strategies for specific clinical conditions. Scientifically accredited evidence of efficacy and studies to elucidate the molecular mechanisms of host-microbiota interactions are needed to lend credence to the use of pharmabiotic strategies in clinical medicine. KEYWORDS: commensal bacteria, enteric infection, inflammation, inflammatory bowel disease, intestinal epithelium, microbiota, pharmabiotic, probiotic INTRODUCTION The human gastrointestinal tract harbours a diverse bacterial community that comprises more than 1000 different species, and outnumbers human somatic and germ cells tenfold Under normal circumstances, commensal bacteria are an essential health asset that exert a conditioning and protective influence on intestinal structure and homeostasis. Intestinal bacteria protect against infection, and actively exchange developmental and regulatory signals with the host that prime and instruct mucosal immunity PROBIOTICS AS A THERAPEUTIC STRATEGY At the turn of the last century, the use of "friendly" microbes present in fermented foods for the purpose of health maintenance and disease prevention was first proposed by Metchnikoff Criteria for designating a commensal strain as a probiotic include human origin; acid and bile resistance; survival of gastrointestinal transit; nonpathogenic, production of antimicrobial substances; and immune modulatory activity By definition, probiotics have a high safety profile and the tolerance is usually excellent. Although many of the commercial probiotic products have been officially designated as "generally regarded as safe", some reports of infections probably caused by probiotics have been published 33 THE EVIDENCE FOR PROBIOTIC EFFICACY Probiotic bacteria have demonstrated health-promoting effects in intervention studies in several clinical conditions. The best evidence for probiotics in any condition is in the treatment and prevention of enteric infections and postantibiotic syndromes. Several meta-analyses studies have established probiotic efficacy in acute infectious diarrhoea and the prevention of antibiotic-associated diarrhoea Necrotising enterocolitis is a severe gastrointestinal inflammatory disease that is a common cause of morbidity among premature, low-birth-weight infants. Factors contributing to its pathogenesis include naïve intestinal and immune function, enteral feeding, and gas-producing bacteria. In a number of studies, probiotics have been shown to reduce the incidence and severity of necrotising enterocolitis by contributing to the establishment of a natural, rather than an abnormal, microbiota Irritable bowel syndrome is a common functional bowel disorder and a role of probiotics in its treatment is promising. The administration of B. infantis 35624, but not lactobacilli, has been shown to improve the symptom profile of patients with irritable bowel syndrome [31,32]. In patients with pouchitis, a nonspecific inflammation of the ileal reservoir, probiotic bacteria have demonstrated efficacy in maintaining remission in chronic pouchitis or preventing the development of pouchitis in the first place [33,34,35]. Nevertheless, the wider open clinical experience with probiotics in pouchitis patients is inconsistent and may be related to variability in patient populations or the choice of probiotic preparation. Ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease, are chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract. In ulcerative colitis, E. coli Nissle 1917, L. rhamnosus GG, and VSL#3 have shown efficacy similar to the drug mesalazine in maintaining remission [36,37,38]. Probiotics have induced remission of acute ulcerative colitis also [38,39]. However, in a randomised, double-blind, placebo-controlled trial, B. infantis 35624 and L. salivarius subspecies salivarius UCC118, probiotics that have attenuated disease severity in animal models of colitis, did not demonstrate efficacy in the maintenance of steroid-induced remission of ulcerative colitis [40]. The differences in efficacy between animal and human inflammatory bowel disease may reflect the timing of administration, differences in disease severity, or effective probiotic dose/body weight. Saccharomyces boulardii and E. coli Nissle 1917 have been effective in the maintenance of remission in patients with Crohn's disease [41,42]. However, controlled studies of probiotics in Crohn's disease did not find efficacy for L. rhamnosus GG or L. johnsonii LA1 as maintenance therapies for Crohn's disease [43,44]. Larger, well-powered, randomised control trials are needed to determine conclusively whether there is a role for certain strains of probiotics or probiotic combinations in Crohn's disease. There is evidence to suggest that the gastric colonisation and activity of Helicobacter pylori can be inhibited by probiotics. Probiotics do not eliminate the pathogen, but suppress its growth and reduce gastric inflammation [45,46]. In patients with severe acute pancreatitis, L. plantarum 299v was protective against pancreatic sepsis [47]. The consumption of probiotics has been linked to the improvement of high cholesterol and lactose intolerance, and the potential therapeutic use of probiotics in the prevention and treatment of human malignancy, atopic/allergic diseases, and rheumatoid arthritis are additional areas of potential application [48,49,50]. TheScientificWorldJOURNAL (2007) 7, 31-46 O'Hara and Shanahan: Mechanisms of Action of Probiotics 34 MECHANISMS OF PROBIOTIC ACTION Experimental models have revealed that probiotics differ greatly in their mechanism of action; any singular mechanism is unlikely to account for all of their clinical effects. Significant differences exist, not only between probiotic species, but also between certain strains. In addition to specific interactions between probiotic bacteria and host immune cells, microbe-microbe interactions confound the complexity of the signalling network in vivo. Such complex interactions probably account for the versatility of probiotic action and could explain some of the varying results observed within the different clinical trials. Understanding the various mechanisms of probiotic action is crucial for the establishment of definitive selection criteria for certain strains or combination of strains for specific clinical conditions. Although the molecular details of probiotic mechanisms remain unresolved, numerous studies have indicated that the beneficial effects of probiotics may be either direct or indirect through modification of the local microbiota, epithelial barrier function, intestinal inflammation, or the immune system O'Hara and Shanahan: Mechanisms of Action of Probiotics 35 Competitive Exclusion Along the Epithelium The intestinal epithelium is an important barrier that restricts the penetration of luminal antigens and microbes. Interaction between bacterial antigens and host cell receptors is a crucial step in the pathogenesis of many intestinal diseases. Preventing such interactions thus represents a potential therapeutic strategy. Several probiotic bacteria including bifidobacteria and lactobacilli adhere to mucosal tissue in a strainspecific manner [51,52, Genomics-based homology searches have led to the identification of several adhesion factors in probiotic bacteria In rotavirus infection, L. casei DN-114001 has been shown to use soluble probiotic-derived factors to modify the glycosylation state of epithelial cell receptors Modification of the Local Microenvironment Studies using in vivo expression screening technology have identified a variety of probiotic genes that are induced in the murine gastrointestinal tract The effects of the administration of probiotic bacteria on the indigenous mucosa-related microenvironment are poorly understood. Nevertheless, a number of recent studies demonstrate that probiotics play a role in the restoration or maintenance of a protective intestinal microbiota. In patients with pouchitis, VSL#3 therapy increased the diversity of the bacterial community, especially the anaerobic members, whereas the diversity of the fungal flora was repressed O'Hara and Shanahan: Mechanisms of Action of Probiotics 36 Enhancement of Epithelial Barrier Function Alterations in epithelial transport and barrier functions are a common consequence of a variety of intestinal disorders including enteric infections. Defects in epithelial barrier function may also precede the onset of inflammation in patients with inflammatory bowel disease Several probiotic bacteria have been shown to preserve epithelial barrier function and prevent and repair mucosal damage triggered by food antigens, drugs (such as aspirin), enteric pathogens, and proinflammatory cytokines Suppression of Intestinal Inflammation Intestinal epithelial cells sense danger signals wit