Irritable bowel syndrome and probiotics: from rationale to clinical use Elena F. Verdu and Stephen M. Collins Purpose of review Introduction Few therapies are of proven efficacy in irritable bowel In this review we discuss the gut-driven pathophysiologic syndrome. Thus, there is great interest in the development pathways involved in gut dysfunction and symptom gen- of a natural therapy that can be both safe and effective. An eration in irritable bowel syndrome (IBS), including immune understanding that probiotics are heterogeneous, with activation, dysmotility, altered mucosal barrier function, multiple targets and mechanisms of action, is fundamental and visceral perception. This allows us to logically review to the development of clinical trials. the possible targets of probiotic therapy in IBS. Finally, we Recent findings evaluate the relevant clinical trials published to date on A bidirectional model for the pathogenesis of irritable bowel probiotics and IBS. syndrome is proposed in which gut-driven and brain-driven mechanisms contribute to the genesis of gut dysfunction and symptoms. In-vitro and animal studies have generated Gut dysfunction in irritable bowel syndrome most of the mechanistic rationale for the use of probiotics The current goal of treatment in IBS is to alleviate symp- in functional bowel disorders. A MEDLINE search of toms and improve quality of life. The gut-driven patho- publications from 1989 to date revealed only eight physiologic mechanisms believed to be involved in the placebo-controlled clinical trials on the subject of origin or maintenance of IBS symptoms include intestinal probiotics and irritable bowel syndrome. All these studies infection and immune activation, dysmotility, abnormal • suffer from methodologic problems. By contrast, fermentation, and visceral hypersensitivity [1–4,5 ,6–10]. numerous reviews have been published in the past 2 years Therapeutic approaches targeting some of these mecha- on this subject. nisms have been developed and used with varied clinical Summary efficacy [11]. Animal research will continue to identify novel targets and elucidate the mechanisms of action of probiotics, thus Increased intestinal permeability and abnormal central providing a rational basis for their use in irritable bowel processing of peripheral stimuli have also been proposed syndrome. The notion of treating irritable bowel syndrome as possible mechanisms leading to or exacerbating IBS with probiotics is particularly attractive to patients and symptoms [12]. Changes in gut permeability have been generates great interest, although clinical evidence is not demonstrated in postinfective IBS (PI-IBS), but this has yet sufficient to enable clear guidelines to be designed. not been proved in the unselected IBS population [2]. Large, well-designed, controlled clinical trials using specific probiotics are warranted. It is the opinion of the authors that low-grade inflamma- tion is the basis for gut dysfunction in a proportion of Keywords patients with IBS. A recent study has shown that Bifido- functional bowel disorders, gut dysfunction, irritable bowel bacterium infantis 35634 improved systemic cytokine abnor- •• syndrome, probiotics malities and normalized symptoms in IBS patients [13 ]. This raises the possibility that specific probiotics may Curr Opin Gastroenterol 21:697——701. ª 2005 Lippincott Williams & Wilkins. modify the natural history of IBS. Intestinal Disease Research Programme, McMaster University, Hamilton, Ontario, Canada Immune activation in irritable bowel syndrome Correspondence to Elena F Verdu, 1200 Main Street West, McMaster University, Hamilton, Ontario, Canada Infectious gastroenteritis is the most significant environ- Tel: 905 525 9140 x22212; fax: 905 521 3454; e-mail: [email protected] mental risk factor identified to date for the development Current Opinion in Gastroenterology 2005, 21:697——701 of IBS [1]. IBS symptoms have been reported to develop Abbreviations in a significant proportion of individuals with documented Campylobacter, Salmonella, Escherichia coli, and Shigella infec- IBS irritable bowel syndrome PI-IBS postinfective irritable bowel syndrome tion as well as viral infection [2,14–16]. Evidence of immune activation is not restricted to patients with ª 2005 Lippincott Williams & Wilkins. PI-IBS, and it has also been reported in a proportion of 0267-1379 unselected IBS patients with no history of gastroenteritis [2–4,5•,17]. 697 698 Immunology There is evidence for an imbalance in the genetic regula- in children with atopic dermatitis [27]. Other studies, tion of counterinflammatory cytokine secretion in patients however, using a variety of probiotic species in critically with IBS [18]. This may promote a defective downregu- ill patients, failed to demonstrate improvement in intes- lation of immune responses to normal inflammatory stim- tinal permeability despite favorable changes in the uli in IBS. A recent study by Van Der Veek et al. [19] systemic inflammatory response and the microbial compo- demonstrated changes in the genetic control of cytokines sition of the gastrointestinal tract [28,29]. The identifi- that play a critical role in regulating inflammation in the cation of subgroups of IBS patients in whom barrier gut. The combination of genotypes encoding for high dysfunction underlies symptom generation should be a tumor necrosis factor-a secretion, a proinflammatory cyto- prior logical step to the application of probiotic therapy kine, and low interleukin-10 secretion, a counterregula- to target barrier dysfunction. tory cytokine, was significantly more prevalent in IBS patients than in control individuals. Phenotypic evidence Dysmotility is considered to underlie altered bowel habit, demonstrating a lower ration of interleukin-10 to tumor whichisacommonsymptominIBSpatients.Until necrosis factor-a in IBS patients has recently confirmed recently, the neuromuscular apparatus was not considered these earlier genotypic studies [13••]. as a possible target for probiotic therapy, presumably because of its distance from the lumen. Of five different Putative mechanisms of action of probiotics probiotic species tested, only L. paracasei was able to sig- in irritable bowel syndrome nificantly attenuate muscle dysfunction in the model of Inflammatory bowel syndrome is heterogeneous both in Trichinella spiralis-induced IBS. The beneficial effect was its clinical presentation and in its pathogenesis. No treat- observed even when the probiotic was administered long ment to date has been proved to be substantially effective, after resolution of the initial infection [25]. L. paracasei although a recent study by O’Mahony et al. [13••]is significantly improved postinfective dysmotility in vivo, encouraging. Probiotics may target one or more patho- as assessed by video fluoroscopy and image analysis. Oral physiologic pathways in IBS, and specific probiotics with administration of spent culture medium from L. paracasei, more than one mechanism of action may prove to be an devoid of live bacteria, also improved postinfective dysmo- attractive ‘natural’ approach compared with conventional tility [30]. Taken together, these studies demonstrate that drug therapy for patients with IBS. Eventually, combina- specific probiotics may target the neuromuscular appara- tions of specific strains carefully selected on the basis of tus and improve muscle function in PI-IBS. documented targets in the gastrointestinal tract may pro- vide the best therapeutic approach. Bloating and abdominal distension is commonly present in patients with IBS. Dysmotility and consequently diffi- A recent metaanalysis has shown that probiotic therapy culty in propelling gas may underlie these symptoms. King reduces the duration of infectious diarrhea in children et al. [31] have shown a greater gas production in IBS [20]. This is particularly relevant to PI-IBS, in which a patients than in control individuals, which suggests that shorter duration of the initial gastroenteritis episode or abnormal fermentation may be responsible for bloating prevention of colonization by pathogens may reduce the in some IBS patients. Probiotics aimed at reducing abnor- risk for the subsequent development of IBS [21,22]. mal fermentation may be useful only in those patients in whom abnormal fermentation due to altered flora can be Numerous studies have demonstrated antiinflammatory documented [32]. effects of probiotics in animal models of inflammatory bowel disease [23,24]. We have shown in a murine model Pain is a cardinal symptom in IBS, and visceral hypersen- of PI-IBS that Lactobacillus paracasei NCC2461 attenuates sitivity is believed to underlie this symptom. There is postinfective muscle contractility, in part through modu- some evidence that specific probiotics may modulate neu- lation of the inflammatory response to infection [25•]. rotransmission in the gut. The administration of Saccaro- Recently, L. salivarius UCC4331 and B. infantis 35624 myces boulardii to pigs has been shown to modulate the have been shown to reduce an abnormal systemic ratio of expression of neuronal markers in the submucous plexus interleukin-10 to interleukin-12 in patients with IBS [13••]. [33]. L. farciminis has been shown to attenuate visceral hypersensitivity in rats [26]. We have found that the Lactobacillus farciminis was shown to enhance barrier func- administration of L. paracasei NCC2461 attenuates the vis- tion and prevent bacterial translocation in trinitrobenzene ceral hypersensitivity and sensory neurotransmitter expres-