Probiotics in the Management of Irritable Bowel Syndrome and Inflammatory Bowel Disease

Kevin Whelan; Eamonn M.M. Quigley

Disclosures

Curr Opin Gastroenterol. 2013;29(2):184-189. 

In This Article

Irritable Bowel Syndrome

IBS is characterized by abdominal pain, bloating and change in stool frequency/consistency in the absence of an organic cause. It is a problematic disorder resulting in impaired quality of life, and with prevalence between 10 and 20% in developed countries, there are considerable economic consequences through increased absenteeism and utilization of healthcare services.

The pathogenesis of IBS is multifactorial, including roles for genetics, abnormal pain processing, behavioural pathways and the gastrointestinal microbiota.[15] Regarding the microbiota, a large case–control study[16] demonstrated that infectious gastroenteritis resulted in almost a four-fold increase in the odds of developing IBS within the subsequent 2 years (odds ratio 3.7). Meanwhile, numerous studies report a luminal dysbiosis in IBS, with many showing that patients have lower lactobacilli and bifidobacteria, the genera frequently used in probiotic products.[17] However, more studies are now investigating the mucosal microbiota in IBS, with recent evidence of lower bifidobacteria in diarrhoea-predominant IBS patients than in controls, together with a negative correlation between mucosal bifidobacteria and the number of days patients experienced pain or discomfort.[18] With all such studies, identifying whether alterations in microbiota are primary events that lead to the development of IBS or merely secondary effects of the syndrome is difficult to determine.

There is also increasing evidence of low-grade mucosal inflammation in IBS. Toll-like receptors (TLRs), the pattern recognition receptors that regulate microbial tolerance, are disregulated with increased TLR-4 and TLR-5 expression and decreased TLR-7 and TLR-8 expression compared with controls.[19]

A recent Rome Foundation group report identified 28 RCTs of probiotics in adults with IBS and four RCTs in children.[17] This report provides considerable details of these older RCTs that are not the focus of the current review. Furthermore, at least six systematic reviews (five of which included meta-analysis) have been published on probiotics in IBS.[20] The six systematic reviews included RCTs in children only,[21] adults only[22–24] and children or adults.[25,26]

Most of the meta-analyses indicated a beneficial impact of probiotics on global symptoms, abdominal pain and flatulence, whereas the impact on bloating was equivocal. However, aggregating the effects of different probiotics into a meta-analysis should be undertaken with caution. Different probiotics have different microbiological characteristics that will inevitably impact on their efficacy. Therefore, converting the findings from meta-analyses into clinical guidelines (e.g. 'probiotics improve global symptoms of IBS') implies that all probiotics will result in a similar benefit, which may not be the case. Recent guidelines have therefore made strain-specific recommendations, including limited weak evidence for Bifidobacteria lactis DN 173010 in improving overall symptoms, abdominal pain and urgency in constipation-predominant IBS and limited weak evidence for VSL#3 (a probiotic mixture containing eight different strains) in reducing flatulence in IBS.[27] Although these are guidelines from the UK focusing only on UK available probiotics, these highlight the need for health professionals to refer to individual RCTs and base their advice on the probiotic and the symptom most relevant to each patient.

Since these systematic reviews, meta-analyses and clinical guidelines, a number of RCTs have been published that investigate the effectiveness of probiotics in IBS. Within the previous year, at least two have been undertaken in large samples (>100).[28,29] In an RCT of 122 patients with IBS, Bifidobacterium bifidum MIMBb75 resulted in a greater reduction in global IBS symptoms, with more patients consuming the probiotic (47%) than the placebo (11%) reporting adequate relief of their symptoms.[28] However, in an RCT of 120 patients with IBS, there was no difference in symptom response rates or quality of life between patients consuming Escherichia coli Nissle 1917 or placebo following 12 weeks, in part due to large placebo responses (although there was significantly greater response rates in the probiotic group at weeks 10 and 11).[29] Interestingly, following subgroup analysis of those who developed IBS following gastroenteritis or antibiotics, more patients had symptom response to the probiotic (60%) compared with placebo (14.3%). However, this subgroup included only 17 patients and the statistical analysis was only one-sided.[29] Despite these clear limitations, this study alludes to the possibility of greater efficacy of probiotics in patients in whom the pathogenesis of their IBS is known to involve the gastrointestinal microbiota and raises hypotheses for testing in future studies.

The evidence from clinical trials and systematic reviews are largely supportive of the use of probiotics in IBS, but only for specific strains. This is important given that focus groups suggest that patients view probiotics as appealing alternatives to drugs and a natural, low-risk management strategy.[30]

Inflammatory Bowel Disease

IBD refers to a group of disorders characterized by chronic inflammation of the gastrointestinal tract of unknown cause. Two principal phenotypes are described: ulcerative colitis wherein inflammation is typically continuous, limited to the mucosa and confined to the colon, and Crohn's disease wherein inflammation is often discontinuous, transmural and may involve any part of the gastrointestinal tract. Both tend to affect adolescents and young adults, and though they vary in disease extent and severity, they can inflict a tremendous impact on quality of life and have considerable socioeconomic consequences for the individual and society.

The rationale for the therapeutic use of probiotics in IBD is derived from the hypothesis that the endogenous intestinal microbiota plays a crucial role in its pathogenesis. These include the genetic predisposition to IBD resulting from polymorphisms in genes coding for molecules involved in bacterial recognition (e.g. nucleotide oligomerization domain-2).[31] In addition, a dysbiosis of the microbiota in ulcerative colitis and Crohn's disease has been described, including altered microbiota in smokers, a risk factor for Crohn's disease.[32,33] Furthermore, Faecalibacterium prausnitzii, an organism with proven anti-inflammatory properties, is lower in people with IBD.[34] However, microbiota–host interactions are highly complex and likely bidirectional, as evidenced by the impact of inflammation per se on the microbiota.[33]

An extensive literature supports the impact of various probiotics in experimental models of IBD. For example, a specific strain of B. infantis produces a marked reduction in caecal and colonic inflammation in the IL-10 knockout model of colitis, with a parallel suppression of the proinflammatory cytokines interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and IL-12.[14] These effects on host immunoregulation are thought to be mediated through direct interactions with host dendritic cells or by the induction of vitamin A or tryptophan metabolic pathways.[14] Furthermore, this same organism has been shown to induce IL-10 secretion and enhance Foxp3 expression in peripheral blood in healthy volunteers.[35]

Genetic manipulation of probiotics can result in profound changes in their immunomodulation, further elucidating the mechanism through which these effects are exerted. For example, genetic engineering a defect in techoic acid (a component of the bacterial cell wall) biosynthesis in Lactobacillus plantarum, converted what was a proinflammatory response to the wild type to an anti-inflammatory response in the mutant, featuring greatly enhanced IL-10 production.[36] In another example, a protein derived from Lactobacillus rhamnosus GG reduced epithelial apoptosis and suppressed inflammation in mouse models of IBD by activating epithelial growth factor receptor.[37]

Despite a convincing rationale and a deluge of convincing animal data, clinical data on probiotics in IBD are rather scanty and far from convincing. One exception is in pouchitis, a variant that occurs in the neo-rectum following a total colectomy and ileo-anal pouch procedure for ulcerative colitis. Here, a systematic review has indicated that VSL#3 is effective in the primary prevention and maintenance of remission in pouchitis.[38]

With regard to ulcerative colitis, a systematic review[39] of controlled trials has suggested efficacy for probiotics such as nonpathogenic E. coli, S. boulardii, as well as Lactobacillus reuterii (by enema)[40] and VSL#3[41] in maintaining remission in ulcerative colitis and in treating mild to moderately active disease. However, other studies have been less favourable and large longer term studies are required.[39] Importantly, in this systematic review, only data from the same probiotics were meta-analysed, avoiding the heterogeneity of aggregating data for different probiotics.

In contrast to these somewhat encouraging findings in ulcerative colitis, the literature on probiotics in the maintenance or treatment of Crohn's disease provides little encouragement.[39] Despite these findings, one study[42] reported that over one-third of patients with IBD were currently using probiotics or had done so within the previous year, indicating a need for the health professionals to question patients regarding probiotic use.

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