Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
Conflict of interest: Dr Quigley is a non-executive director of a campus company, Alimentary Health, which holds patents in the area of the gut microbiota and has received honoraria from Procter and Gamble, Salix, Danone, Yakult Japan, Yakult Korea and Sanofi Synthelabo (India).
Reprints: Eamonn M.M. Quigley, MD, FRCP, FACP, FACG, FRCPI, Department of Medicine, Clinical Sciences Building, Cork University Hospital, Cork, Ireland (e-mail: email@example.com).
Community surveys and the records of primary care and gastroenterology clinics tell us quite clearly that those complaints that are usually lumped together as “functional” bowel symptoms are very common and, for some individuals, a source of much discomfiture.1–3 As a consequence, the costs to the affected individual and to society are considerable. Yet, our ability to relieve, not to mind eradicate, these symptoms is limited and, as a category, functional bowel complaints have seen more drug withdrawals than successful launches in recent years. While sufferers have sought help from the complementary and alternative medical arena,4 researchers have been engaged in exploring novel and, to traditionalists, surprising hypotheses regarding the etiology of irritable bowel syndrome (IBS)5 and the pathogenesis of such abdominal symptoms as pain, discomfort, bloating and distension, as well as bowel dysfunction.6,7 These two seemingly widely divergent approaches have, of late, converged with the advent of interventions that seek to modify the gut microbiota in IBS and related disorders: antibiotics, prebiotics, and probiotics.8 Thus the interest that the consumer has long had in using a variety of probiotic and prebiotic preparations in the management of a variety of gastrointestinal ills is now being shared with the scientist and clinical researcher.
In this issue of the journal, Ringel-Kulka and colleagues present the results of their randomized, double-blind, placebo-controlled study of a probiotic combination among community-based subjects with functional bowel disorders, specifically, nonconstipated IBS, functional diarrhea, and functional bloating.9 In a relatively small study, (60 randomized, 53 completed) subjects were randomized to receive either a combination of Lactobacillus acidophilus NCFM and Bifidobacterium animalis spp. lactis Bi-07 (total dose 1×1011 CFU per pill) or placebo for 8 weeks and the impact on 2 primary end points, global relief of gastrointestinal symptoms and satisfaction with treatment, as well as a number of secondary end points, which included quality of life and individual functional gastrointestinal symptoms, assessed. Though no significant differences were seen between probiotic and placebo groups for the co-primary end points, bloating was significantly alleviated in the treatment group, whether treated as a whole or assessed among the subgroup with IBS. For the entire group, bloating severity decreased by approximately 1.5 points on a 10-point scale from a baseline of 5.7 to 4.1 at 4 weeks (midpoint of treatment phase) and 4.26 at 8 weeks (the end of the treatment phase). Importantly, these investigators confirmed, using molecular techniques, transit and survival of both probiotic species in the stool.
What can we learn from this study which, at first glance, has all the appearances of yet another pyrrhic victory in the annals of IBS and functional bowel disease therapeutics? First, the negatives. This was, as the authors concede, a pilot study and undoubtedly underpowered to detect the small differences that have been deemed significant in studies of pharmacological agents in IBS, for example. The probiotic product studied was a combination of a Lactobacillus and a Bifidobacterium rather than a single organism preparation rendering it difficult to discern which truly benefited bloating or, alternately, whether one contributed more to the failure to meet the primary end points? This is not an unreasonable question given that a recent meta-analysis concluded that lactobacilli had no evidence of efficacy in terms of global symptom responses in IBS, whereas bifidobacteria had some.10 Then there is the inescapable and painful truth: neither co-primary broke in favor of the probiotic! The positive results for bloating should, therefore, be treated, with all the respect and caution than any post hoc analysis deserves: interesting finding but needs confirmation.
On the positive side, well-designed studies of probiotics in IBS are to be welcomed given the poor quality of many trials in the past11 and the challenges that are presented by any study in such a heterogeneous population and, especially, of one recruited from the general population where relatively low baseline symptom scores are the norm and considerable placebo responses are to be expected. The authors are also to be lauded on their careful microbiological analysis of probiotic transit and survival, parameters sadly lacking from many studies in this area, which render their interpretation, especially if negative, nigh impossible.
Understandably, given its prevalence and apparent intractability,6,7,12 the authors emphasize the impact of their probiotic cocktail on bloating. It is quite remarkable that, among individual functional symptoms, bloating, distension, and flatulence have been those most amenable to improvement with probiotics11,13 and in 1 study another bacterium, Bifidobacterium lactis DN-173-010A was shown, not only to alleviate bloating and distension, but also to accelerate colonic transit and produce an objective reduction in abdominal girth.14 These are important observations given the proposed role of impaired gas transit in the pathogenesis of bloating and distension.6 Ringel-Kulka and colleagues concede that, in retrospect, a bloated, constipated IBS subgroup may have been a more appropriate study population. How probiotics, or for that matter antibiotics, such as rifaximin,15 impact on bloating and distension is unclear but observations that they do certainly support the contention that the microbiota, whether in the colon or small intestine or both, is playing a role in IBS and related disorders.
This study illustrates simultaneously the promise and the shortcomings of probiotic studies in functional bowel disorders. Although effects on some aspects of these multi-symptom disorders tantalize us, variations and, in some cases, shortcomings in study design, execution, and analysis cloud our interpretation and the use of a great variety of probiotic preparations (single organism, cocktail, combination) renders comparisons between studies nigh impossible. Other limitations must be emphasized: few studies have attempted to compare different strains or determine optimal dose and only a very few have been of long-term duration in a group of disorders that often spans years, not weeks or months. Nevertheless, in adults, at least, as again demonstrated by the study of Ringel-Kulka and colleagues, there seems to be some overall, albeit modest, benefit and certainly a continued impetus for large, long-term studies.
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