Intestinal microbiota in functional bowel disorders: a Rome foundation report

Magnus Simrén, Giovanni Barbara, Harry J Flint, Brennan M R Spiegel, Robin C Spiller, Stephen Vanner, Elena F Verdu, Peter J Whorwell, Erwin G Zoetendal, Rome Foundation Committee, Magnus Simrén, Giovanni Barbara, Harry J Flint, Brennan M R Spiegel, Robin C Spiller, Stephen Vanner, Elena F Verdu, Peter J Whorwell, Erwin G Zoetendal, Rome Foundation Committee

Abstract

It is increasingly perceived that gut host-microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID). The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis. There has been a great deal of interest in the potential clinical and therapeutic implications of small intestinal bacterial overgrowth in IBS. However, this theory has generated much debate because the evidence is largely based on breath tests which have not been validated. The introduction of culture-independent molecular techniques provides a major advancement in our understanding of the microbial community in FGID. Results from 16S rRNA-based microbiota profiling approaches demonstrate both quantitative and qualitative changes of mucosal and faecal gut microbiota, particularly in IBS. Investigators are also starting to measure host-microbial interactions in IBS. The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system. While we await important insights in this field, the microbiota is already a therapeutic target. Existing controlled trials of dietary manipulation, prebiotics, probiotics, synbiotics and non-absorbable antibiotics are promising, although most are limited by suboptimal design and small sample size. In this article, the authors provide a critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID and evaluate the results of microbiota-directed interventions. The authors also provide clinical guidance on modulation of gut microbiota in IBS.

Conflict of interest statement

Competing interests: This is a Rome Working Team Report. All authors are responsible for writing the study interpretation of data, and critical revision of the manuscript. The authors would like to disclose the following potential competing interests: Alfa-Wasserman, Prometheus, Shire/Movetis, Sofar (GB); Danone Research, Arla Foods, Novartis, Shire/Movetis, AstraZeneca (MS); Ironwood, Shire/Movetis, Prometheus (BS); Boeringer Ingelheim & Ironwood (RS); Ferring Canada and US (SV); Nestec grant support (EFV); Novartis Pharmaceuticals, GlaxoSmithKline, Solvay Pharmaceuticals, Pfizer Global Research and Development, Rotta Research, Proctor and Gamble, Danone Research, Astellas Pharma, Ironwood Pharmaceuticals, Sucampo Pharmaceuticals, Almirall Pharma, Movetis UK, Norgine, Chr Hansen, Boehringer-Ingelheim, and Heel GMBH (PW).

Figures

Figure 1
Figure 1
Gut microbiota and the intrinsic and extrinsic factors that can affect its distribution and composition. A number of host mechanisms participate in gut microbiota modulation, including gastric acid secretion, fluid, anticommensal sIgA and antimicrobial peptide production, and gastrointestinal (GI) motility. Drugs that block acid secretion and affect GI motility can indirectly alter the microbiota. Antibiotics, depending on spectrum and dosage, will directly affect microbiota composition. Dietary modifications, including probiotic and fibre supplements, will also affect microbiota composition. MMC, migrating motor complexes; H+ hydrogen ions; O2, partial oxygen tension; sIgA, secretory immunoglobulin A; PPI, proton pump inhibitor; NSAID, non-steroidal anti-inflammatory drug.
Figure 2
Figure 2
Gut microbiota composition in African children living in rural areas with a polysaccharide-rich diet when compared with Italian city children. (Reprinted with permission from Proc Natl Acad Sci USA).
Figure 3
Figure 3
The lactulose hydrogen breath test (LHBT) predominantly measures small intestinal transit rather than small intestinal bacterial overgrowth (SIBO) in irritable bowel syndrome (IBS) patients. Upper schematic shows ingestion of test meal with subsequent serial measurement of both H2 gas, resulting from fermentation of the lactulose by intestinal bacteria, and Tc99 scanning in the caecum. This latter measurement detects when the test meal has reached the caecum. The stylised drawing below shows a representative result from an IBS patient with serial measurements over time. The Tc99 had already reached the caecum in large quantities before the H2 PPM level has reached the threshold for an abnormal test. This demonstrates that the increased H2 production results from fermentation by colonic bacteria, not by abnormal bacteria small intestine (ie, SIBO).
Figure 4
Figure 4
Plot chart of currently available strategies for modifying gut microbiota aiming to demonstrate the relationship between the effectiveness and invasiveness/safety of the proposed approach. FODMAP, fermentable oligo-, di- and mono-saccharides and polyols; PPI, proton pump inhibitor.

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