Foods high in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) exacerbate symptoms of irritable bowel syndrome (IBS); however, their mechanism of action is unknown. We hypothesized that a high-FODMAP (HFM) diet increases visceral nociception by inducing dysbiosis and that the FODMAP-altered gut microbial community leads to intestinal pathology. We fed rats an HFM and showed that HFM increases rat fecal Gram-negative bacteria, elevates lipopolysaccharides (LPS), and induces intestinal pathology, as indicated by inflammation, barrier dysfunction, and visceral hypersensitivity (VH). These manifestations were prevented by antibiotics and reversed by low-FODMAP (LFM) diet. Additionally, intracolonic administration of LPS or fecal supernatant (FS) from HFM-fed rats caused intestinal barrier dysfunction and VH, which were blocked by the LPS antagonist LPS-RS or by TLR4 knockdown. Fecal LPS was higher in IBS patients than in healthy subjects (HS), and IBS patients on a 4-week LFM diet had improved IBS symptoms and reduced fecal LPS levels. Intracolonic administration of FS from IBS patients, but not FS from HS or LFM-treated IBS patients, induced VH in rats, which was ameliorated by LPS-RS. Our findings indicate that HFM-associated gut dysbiosis and elevated fecal LPS levels induce intestinal pathology, thereby modulating visceral nociception and IBS symptomatology, and might provide an explanation for the success of LFM diet in IBS patients.
Shi-Yi Zhou, Merritt Gillilland III, Xiaoyin Wu, Pornchai Leelasinjaroen, Guanpo Zhang, Hui Zhou, Bo Ye, Yuanxu Lu, Chung Owyang
Submitter: Fabien Wuestenberghs | firstname.lastname@example.org
Authors: Fabien Wuestenberghs, Guillaume Gourcerol, Pierre Déchelotte, and Moïse Coëffier
Normandie Univ, UNIROUEN, INSERM UMR 1073, Nutrition, Gut & Brain Laboratory, Institute for Biomedical Research and Innovation (IRIB) and Rouen University Hospital, Nutrition and Physiology Departments, Rouen, France
Published October 17, 2018
We have read with interest the research paper of Zhou et al. concerning the impact of FODMAPs on visceral nociception. Interestingly, authors reported that Akkermancia muciniphila was increased by 4.7-fold among Gram-negative bacteria following a high-FODMAP diet. This mucin-degrading bacterium is usually considered beneficial for gut epithelium and in metabolic syndrome. However, its role in irritable bowel syndrome (IBS) seems ambiguous. Indeed, Zhou et al. have shown that rats developed micro-inflammation, increased gut permeability and visceral hypersensitivity following a high-FODMAP diet. These alterations were driven by diet-induced change in microbiota. Since A. muciniphila shows the highest relative change in their model, authors speculate that the bacterium plays a key role in the pathophysiology. Clinically, even if we can accept that increased A. muciniphila in the microbiota of pediatric IBS patients seems to be correlated with digestive complaints (1), it is less clear in adults since the correlation coefficient was only 0.27 in the study of Rajilic et al. (2). Other studies in the literature rather suggest a beneficial effect of A. muciniphila on intestinal barrier: in vitro studies suggest that A. muciniphila strengthens the integrity of epithelial cell layer in the gut (3). Finally, the bacterium exhibited a preventive effect on DSS-induced colitis (4) and its extracellular vesicles enhanced tight junction function (5).
In conclusion, the implication of A. muciniphila with gut health is more complex than suggested by Zhou et al. and requires further studies. The observed increase in A. muciniphila relative abundance after high FODMAPs may be just an adaptative process tending to reduce inflammation rather than a contributor to hypersensitivity. Further studies are needed, including quantitative microbiome profiling approaches as well as molecular/mechanistic studies to substantiate the role of A. muciniphila in IBS.
(1) Saulnier DM, et al. Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. Gastroenterology. 2011;141(5):1782-91.
(2) Rajilic-Stojanovic M, et al. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology. 2011;141(5):1792-801.
(3) Reunanen J, et al. Akkermansia muciniphila adheres to enterocytes and strengthens the integrity of the epithelial cell layer. Appl Environ Microbiol. 2015;81(11):3655-62.
(4) Gobert AP, et al. The human intestinal microbiota of constipated-predominant irritable bowel syndrome patients exhibits anti-inflammatory properties. Sci Rep. 2016;6:39399.
(5) Chelakkot C, et al. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp Mol Med. 2018;50(2):e450.