Irritable bowel syndrome (IBS) is a globally present disorder characterized by recurrent abdominal pain and changes in stool form and frequency. Its varying manifestations have led to the division of IBS into constipation predominant (IBS-C), diarrhea predominant (IBS-D) or mixed (IBS-M) subtypes.
How the gut microbiome fits into the large and complex pathogeny of IBS remains poorly understood, thus emphasizing the need for personalized approaches to accurately diagnose patients with IBS. However, studies exploring the gut microbiome’s contribution to IBS development are mainly experimental and those performed in humans are limited in their generalized findings due to their cross-sectional nature.
To overcome the challenge of exploring the temporal variability of IBS in human studies that focus on one-time snapshots of participants, Ruben A. T. Mars, Yi Yang and colleagues used a multi-omics analysis to gain better knowledge of the gut microbiota’s mechanistic contribution to IBS over a follow-up period of 6 months.
The authors integrated data on diet, patient symptoms, measurement of intestinal secretion, gene expression changes in the gastrointestinal tract, gut microbiota composition and fecal metabolites related to gut microbiota, diet or the host to elucidate whether changes in gut microbial metabolism relate to host physiology.
Patients with IBS-C exhibited greater variability in terms of fecal microbiota composition, mucosa-associated microbiota and luminal microbiota compared to IBS-D patients and healthy controls. It was also found that IBS symptom severity was linked to functional changes in the gut microbiota. For instance, the activity of alcohol dehydrogenase was found to be higher in severe IBS-C and IBS-D compared to mild-moderate IBS.
A new metabolic pathway involving hypoxanthine—which takes part in modulating colonic epithelial energy and maintaining gut barrier integrity—has been shown to be crucial in IBS. Both the host and the gut microbiome are involved in producing hypoxanthine, the levels of which were decreased in colonic biopsies of the IBS-C and IBS-D subtypes as a result of its utilization and breakdown by the gut microbiome.
It was found that IBS symptom severity was linked to functional changes in the gut microbiota
Other bacterial metabolites were identified to be important in IBS. For instance, in patients with IBS-D, there was an increase in bacterial production of tryptamine, which increases water secretion in the intestine. Those patients also harbored reduced bacterial metabolism of bile acids. As a result, high levels of primary bile acids were present, which can irritate the colon and increase water secretion: a common hallmark of the IBS-D subtype.
Meanwhile, patients with IBS-C showed a decrease in short-chain fatty acids butyrate and acetate, which are involved in increasing stool movements across the intestine.
Interestingly, individual-specific patterns underlying symptom flares were also found, with both primary bile acids and the archeon Halobiforma nitratireducens elevated in flare stool samples.
Altogether, the prospective observational data of human and gut microbial origin allows for identifying specific metabolites that drive subtype-specific phenotypes in IBS.
The authors argue in the discussion that bacteria that produce short-chain fatty acids or tryptamine might potentially be used in managing IBS with constipation. Likewise, bacteria that convert primary into secondary bile acids could be used to treat IBS with diarrhea. Finally, hypoxanthine-producing bacteria could help treat symptoms of patients with both subtypes.
As not all patients with IBS respond the same way to treatment, exploring fluctuating changes in the gut microbiome across time is worth considering in future studies, rather than focusing only on specific time points.
Mars RAT, Yang Y, Ward T, et al. Longitudinal multi-omics reveals subset-specific mechanisms underlying irritable bowel syndrome. Cell. 2020; 182(6):1460-73. doi: 10.1016/j.cell.2020.08.007.