A Clostridia-rich microbiota enhances bile acid excretion in diarrhea-predominant irritable bowel syndrome

Abstract

An excess of fecal bile acids (BAs) is thought to be one of the mechanisms for diarrhea-predominant irritable bowel syndrome (IBS-D). However, the factors causing excessive BA excretion remain incompletely studied. Given the importance of gut microbiota in BA metabolism, we hypothesized that gut dysbiosis might contribute to excessive BA excretion in IBS-D. By performing BA-related metabolic and metagenomic analyses in 290 IBS-D patients and 89 healthy volunteers, we found that 24.5% of IBS-D patients exhibited excessive excretion of total BAs and alteration of BA-transforming bacteria in feces. Notably, the increase in Clostridia bacteria (e.g., C. scindens) was positively associated with the levels of fecal BAs and serum 7α-hydroxy-4-cholesten-3-one (C4), but negatively correlated with serum fibroblast growth factor 19 (FGF19) concentration. Furthermore, colonization with Clostridia-rich IBS-D fecal microbiota or C. scindens individually enhanced serum C4 and hepatic conjugated BAs but reduced ileal FGF19 expression in mice. Inhibition of Clostridium species with vancomycin yielded opposite results. Clostridia-derived BAs suppressed the intestinal FGF19 expression in vitro and in vivo. In conclusion, this study demonstrates that the Clostridia-rich microbiota contributes to excessive BA excretion in IBS-D patients, which provides a mechanistic hypothesis with testable clinical implications.

Chronic diarrhea, bile acids, and Clostridia

“…Importantly, the authors showed that the BA-positive group, when compared to the BA-negative group, also showed raised serum C4 and total BA levels, with lower FGF19. Total fecal BAs were associated with increased symptom severity, increased BA synthesis and impaired FGF19 feedback, making the Zhao et al study patients representative of those studied previously (16).…”

“…This group had an increase in their microbiota in Firmicutes, including Clostridia and especially Clostridium scindens, with significantly higher abundance of 7-dehydroxylation/dehydrogenation genes. The abundance of C. scindens was positively associated with total fecal BA and serum C4, and, notably, was inversely related to serum FGF19 levels (16).…”

“…No differences in ileal BA transporters or hepatic receptors was identified. The Firmicutes/Bacteroidetes ratio was higher, and increases in Clostridium cluster XIVa and C. scindens were found (16).…”

“…C. scindens enhanced BA synthesis and excretion, reducing ileal FGF15 at both transcript and protein levels. Conversely, vancomycin increased ileal Fgf15 and inhibited hepatic Cyp7a1 gene expression (16).…”

“…In this issue of the JCI, Zhao et al investigated the relevance of the BA-FXR signalling pathway and the effects of microbial metabolism of BA in relation to the possible cause of PBAD (16). Starting with an unselected population of 345 Chinese adults who met Rome IV criteria for IBS-D (1), the authors identified around 25% of these with excess total fecal BA (called the BA + IBS-D group by Zhao et al).…”