Microbiome-encoded bile acid metabolism modulates colonic transit times

Abstract

Summary Gut motility is regulated by the microbiome via mechanisms that include bile acid metabolism. To localize the effects of microbiome-generated bile acids, we colonized gnotobiotic mice with different synthetic gut bacterial communities that were metabolically phenotyped using a functional in vitro screen. Using two different marker-based assays of gut transit, we inferred that bile acids exert effects on colonic transit. We validated this using an intra-colonic bile acid infusion assay and determined that these effects were dependent upon signaling via the bile acid receptor, TGR5. The intra-colonic bile acid infusion experiments further revealed sex-biased bile acid-specific effects on colonic transit, with lithocholic acid having the largest pro-motility effect. Transcriptional responses of the enteric nervous system (ENS) were stereotypic, regional, and observed in response to different microbiota, their associated bile acid profiles, and even to a single diet ingredient, evidencing exquisite sensitivity of the ENS to environmental perturbations.

Comparison of biochemical, microbial and mucosal mRNA expression in bile acid diarrhoea and irritable bowel syndrome with diarrhoea

“…Thus, patients with BAD have a higher Firmicutes to Bacteroidetes ratio in stool. Increased colonic BAs reduce microbial diversity, decrease Bacteroidetes and increase Firmicutes, which in turn increases secondary BA production, stimulates colonic secretion by DCA and accelerates colonic transit (eg, by stimulation of TGR5 receptors) by both LCA and DCA 40 41. Our observations in patients are consistent with studies in rodents fed BAs or high fat diets that displayed decreased Bacteroidetes and expansion of Firmicutes 42.…”

“…The other major actions of the colonic microbiota on BAs are dehydroxylation and sulfation. Dehydroxylation may result in a balanced effect on the overall detergent properties of BAs, since CDCA is converted to LCA (which has no detergent effects, but it can certainly stimulate colonic motility via TGR5 receptors40 47) and CA is converted to the detergent molecule, DCA. Our functional analysis of the microbiota in BAD revealed decreased BA thiol ligases which are involved in the transformation of primary to secondary BAs.…”

Role of gut microbiota-derived signals in the regulation of gastrointestinal motility

“…GI transit time is significantly decreased in mice colonized with BSH-positive microbiota, indicating that GI motility is dependent on gut microbiotamediated deconjugation of BAs (85). Moreover, greater BSH activity of gut bacteria drives faster colonic transit, with greater prokinetic effects in males than in females (86). In summary, gut microbiota indirectly regulates GI motility through its effect on the modification of BAs composition by deconjugation and dehydroxylation (Figure 4).…”

Gut feelings: the microbiota-gut-brain axis on steroids

“…For instance, CDCA is more potent in activating FXR compared to DCA and LCA (147), while the murine specific tauro-beta-muricholic acid is recognized as an FXR-antagonist (212). Also, unconjugated bile acids, particularly LCA and DCA promote colonic transit, with more potent effects on male compared to female mice (134) (8). Mechanistically, the effect could be mediated through TGR5 activation and/or the serotonergic system.…”