Inhibition of microbial deconjugation of micellar bile acids protects against intestinal permeability and liver injury

Abstract

Altered host-microbe interactions and increased intestinal permeability have been implicated in disease pathogenesis. However, the mechanisms by which intestinal microbes affect epithelial barrier integrity remain unclear. Here, we investigate the impact of bacterial metabolism of host-produced bile acid (BA) metabolites on epithelial barrier integrity. We observe that rats fed a choline-deficient, l -amino acid–defined, high-fat diet (CDAHFD) exhibit reduced intestinal abundance of host-produced conjugated BAs at early time points, coinciding with increased gut permeability. We show that in vitro, conjugated BAs protect gut epithelial monolayers from damage caused by bacterially produced unconjugated BAs through micelle formation. We then demonstrate that inhibition of bacterial BA deconjugation with a small-molecule inhibitor prevents the development of pathologic intestinal permeability and hepatic inflammation in CDAHFD-fed rats. Our study identifies a signaling-independent, physicochemical mechanism for conjugated BA-mediated protection of epithelial barrier function and suggests that rational manipulation of microbial BA metabolism could be leveraged to regulate gut barrier integrity.

Rosmarinic Acid Restores Colonic Mucus Secretion in Colitis Mice by Regulating Gut Microbiota-Derived Metabolites and the Activation of Inflammasomes

“…Bile acids, including the primary bile acid and the secondary bile acids, were crucial for helping to absorb lipids, inhibiting the expression of proinflammatory cytokines and maintaining the epithelial barrier integrity of intestine and regulating mucosal barrier functions. − A lack of bile in the intestine leads to atrophy of the intestinal mucosa. In fact, there is a mutually beneficial relationship between bile acid and microbiota.…”

Copy number variation onABCC2-DNMBP lociimpacts the diversity and composition of the gut microbiota in pigs

“…Regarding BAs, GF mice showed significant differences on enterohepatic circulation and BA composition compared with conventional mice [45] with a lower proportion of secondary and tertiary unconjugated and glycine-conjugated BA in tissues of GF rats [46]. In addition, conjugated BAs can have a protective role on gut barrier integrity [47]. The oral administration of two major conjugated BAs, tauro-cholic acid and β-tauro-murocholic acid, increased the richness of neonatal small intestinal microbiota with a positive effect on the postnatal microbiota maturation [48].…”

Chemoproteomic Approaches for Unraveling Prokaryotic Biology

“…Chemoproteomic profiling with a clickable analog (N 3 ‐CDC‐FMK, Figure 15b) validated its specificity to BSH and showed little off‐target effects on host proteins [161] . A second‐generation inhibitor (AAA‐10, Figure 15d) [165] protected against intestinal barrier erosion and liver inflammation in rats fed a high‐fat diet [166] . This protective effect was shown to be caused by the formation of protective micelles by conjugated bile acids, which sequestered the unconjugated bile acids that cause intestinal barrier damage [166] …”

“…[161] A second-generation inhibitor (AAA-10, Figure 15d) [165] protected against intestinal barrier erosion and liver inflammation in rats fed a high-fat diet. [166] This protective effect was shown to be caused by the formation of protective micelles by conjugated bile acids, which sequestered the unconjugated bile acids that cause intestinal barrier damage. [166] Chemoproteomic profiling with photoaffinity labeling has provided insight into bile acid signaling.…”