Disruption of a key bile acid synthesis enzyme, CYP8B1, results in the absence of cholic acid (CA), increased levels of chenodeoxycholic acid (CDCA) and improved glucose metabolism in mice. However, the mechanism by which the BAs affect glucose metabolism remains unclear. We found that the absence of CYP8B1 increases insulin sensitivity in chow-fed mice, making them phenotypically similar to antibiotic-treated wild type mice, suggesting a role for the microbiome in the beneficial effect derived from CYP8B1 depletion. The aim of this study is to determine if the gut microbiome contributes to the increased insulin sensitivity observed in the absence of CYP8B1. Ten to twelve weeks old female CYP8B1-/- and CYP8B1+/+ mice (n=8-10/group) were fed chow diet ad libitum and OGTT, ITT and GSIS were evaluated. The C2C12 mouse myotubes were exposed to either CA or CDCA, and Insr and Tgr5 levels were measured by qPCR. Moreover, 10 to 12 weeks old female CYP8B1-/- and CYP8B1+/+ mice (n=8-10/group) received a cocktail of antibiotics (1 g/L) in drinking water. Plasma bile acids were measured by GC-MS and ITT was evaluated every two weeks. CYP8B1-/- mice showed significantly increased insulin sensitivity compared to wild type littermates (p<0.001) but no differences in OGTT and GSIS. In addition, the in vitro studies show that exposure of the myotubes to CDCA resulted in significant increases in Insr (t-test, p=0.009) and Tgr5 (t-test, p=0.02). We found that the alteration of the gut microbiome by antibiotics in the wild type mice abolished the difference in ITT between CYP8B1-/- and CYP8B1+/+ mice (p=0.08). Furthermore, the antibiotic-treated wild type mice displayed a significant increase in the CA:CDCA ratio (p<0.0001), mimicking the bile acid pool composition of the untreated CYP8B1-/- littermates. Our results suggest that the specific microbiome composition in the absence of CYP8B1 might play a critical role in enhancing the insulin sensitivity, and therefore glucose metabolism in mice.


M. Corlianò: None. S. Zhong: None. R.R. Singaraja: None.

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