Portal bile acid composition and microbiota along the murine intestinal tract exhibit sex differences in physiology.

Microbes in the intestine transform bile acids during transit, altering their functional and signaling capacities before recirculation via the portal vein. Sex differences in the gut microbiota have been noted, but their consequence on bile acid composition is unclear. Here, we investigated the composition and functional potential of microbes in the small and large intestines together with portal and systemic bile acid levels. Female and male mice exhibit distinct microbial diversity throughout the length of the intestine, leading to dimorphism in genes related to bile acid transformation. Of note, genes linked to bacterial oxidative properties were abundant in males, and consistently, we found 3X higher oxo-bile acids in portal circulation in males than females. Conversely, conjugated primary bile acids were 1.8X more abundant in the portal bile acid pool of female mice. Oxidized and deconjugated bile acids were absent in germ-free mice consistent with microbe-mediated bile acid transformation. More importantly, gnotobiotic mice do not show sex differences in portal bile acids. Taken together, we demonstrate that sex differences in gut microbiota with subsequent changes in microbially transformed bile acid levels contribute to distinct sex-specific bile acid pools within the enterohepatic loop.