Abstract
Bile acids, which are synthesized from cholesterol by the liver, are chemically transformed along the intestinal tract by the gut microbiota, and the products of these transformations signal through host receptors, affecting overall host health. These transformations include bile acid deconjugation, oxidation, and 7α-dehydroxylation. An understanding of the biogeography of bile acid transformations in the gut is critical because deconjugation is a prerequisite for 7α-dehydroxylation and because most gut microorganisms harbor bile acid transformation capacity. Here, we used a coupled metabolomic and metaproteomic approach to probe in vivo activity of the gut microbial community in a gnotobiotic mouse model. Results revealed the involvement of Clostridium scindens in 7α-dehydroxylation, of the genera Muribaculum and Bacteroides in deconjugation, and of six additional organisms in oxidation (the genera Clostridium, Muribaculum, Bacteroides, Bifidobacterium, Acutalibacter, and Akkermansia). Furthermore, the bile acid profile in mice with a more complex microbiota, a dysbiosed microbiota, or no microbiota was considered. For instance, conventional mice harbor a large diversity of bile acids, but treatment with an antibiotic such as clindamycin results in the complete inhibition of 7α-dehydroxylation, underscoring the strong inhibition of organisms that are capable of carrying out this process by this compound. Finally, a comparison of the hepatic bile acid pool size as a function of microbiota revealed that a reduced microbiota affects host signaling but not necessarily bile acid synthesis. In this study, bile acid transformations were mapped to the associated active microorganisms, offering a systematic characterization of the relationship between microbiota and bile acid composition.
Highlights
Supplementary key words biosynthesis metabolome microbiome proteomics Oligo-MM12 fibroblast growth factor 15 Cyp7a1 Sult2a8 farnesoid X receptor
We characterized the biogeography of bile acid (BA) transformation in gnotobiotic mice
We identified the main organisms involved in BA metabolism in a gnotobiotic mouse model and the localization of their activity in the gut
Summary
Primary BAs are synthesized in the liver from cholesterol (dietary or endogenous). In the hepatocytes, they are conjugated to glycine or taurine and stored continuously in the gall bladder as the main component of bile. Primary BAs undergo several chemical transformations that are catalyzed by gut microorganisms, leading to the formation of secondary BAs. the activity of the gut microbiota increases the diversity of the BA pool. The secondary BAs deoxycholic acid (DCA) and lithocholic acid (LCA), resulting from microbial 7 dehydroxylation of CA and CDCA, have a higher affinity for the membrane receptor Takeda G-protein receptor 5 (TGR5) compared with the host liver-derived primary BAs [2, 4].
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