A gut microbiota-independent mechanism shapes the bile acid pool in mice with MASH

Background & Aims: An imbalance between primary and secondary bile acids contributes to the development of metabolic dysfunction-associated steatohepatitis (MASH). The precise mechanisms underlying changes in the bile acid pool in MASH remain to be identified. As gut bacteria convert primary bile acids to secondary bile acids, we investigated the contribution of the gut microbiota and its metabolizing activities to bile acid alterations in MASH.<br /> Methods: To disentangle the influence of MASH from environmental and dietary factors, high-fat diet fed foz/foz mice were compared with their high-fat diet fed wildtype littermates. We developed functional assays (stable isotope labeling and in vitro experiments) to extend the analyses beyond a mere study of gut microbiota composition (16S rRNA gene sequencing). Key findings were confirmed in C57BL/6J mice were fed a Western and high-fructose diet, as an independent mouse model of MASH.<br /> Results: Although mice with MASH exhibited lower levels of secondary 7 alpha-dehydroxylated bile acids (3.5-fold lower, p = 0.0008), the gut microbial composition was similar in mice with and without MASH. Similar gut microbial bile salt hydrolase and 7 alpha-dehydroxylating activities could not explain the low levels of secondary 7 alpha-dehydroxylated bile acids. Furthermore, the 7 alpha-dehydroxylating activity was unaffected by Clostridium scindens administration in mice with a non-standardized gut microbiota. By exploring alternative mechanisms, we identified an increased bile acid 7 alpha-rehydroxylation mediated by liver CYP2A12 and CYP2A22 enzymes (4.0-fold higher, p <0.0001), that reduces secondary 7 alpha-dehydroxylated bile acid levels in MASH.<br /> Conclusions: This study reveals a gut microbiota-independent mechanism that alters the level of secondary bile acids and contributes to the development of MASH in mice.<br /> (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).