Gut microbiome determines therapeutic effects of OCA on NALFD by modulating bile acid metabolism

Abstract Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease with no approved pharmacological agents yet. Obeticholic acid (OCA), a novel bile acid derivative, has been demonstrated to ameliorate NAFLD-related manifestations. Regarding the role of gut-liver axis in liver disease development, this study aimed to explore the potential role of gut microbiota in the treatment of OCA to NALFD mice induced by the high-fat diet (HFD). Antibiotic-induced microbiome depletion (AIMD) confirmed the critical role of gut microbiota in OCA treatment to NALFD which could effectively alleviate histopathological traits and damaged liver function induced by HFD. Metagenomic analysis indicated that OCA intervention in HFD mice remarkably increased the abundance of Akkermansia miciniphila, Bacteroides massiliensis, Streptococcus thermophilus, and Bifidobacterium spp. Targeted metabolomics analysis indicated that OCA could modulate host bile acids pool by reducing the levels of hydrophobic cholic acid (CA) and chenodeoxycholic acid (CDCA), and increasing levels of hydrophilic conjugated bile acids, such as taurodeoxycholic acid (TDCA) and tauroursodesoxycholic acid (TUDCA) in the serum of HFD-fed mice. Strong correlations were found between differentially abundant microbes and the shifted bile acids. Furthermore, bacteria enriched in OCA intervention exhibited much greater potential in encoding 7alpha-hydroxysteroid dehydrogenase (7α-HSDs) producing secondary bile acids rather than bile salt hydrolases (BSHs) responsible for primary bile acids synthesis. In conclusion, the current study demonstrated that OCA intervention altered gut microbiota composition, thus enriching special gut microbes modulating dynamic homeostasis of bile acids which ultimately influenced therapeutic effects on NAFLD.