Gut bacteria contributes to NAFLD pathogenesis by promoting secondary bile acids biosynthesis

Objective The gut microbiota affect liver metabolism and health through its metabolites. We previously observed that the microbiome may have a negative effect on non‐alcoholic fatty liver disease (NAFLD) through elevated secondary bile acids (BAs) production, and consequently suppressed BA‐mediated signaling. In this study, we examined the whole genome sequencing (WGS) data from NAFLD microbiome aiming to identify the species that contribute to the altered BA metabolism in NAFLD. Methods The metagenome data of the gut microbiota from 79 NAFLD patients were compared to those from 18 healthy controls. Metaphlan2 and HUMAnN were used to examine the gene‐based taxonomic and functional profiles of gut microbiota. Genome‐based analysis was further performed to obtain insights on the microbial genomes and to identify BA metabolizing microbes. Statistical tests, feature selection and microbial interaction analysis were integrated to identify disease markers and structural alterations in NAFLD gut microbiome. Results The gut microbiota of NAFLD were less diverse than those of healthy subjects. In addition, interactions among the members of the gut community in NAFLD were less than those in healthy subjects. We identified 37 differential species markers, including Ruminococcus torques, Clostridium leptum , and Escherichia coli ; and 32 differential pathway markers including secondary BA biosynthesis and arachidonic acid metabolism, that distinguish NAFLD from healthy controls. Subsequently, 115 high‐quality microbial genomes (HQMGs) were re‐assembled, and taxonomy determined at strain level. Notably, metabolic potentials analysis identified 15 HQMGs, from Clostridium saccharolyticum and Ruminococcus bromii , that are involved in secondary BA biosynthesis, and were dominant in NAFLD and interplayed as a synergetic ecological guild. Conclusions In‐depth analysis of the WGS data from NAFLD patients and healthy controls revealed the structural and functional alterations of the gut microbiota. We identified the bacterial strains responsible for elevated secondary BA production in NAFLD, supporting our hypothesis that elevated secondary BA biosynthesis contributes to the development of NAFLD. The 15 BA‐metabolizing strains dominant in NAFLD could be novel therapeutic targets for NAFLD. In addition, our WGS study revealed strain‐specific functional differences within certain gut microbial species. Support or Funding Information This work was supported by National Natural Science Foundation of China 81770571 (to LZ), 81774152(to RZ), 41530105 (to RZ). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .