Alterations in bile acid metabolizing gut microbiota and specific bile acid genes as a precision medicine to subclassify NAFLD

Multiple mechanisms for the gut microbiome contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) have been implicated. Here, this post-hoc study aim to investigate the contribution and potential application for altered bile acid (BA) metabolizing microbes in NAFLD using whole metagenome sequencing (WMS) data. The discovery cohort consisted of 86 well-characterized biopsy-proven NAFLD patients and 38 healthy controls. Assembly-based analysis was performed to identify BA-metabolizing microbes. Statistical tests, feature selection and microbial co-abundance analysis were integrated to identify microbial alterations and markers in NAFLD. An independent validation cohort was subjected to similar analyses. NAFLD microbiota exhibited decreased diversity and microbial associations. We established a classifier model with 53 differential species exhibiting a robust diagnostic accuracy (AUC=0.97) for dectecting NAFLD. Next, eight important differential pathway markers including secondary BA biosynthesis were identified. Specifically, increased abundance of 7α-HSDH, baiA and baiB were detected in NAFLD. Further, 10 of 50 BA-metabolizing metagenome-assembled genomes (MAGs) from <i>Bacteroides ovatus</i> and <i>Eubacterium biforme</i>, were dominant in NAFLD and interplayed as a synergetic ecological guild. Importantly, two subtypes of NAFLD patients were observed according to secondary BA metabolism potentials. Elevated capability for secondary BA biosynthesis was also observed in the validation cohort. These bacterial BA-metabolizing genes and microbes identified in this study may associate with NAFLD pathogenesis and serve as potential disease markers. Microbial differences in BA-metabolism and strain-specific differences among patients highlight the potential for precision medicine in NAFLD treatment.