RT Journal Article SR Electronic T1 Alterations in bile acid metabolizing gut microbiota and specific bile acid genes as a precision medicine to subclassify NAFLD JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.08.14.251876 DO 10.1101/2020.08.14.251876 A1 Na Jiao A1 Rohit Loomba A1 Zi-Huan Yang A1 Dingfeng Wu A1 Sa Fang A1 Richele Bettencourt A1 Ping Lan A1 Ruixin Zhu A1 Lixin Zhu YR 2020 UL http://biorxiv.org/content/early/2020/08/14/2020.08.14.251876.abstract AB Background & Aims Multiple mechanisms for the gut microbiome contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) have been implicated. Here, we aim to investigate the contribution and potential application for altered bile acid (BA) metabolizing microbe in NAFLD using whole metagenome sequencing (WMS) data.Methods 86 well-characterized biopsy-proven NAFLD patients and 38 healthy controls were included in the discovery cohort. Assembly-based analysis was performed to identify BA-metabolizing microbes. Statistical tests, feature selection and microbial interaction analysis were integrated to identify microbial alterations and markers in NAFLD. An independent validation cohort was subjected to similar analyses.Results NAFLD microbiota exhibited decreased diversity and microbial interactions. We established a classifier model with 53 differential species exhibiting a robust diagnostic accuracy (AUC=0.97) for dectecting NAFLD. Next, 8 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 (MAG)s, from Bacteroides ovatus and Eubacterium biforme, 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.Conclusions We identified novel bacterial BA-metabolizing genes and microbes that may contribute to NAFLD pathogenesis and serve as disease markers. Microbial differences in BA-metabolism and strain-specific differences among patients highlight the potential for precision medicine in NAFLD treatment.Competing Interest StatementThe authors have declared no competing interest.baiA3α-hydroxysteroid dehydrogenase;baiBbile acid-coenzyme A ligase;baiCD7α -hydroxy-3-oxo-D4-cholenoic acid oxidoreductase;baiEbile acid 7α- dehydratase;baiFbile acid coenzyme A transferase/hydrolase;baiGprimary bile acid transporter;baiH7beta-hydroxy-3-oxochol-24-oyl-CoA 4-desaturase;baiIbile acid 7beta-dehydratase;BAsbile acids;BSHbile salt hydrolase;FXRfarnesoid X receptor;HMMhidden Markov model;HSDHhydroxysteroid dehydrogenase;MAGmetagenome-assembled genome;NAFLDnon- alcoholic fatty liver disease;NASHnon-alcoholic steatohepatitis;WMSwhole metagenome sequences.