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In this study, we collected fecal samples from mice fed a high\u2010fat diet (HFD) and those on a standard diet (SD), then conducted 16S rRNA sequencing to analyze their gut microbiota. The analysis revealed distinct differences in the dominant bacterial species between the two groups, with a significant decrease in indole\u2010producing probiotics in the HFD mice compared to the SD group. Then we administered oral indole treatment to male C57BL\/6J mice with HFD\u2010induced NAFLD and observed a significant improvement in hepatic steatosis and inflammation. Notably, indole alleviated the HFD\u2010induced decline in serum Angiotensin\u2010(1\u20137) [Ang\u2010(1\u20137)] levels and Angiotensin\u2010Converting Enzyme 2 (ACE2) expression. To further investigate the role of indole and ACE2 in NAFLD, we conducted experiments using ACE2 knockout (ACE2KO) mice that were also induced with HFD\u2010induced NAFLD and treated with indole. Interestingly, the protective effects of indole were compromised in the absence of ACE2. In HepG2 cells, indole similarly stimulated ACE2 expression and, in an ACE2\u2010dependent manner, reduced ROS generation, maintained mitochondrial membrane potential stability, and increased SIRT3 expression. In summary, our results highlight the formation of a biologically active gut\u2010liver axis between the gut microbiota and the liver through the tryptophan metabolite indole, which mitigates NAFLD in an ACE2\u2010dependent manner. Elevating dietary tryptophan and increasing indole levels may represent an effective approach for preventing and treating NAFLD.<\/jats:p>","DOI":"10.1096\/fj.202401172rr","type":"journal-article","created":{"date-parts":[[2024,9,21]],"date-time":"2024-09-21T04:14:36Z","timestamp":1726892076000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Indole alleviates nonalcoholic fatty liver disease in an\n                    <scp>ACE2<\/scp>\n                    \u2010dependent manner"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4685-6310","authenticated-orcid":false,"given":"Yuanyuan","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan 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