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Our previous studies indicated that VVYP could protect against acetaminophen and carbon tetrachloride\u2010induced acute liver failure in mice and decrease blood lipid level. However, the effects and underlying mechanisms of VVYP in the treatment of non\u2010alcoholic steatohepatitis (NASH) have not been discovered. Our present study was designed to investigate the preventive effect of VVYP on NASH and its underlying specific mechanisms. We found that VVYP inhibited the cytotoxicity and lipid accumulation in L\u201002 cells that were exposed to a mixture of free fatty acid (FFA). VVYP effectively alleviated the liver injury induced by methionine\u2010choline\u2010deficient (MCD) diet, demonstrated by reducing the levels of serum alanine aminotransferase (ALT)\/aspartate aminotransferase (AST)\/triglycerides (TG)\/non\u2010esterified fatty acids (NEFA) and improving liver histology. VVYP decreased expression levels of lipid synthesis\u2010related genes and reduced levels of the proinflammation cytokines in the liver of mice fed by MCD diet. Moreover, VVYP inhibited the increased level of LPS and reversed the liver mitochondria dysfunction induced by MCD diet. Meanwhile, VVYP significantly increased the abundance of beneficial bacteria such as <jats:italic>Eubacteriaceae<\/jats:italic>, <jats:italic>coriobacteriacease, Desulfovibrionaceae, S24\u20107<\/jats:italic> and <jats:italic>Bacteroidia<\/jats:italic> in high\u2010fat diet (HFD)\u2010fed mice, however, VVYP reduced the abundance of <jats:italic>Lactobacillus<\/jats:italic>. Moreover, VVYP conferred the protective effect of intestinal barrier via promoting the expression of the mucins and tight junction (TJ)\u2010associated genes and inhibited subsequent liver inflammatory responses. These results indicated that the protective role of VVYP on NASH is mediated by modulating gut microbiota imbalance and related gut\u2010liver axis activation. VVYP might be a promising drug candidate for NASH.<\/jats:p>","DOI":"10.1111\/jcmm.16229","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T07:42:51Z","timestamp":1609918971000},"page":"1439-1455","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Val\u2010Val\u2010Tyr\u2010Pro protects against non\u2010alcoholic steatohepatitis in mice by modulating the gut microbiota and gut\u2010liver axis activation"],"prefix":"10.1111","volume":"25","author":[{"given":"Xinshu","family":"Xie","sequence":"first","affiliation":[{"name":"National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine Jiangxi University of Traditional Chinese Medicine Nanchang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Children's Hospital Nanchang 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