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The loss of the hepatic farnesoid X receptor (FXR)\/SHP signal can cause severe cholestatic liver injury (CLI). FXR and SHP have overlapping and nonoverlapping functions in bile acid homeostasis. However, the key role played by SHP in CLI is unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, an alpha\u2010naphthylisothiocyanate (ANIT)\u2010induced cholestasis mouse model was established. The effect of SHP knockout (SHP\u2010KO) on liver and ileal pathology was evaluated. 16S rRNA gene sequencing analysis combined with untargeted metabolomics was applied to reveal the involvement of SHP in the pathogenesis of CLI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results showed that ANIT (75\u00a0mg\/kg) induced cholestasis in WT mice. No significant morphological changes were found in the liver and ileal tissue of SHP\u2010KO mice. However, the serum metabolism and intestinal flora characteristics were significantly changed. Moreover, compared with the WT\u00a0+\u00a0ANIT group, the serum levels of ALT and AST in the SHP\u2010KO\u00a0+\u00a0ANIT group were significantly increased, and punctate necrosis in the liver tissue was more obvious. The ileum villi showed obvious shedding, thinning, and shortening. In addition, SHP\u2010KO\u2010associated differential intestinal flora and differential biomarkers were significantly associated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In this study, we elucidated the serum metabolic characteristics and intestinal flora changes related to the aggravation of CLI in SHP\u2010KO mice induced by ANIT.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jgh.16544","type":"journal-article","created":{"date-parts":[[2024,4,14]],"date-time":"2024-04-14T06:30:05Z","timestamp":1713076205000},"page":"1134-1144","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The contribution of small heterodimer partner to the occurrence and progression of cholestatic liver 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