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Dysfunction of E74-like ETS transcription factor 4 (ELF4) leads to colitis. We aimed to test the hypothesis that intestinal ELF4 plays a critical role in maintaining the normal function of intestinal barrier and gut homeostasis in a mouse model of ALD. Intestinal ELF4 deficiency resulted in dysfunction of the intestinal barrier. Elf4\u2212\/\u2212 mice exhibited gut microbiota (GM) dysbiosis with the characteristic of a larger proportion of Proteobacteria. The LPS increased in Elf4\u2212\/\u2212 mice and was the most important differential metabolite between Elf4\u2212\/\u2212 mice and WT mice. Alcohol exposure increased liver-to-body weight ratio, and hepatic inflammation response and steatosis in WT mice. These deleterious effects were exaggerated in Elf4\u2212\/\u2212 mice. Alcohol exposure significantly increased serum levels of TG, ALT, and AST in Elf4\u2212\/\u2212 mice but not in WT mice. In addition, alcohol exposure resulted in enriched expression of genes associated with cholesterol metabolism and lipid metabolism in livers from Elf4\u2212\/\u2212 mice. 16S rRNA sequencing showed a decrease abundance of Akkermansia and Bilophila in Elf4\u2212\/\u2212 mice. In conclusion, intestinal ELF4 is an important host protective factor in maintaining gut homeostasis and alleviating alcohol exposure-induced hepatic steatosis and injury.<\/jats:p>","DOI":"10.3390\/ijms23094825","type":"journal-article","created":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T13:40:57Z","timestamp":1651066857000},"page":"4825","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Intestinal ELF4 Deletion Exacerbates Alcoholic Liver Disease by Disrupting Gut Homeostasis"],"prefix":"10.3390","volume":"23","author":[{"given":"Tongtong","family":"Liu","sequence":"first","affiliation":[{"name":"Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haitao","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunfei","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Center for Infectious Diseases, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"},{"name":"School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7444-729X","authenticated-orcid":false,"given":"Fuping","family":"You","sequence":"additional","affiliation":[{"name":"Institute of Systems Biomedicine, Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s41575-018-0099-1","article-title":"Alcohol, liver disease and the gut microbiota","volume":"16","author":"Bajaj","year":"2019","journal-title":"Nat. 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