{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:33:29Z","timestamp":1791725609854,"version":"4.3.4"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T00:00:00Z","timestamp":1615939200000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T00:00:00Z","timestamp":1614556800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Chronic\u00a0alcohol\u00a0consumption is accompanied by intestinal inflammation. However, little is known about how alterations to the intestinal immune system and sphingolipids contribute to the pathogenesis of alcohol\u2010associated liver disease (ALD).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We used wild\u2010type mice, retinoid\u2010related orphan receptor gamma t (ROR\u03b3t)\u2010deficient mice, sphingosine kinase\u2013deficient mice, and local gut anti\u2010inflammatory, 5\u2010aminosalicyclic acid\u2013treated mice in a chronic\u2010binge\u00a0ethanol\u00a0feeding model. Targeted lipidomics assessed the sphingolipids in gut and liver samples. Gut immune cell populations, the amounts of sphingolipids, and the level of liver injury were examined. Alcohol intake induces a pro\u2010inflammatory shift in immune cell populations in the gut, including an increase in Th17 cells. Using ROR\u03b3t\u2010deficient mice, we found that Th17 cells are required for alcohol\u2010associated gut inflammation and the development of ALD. Treatment with 5\u2010aminosalicyclic acid decreases alcohol\u2010induced liver injury and reverses gut inflammation by the suppression of CD4<jats:sup>+<\/jats:sup>\/ROR\u03b3t<jats:sup>+<\/jats:sup>\/interleukin\u201017A<jats:sup>+<\/jats:sup> cells. Increased Th17 cells were due to up\u2010regulation of sphingosine kinase 1 activity and ROR\u03b3t activation. We found that S1P\/S1PR1 signaling is required for the development of Th17 cell\u2013mediated ALD. Importantly, <jats:italic toggle=\"yes\">in vivo<\/jats:italic> intervention blocking of S1P\/S1PR1 signaling markedly attenuated alcohol\u2010induced liver inflammation, steatosis, and damage.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Gut inflammation is a functional alteration of immune cells in ALD. Reducing gut Th17 cells leads to reduced liver damage. S1P signaling was crucial in the pathogenesis of ALD in a Th17 cell\u2013dependent manner. Furthermore, our findings suggest that compounds that reduce gut inflammation locally may represent a unique targeted approach in the treatment of ALD.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31321","type":"journal-article","created":{"date-parts":[[2020,5,17]],"date-time":"2020-05-17T14:15:53Z","timestamp":1589724953000},"page":"952-967","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":51,"title":["Inhibition of Sphingosine\u20101\u2010Phosphate\u2010Induced Th17 Cells Ameliorates Alcohol\u2010Associated Steatohepatitis in Mice"],"prefix":"10.1097","volume":"73","author":[{"given":"Shenghui","family":"Chu","sequence":"first","affiliation":[{"name":"Department of Medicine,University of Louisville,Louisville,KY"},{"name":"School of Pharmaceutical Science,Wenzhou Medical 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Medicine,University of Louisville,Louisville,KY"},{"name":"Alcohol Research Center,University of Louisville,Louisville,KY"},{"name":"Hepatobiology & Toxicology Center,University of Louisville,Louisville,KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig J.","family":"McClain","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Louisville,Louisville,KY"},{"name":"Alcohol Research Center,University of Louisville,Louisville,KY"},{"name":"Hepatobiology & Toxicology Center,University of Louisville,Louisville,KY"},{"name":"Robley Rex VA Medical Center,Louisville,KY"},{"name":"Department of Pharmacology & Toxicology,University of Louisville,Louisville,KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongbin","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Medicine,University of Louisville,Louisville,KY"},{"name":"James Graham Brown Cancer Center,University of 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