{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:37:22Z","timestamp":1791326242367,"version":"4.3.1"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T00:00:00Z","timestamp":1697414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["R21AA026062, R01AA020212"],"award-info":[{"award-number":["R21AA026062, R01AA020212"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The hepatoprotective effect of interleukin 22 (IL-22) has been reported in several models of liver injuries, including alcohol-associated liver disease (ALD). However, the intestinal role of IL-22 in alcoholic hepatitis remains to be elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Intestinal IL-22 levels were measured in mice fed with alcohol for 8 weeks. IL-22 was then administered to alcohol-fed mice to test its protective effects on alleviating alcoholic hepatitis, focusing on intestinal protection. Acute IL-22 treatment was conducted in mice to further explore the link between IL-22 and the induction of antimicrobial peptide (AMP). Intestinal epithelial cell-specific knockout of signal transducer and activator of transcription 3 (STAT3) mice were generated and used for organoid study to explore its role in IL-22-mediated AMP expression and gut barrier integrity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After alcohol feeding for 8 weeks, the intestinal levels of IL-22 were significantly reduced in mice. IL-22 treatment to alcohol-fed mice mitigated liver injury as indicated by normalized serum transaminase levels, improved liver histology, reduced lipid accumulation, and attenuated inflammation. In the intestine, alcohol-reduced Reg3\u03b3 and \u03b1-defensins levels were reversed by IL-22 treatment. IL-22 also improved gut barrier integrity and decreased endotoxemia in alcohol-fed mice. While alcohol feeding significantly reduced <jats:italic>Akkermansia<\/jats:italic>, IL-22 administration dramatically expanded this commensal bacterium in mice. Regardless of alcohol, acute IL-22 treatment induced a fast and robust induction of intestinal AMPs and STAT3 activation. By using <jats:italic>in vitro<\/jats:italic> cultured intestinal organoids isolated from WT mice and mice deficient in intestinal epithelial-STAT3, we further demonstrated that STAT3 is required for IL-22-mediated AMP expression. In addition, IL-22 also regulates intestinal epithelium differentiation as indicated by direct regulation of sodium-hydrogen exchanger 3 via STAT3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study suggests that IL-22 not only targets the liver but also benefits the intestine in many aspects. The intestinal effects of IL-22 include regulating AMP expression, microbiota, and gut barrier function that is pivotal in ameliorating alcohol induced translocation of gut-derived bacterial pathogens and liver inflammation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1289356","type":"journal-article","created":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T04:44:59Z","timestamp":1697431499000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Promoting intestinal antimicrobial defense and microbiome symbiosis contributes to IL-22-mediated protection against alcoholic hepatitis in 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