Promoting intestinal antimicrobial defense and microbiome symbiosis contributes to IL-22-mediated protection against alcoholic hepatitis in mice
BackgroundThe 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.MethodsIntestinal IL-22 levels were measured...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1289356/full |
| _version_ | 1827793412120641536 |
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| author | Ruichao Yue Xiaoyuan Wei Liuyi Hao Haibo Dong Wei Guo Xinguo Sun Jiangchao Zhao Zhanxiang Zhou Zhanxiang Zhou Wei Zhong Wei Zhong |
| author_facet | Ruichao Yue Xiaoyuan Wei Liuyi Hao Haibo Dong Wei Guo Xinguo Sun Jiangchao Zhao Zhanxiang Zhou Zhanxiang Zhou Wei Zhong Wei Zhong |
| author_sort | Ruichao Yue |
| collection | DOAJ |
| description | BackgroundThe 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.MethodsIntestinal 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.ResultsAfter 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 Reg3γ and α-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 Akkermansia, 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 in vitro 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.ConclusionOur 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. |
| first_indexed | 2024-03-11T18:18:11Z |
| format | Article |
| id | doaj.art-5f3436445cc8417c89cc5864020e6194 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T18:18:11Z |
| publishDate | 2023-10-01 |
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| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5f3436445cc8417c89cc5864020e61942023-10-16T04:44:43ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12893561289356Promoting intestinal antimicrobial defense and microbiome symbiosis contributes to IL-22-mediated protection against alcoholic hepatitis in miceRuichao Yue0Xiaoyuan Wei1Liuyi Hao2Haibo Dong3Wei Guo4Xinguo Sun5Jiangchao Zhao6Zhanxiang Zhou7Zhanxiang Zhou8Wei Zhong9Wei Zhong10Center for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United StatesDepartment of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, United StatesCenter for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United StatesCenter for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United StatesCenter for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United StatesCenter for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United StatesDepartment of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, United StatesCenter for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United StatesDepartment of Nutrition, University of North Carolina at Greensboro, Greensboro, NC, United StatesCenter for Translational Biomedical Research, University of North Carolina at Greensboro, Kannapolis, NC, United StatesDepartment of Nutrition, University of North Carolina at Greensboro, Greensboro, NC, United StatesBackgroundThe 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.MethodsIntestinal 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.ResultsAfter 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 Reg3γ and α-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 Akkermansia, 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 in vitro 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.ConclusionOur 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1289356/fullAlcohol-associated liver diseaseIL-22STAT3antimicrobial peptidemicrobiotaPAMP translocation |
| spellingShingle | Ruichao Yue Xiaoyuan Wei Liuyi Hao Haibo Dong Wei Guo Xinguo Sun Jiangchao Zhao Zhanxiang Zhou Zhanxiang Zhou Wei Zhong Wei Zhong Promoting intestinal antimicrobial defense and microbiome symbiosis contributes to IL-22-mediated protection against alcoholic hepatitis in mice Frontiers in Immunology Alcohol-associated liver disease IL-22 STAT3 antimicrobial peptide microbiota PAMP translocation |
| title | Promoting intestinal antimicrobial defense and microbiome symbiosis contributes to IL-22-mediated protection against alcoholic hepatitis in mice |
| title_full | Promoting intestinal antimicrobial defense and microbiome symbiosis contributes to IL-22-mediated protection against alcoholic hepatitis in mice |
| title_fullStr | Promoting intestinal antimicrobial defense and microbiome symbiosis contributes to IL-22-mediated protection against alcoholic hepatitis in mice |
| title_full_unstemmed | Promoting intestinal antimicrobial defense and microbiome symbiosis contributes to IL-22-mediated protection against alcoholic hepatitis in mice |
| title_short | Promoting intestinal antimicrobial defense and microbiome symbiosis contributes to IL-22-mediated protection against alcoholic hepatitis in mice |
| title_sort | promoting intestinal antimicrobial defense and microbiome symbiosis contributes to il 22 mediated protection against alcoholic hepatitis in mice |
| topic | Alcohol-associated liver disease IL-22 STAT3 antimicrobial peptide microbiota PAMP translocation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1289356/full |
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