Zhonglin Li , Wenkang Gao , Hang Yuan , Xiaoli Pan , Ruiqing Yuan , Weijun Wang , Lei Guan , Lilin Hu , Yue Chen , Zilu Cheng , Ruohang He , Lei Zhang , Bowen Yang , Qingjing Zhu , Minglu Liang , Ekihiro Seki , Rong Lin , Huikuan Chu , Ling Yang
{"title":"通过 Akkermansia muciniphila QAA37749.1 介导的甜菜碱转化，抑制肠道 Ticam1 可改善 MASH。","authors":"Zhonglin Li , Wenkang Gao , Hang Yuan , Xiaoli Pan , Ruiqing Yuan , Weijun Wang , Lei Guan , Lilin Hu , Yue Chen , Zilu Cheng , Ruohang He , Lei Zhang , Bowen Yang , Qingjing Zhu , Minglu Liang , Ekihiro Seki , Rong Lin , Huikuan Chu , Ling Yang","doi":"10.1016/j.bbadis.2024.167571","DOIUrl":null,"url":null,"abstract":"<div><h3>Background & aims</h3><div>Gut inflammation caused by diets could damage the intestinal barrier, which increases the liver exposition to pathogenic substances. Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (Ticam1) is a key molecule in the Toll-like receptors (TLRs) pathway, which is important for the immune defense against pathogens such as bacteria or viruses. In this study, mouse intestinal epithelial cell (IEC) Ticam1 was knocked out to suppress the intestinal inflammation response in metabolic dysfunction-associated steatohepatitis (MASH) to investigate its influence on the development of MASH.</div></div><div><h3>Methods</h3><div>The IEC-specific Ticam1 knockout (<em>Ticam1</em><sup><em>ΔIEC</em></sup>) mice and the control (<em>Ticam1</em><sup><em>fl/fl</em></sup>) mice were fed with high-fat high-fructose diet (HFD) for 22 weeks to evaluate the gut alteration and the MASH-associated disorders. The intestinal secreted immunoglobulin A (sIgA) and IgA-secreting immune cells were detected. Shotgun metagenomic sequencing was used to find the gut microbiome shift in different groups. Liquid chromatography mass spectrometry was also performed to evaluate the change of serum metabolites caused by the gut microbiome alteration.</div></div><div><h3>Results</h3><div>The gut inflammation and gut barrier dysfunction were both alleviated in HFD-fed <em>Ticam1</em><sup><em>ΔIEC</em></sup> mice, which had improved MASH disorders compared with <em>Ticam1</em><sup><em>fl/fl</em></sup>. Additionally, HFD-fed <em>Ticam1</em><sup><em>ΔIEC</em></sup> mice had increased sIgA and intestinal IgA-secreting immune cells. It showed a significantly higher content of <em>Akkermansia muciniphila</em>. We proved that <em>Akkermansia muciniphila</em> encoded a protein named QAA37749.1 that could promote the conversion of choline to betaine, through which the development of MASH was inhibited in HFD-<em>Ticam1</em><sup><em>ΔIEC</em></sup> mice.</div></div><div><h3>Conclusion</h3><div>Deletion of IEC Ticam1 alleviated MASH disorder and gut dysfunction in mice. It enhanced the level of intestinal sIgA and the growth of <em>Akkermansia muciniphila</em>, which supported the betaine transformation by QAA37749.1. Suppressing IEC Ticam1 might be a promising strategy for MASH disorder.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167571"},"PeriodicalIF":4.2000,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Suppression of intestinal Ticam1 ameliorated MASH via Akkermansia muciniphila QAA37749.1 mediated betaine transformation\",\"authors\":\"Zhonglin Li , Wenkang Gao , Hang Yuan , Xiaoli Pan , Ruiqing Yuan , Weijun Wang , Lei Guan , Lilin Hu , Yue Chen , Zilu Cheng , Ruohang He , Lei Zhang , Bowen Yang , Qingjing Zhu , Minglu Liang , Ekihiro Seki , Rong Lin , Huikuan Chu , Ling Yang\",\"doi\":\"10.1016/j.bbadis.2024.167571\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background & aims</h3><div>Gut inflammation caused by diets could damage the intestinal barrier, which increases the liver exposition to pathogenic substances. Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (Ticam1) is a key molecule in the Toll-like receptors (TLRs) pathway, which is important for the immune defense against pathogens such as bacteria or viruses. In this study, mouse intestinal epithelial cell (IEC) Ticam1 was knocked out to suppress the intestinal inflammation response in metabolic dysfunction-associated steatohepatitis (MASH) to investigate its influence on the development of MASH.</div></div><div><h3>Methods</h3><div>The IEC-specific Ticam1 knockout (<em>Ticam1</em><sup><em>ΔIEC</em></sup>) mice and the control (<em>Ticam1</em><sup><em>fl/fl</em></sup>) mice were fed with high-fat high-fructose diet (HFD) for 22 weeks to evaluate the gut alteration and the MASH-associated disorders. The intestinal secreted immunoglobulin A (sIgA) and IgA-secreting immune cells were detected. Shotgun metagenomic sequencing was used to find the gut microbiome shift in different groups. Liquid chromatography mass spectrometry was also performed to evaluate the change of serum metabolites caused by the gut microbiome alteration.</div></div><div><h3>Results</h3><div>The gut inflammation and gut barrier dysfunction were both alleviated in HFD-fed <em>Ticam1</em><sup><em>ΔIEC</em></sup> mice, which had improved MASH disorders compared with <em>Ticam1</em><sup><em>fl/fl</em></sup>. Additionally, HFD-fed <em>Ticam1</em><sup><em>ΔIEC</em></sup> mice had increased sIgA and intestinal IgA-secreting immune cells. It showed a significantly higher content of <em>Akkermansia muciniphila</em>. We proved that <em>Akkermansia muciniphila</em> encoded a protein named QAA37749.1 that could promote the conversion of choline to betaine, through which the development of MASH was inhibited in HFD-<em>Ticam1</em><sup><em>ΔIEC</em></sup> mice.</div></div><div><h3>Conclusion</h3><div>Deletion of IEC Ticam1 alleviated MASH disorder and gut dysfunction in mice. It enhanced the level of intestinal sIgA and the growth of <em>Akkermansia muciniphila</em>, which supported the betaine transformation by QAA37749.1. Suppressing IEC Ticam1 might be a promising strategy for MASH disorder.</div></div>\",\"PeriodicalId\":8821,\"journal\":{\"name\":\"Biochimica et biophysica acta. Molecular basis of disease\",\"volume\":\"1871 1\",\"pages\":\"Article 167571\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-11-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochimica et biophysica acta. 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Suppression of intestinal Ticam1 ameliorated MASH via Akkermansia muciniphila QAA37749.1 mediated betaine transformation
Background & aims
Gut inflammation caused by diets could damage the intestinal barrier, which increases the liver exposition to pathogenic substances. Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (Ticam1) is a key molecule in the Toll-like receptors (TLRs) pathway, which is important for the immune defense against pathogens such as bacteria or viruses. In this study, mouse intestinal epithelial cell (IEC) Ticam1 was knocked out to suppress the intestinal inflammation response in metabolic dysfunction-associated steatohepatitis (MASH) to investigate its influence on the development of MASH.
Methods
The IEC-specific Ticam1 knockout (Ticam1ΔIEC) mice and the control (Ticam1fl/fl) mice were fed with high-fat high-fructose diet (HFD) for 22 weeks to evaluate the gut alteration and the MASH-associated disorders. The intestinal secreted immunoglobulin A (sIgA) and IgA-secreting immune cells were detected. Shotgun metagenomic sequencing was used to find the gut microbiome shift in different groups. Liquid chromatography mass spectrometry was also performed to evaluate the change of serum metabolites caused by the gut microbiome alteration.
Results
The gut inflammation and gut barrier dysfunction were both alleviated in HFD-fed Ticam1ΔIEC mice, which had improved MASH disorders compared with Ticam1fl/fl. Additionally, HFD-fed Ticam1ΔIEC mice had increased sIgA and intestinal IgA-secreting immune cells. It showed a significantly higher content of Akkermansia muciniphila. We proved that Akkermansia muciniphila encoded a protein named QAA37749.1 that could promote the conversion of choline to betaine, through which the development of MASH was inhibited in HFD-Ticam1ΔIEC mice.
Conclusion
Deletion of IEC Ticam1 alleviated MASH disorder and gut dysfunction in mice. It enhanced the level of intestinal sIgA and the growth of Akkermansia muciniphila, which supported the betaine transformation by QAA37749.1. Suppressing IEC Ticam1 might be a promising strategy for MASH disorder.
期刊介绍：
BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.
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