Bin Bao , Youyuan Wang , Pavl Boudreau , Xinyang Song , Meng Wu , Xi Chen , Izabel Patik , Ying Tang , Jodie Ouahed , Amit Ringel , Jared Barends , Chuan Wu , Emily Balskus , Jay Thiagarajah , Jian Liu , Michael R. Wessels , Wayne Isaac Lencer , Dennis L. Kasper , Dingding An , Bruce Harold Horwitz , Scott B. Snapper
{"title":"细菌鞘磷脂通过抑制 ILC3 衍生的 IL-22 的产生加剧结肠炎","authors":"Bin Bao , Youyuan Wang , Pavl Boudreau , Xinyang Song , Meng Wu , Xi Chen , Izabel Patik , Ying Tang , Jodie Ouahed , Amit Ringel , Jared Barends , Chuan Wu , Emily Balskus , Jay Thiagarajah , Jian Liu , Michael R. Wessels , Wayne Isaac Lencer , Dennis L. Kasper , Dingding An , Bruce Harold Horwitz , Scott B. Snapper","doi":"10.1016/j.jcmgh.2024.04.007","DOIUrl":null,"url":null,"abstract":"<div><h3>Background & Aims</h3><p>Gut bacterial sphingolipids, primarily produced by Bacteroidetes, have dual roles as bacterial virulence factors and regulators of the host mucosal immune system, including regulatory T cells and invariant natural killer T cells. Patients with inflammatory bowel disease display altered sphingolipids profiles in fecal samples. However, how bacterial sphingolipids modulate mucosal homeostasis and regulate intestinal inflammation remains unclear.</p></div><div><h3>Methods</h3><p>We used dextran sodium sulfate (DSS)-induced colitis in mice monocolonized with <em>Bacteroides fragilis</em> strains expressing or lacking sphingolipids to assess the influence of bacterial sphingolipids on intestinal inflammation using transcriptional, protein, and cellular analyses. Colonic explant and organoid were used to study the function of bacterial sphingolipids. Host mucosal immune cells and cytokines were profiled and characterized using flow cytometry, enzyme-linked immunosorbent assay, and Western blot, and cytokine function in vivo was investigated by monoclonal antibody injection.</p></div><div><h3>Results</h3><p><em>B fragilis</em> sphingolipids exacerbated intestinal inflammation. Mice monocolonized with <em>B fragilis</em> lacking sphingolipids exhibited less severe DSS-induced colitis. This amelioration of colitis was associated with increased production of interleukin (IL)-22 by ILC3. Mice colonized with <em>B fragilis</em> lacking sphingolipids following DSS treatment showed enhanced epithelial STAT3 activity, intestinal cell proliferation, and antimicrobial peptide production. Protection against DSS colitis associated with <em>B fragilis</em> lacking sphingolipids was reversed on IL22 blockade. Furthermore, bacterial sphingolipids restricted epithelial IL18 production following DSS treatment and interfered with IL22 production by a subset of ILC3 cells expressing both IL18R and major histocompatibility complex class II.</p></div><div><h3>Conclusions</h3><p><em>B fragilis</em>–derived sphingolipids exacerbate mucosal inflammation by impeding epithelial IL18 expression and concomitantly suppressing the production of IL22 by ILC3 cells.</p></div>","PeriodicalId":55974,"journal":{"name":"Cellular and Molecular Gastroenterology and Hepatology","volume":"18 2","pages":"Article 101350"},"PeriodicalIF":7.1000,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352345X24001048/pdfft?md5=59a34194ef86160c5f3532ad4c9dd497&pid=1-s2.0-S2352345X24001048-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Bacterial Sphingolipids Exacerbate Colitis by Inhibiting ILC3-derived IL-22 Production\",\"authors\":\"Bin Bao , Youyuan Wang , Pavl Boudreau , Xinyang Song , Meng Wu , Xi Chen , Izabel Patik , Ying Tang , Jodie Ouahed , Amit Ringel , Jared Barends , Chuan Wu , Emily Balskus , Jay Thiagarajah , Jian Liu , Michael R. Wessels , Wayne Isaac Lencer , Dennis L. Kasper , Dingding An , Bruce Harold Horwitz , Scott B. Snapper\",\"doi\":\"10.1016/j.jcmgh.2024.04.007\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background & Aims</h3><p>Gut bacterial sphingolipids, primarily produced by Bacteroidetes, have dual roles as bacterial virulence factors and regulators of the host mucosal immune system, including regulatory T cells and invariant natural killer T cells. Patients with inflammatory bowel disease display altered sphingolipids profiles in fecal samples. However, how bacterial sphingolipids modulate mucosal homeostasis and regulate intestinal inflammation remains unclear.</p></div><div><h3>Methods</h3><p>We used dextran sodium sulfate (DSS)-induced colitis in mice monocolonized with <em>Bacteroides fragilis</em> strains expressing or lacking sphingolipids to assess the influence of bacterial sphingolipids on intestinal inflammation using transcriptional, protein, and cellular analyses. Colonic explant and organoid were used to study the function of bacterial sphingolipids. Host mucosal immune cells and cytokines were profiled and characterized using flow cytometry, enzyme-linked immunosorbent assay, and Western blot, and cytokine function in vivo was investigated by monoclonal antibody injection.</p></div><div><h3>Results</h3><p><em>B fragilis</em> sphingolipids exacerbated intestinal inflammation. Mice monocolonized with <em>B fragilis</em> lacking sphingolipids exhibited less severe DSS-induced colitis. This amelioration of colitis was associated with increased production of interleukin (IL)-22 by ILC3. Mice colonized with <em>B fragilis</em> lacking sphingolipids following DSS treatment showed enhanced epithelial STAT3 activity, intestinal cell proliferation, and antimicrobial peptide production. Protection against DSS colitis associated with <em>B fragilis</em> lacking sphingolipids was reversed on IL22 blockade. 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Bacterial Sphingolipids Exacerbate Colitis by Inhibiting ILC3-derived IL-22 Production
Background & Aims
Gut bacterial sphingolipids, primarily produced by Bacteroidetes, have dual roles as bacterial virulence factors and regulators of the host mucosal immune system, including regulatory T cells and invariant natural killer T cells. Patients with inflammatory bowel disease display altered sphingolipids profiles in fecal samples. However, how bacterial sphingolipids modulate mucosal homeostasis and regulate intestinal inflammation remains unclear.
Methods
We used dextran sodium sulfate (DSS)-induced colitis in mice monocolonized with Bacteroides fragilis strains expressing or lacking sphingolipids to assess the influence of bacterial sphingolipids on intestinal inflammation using transcriptional, protein, and cellular analyses. Colonic explant and organoid were used to study the function of bacterial sphingolipids. Host mucosal immune cells and cytokines were profiled and characterized using flow cytometry, enzyme-linked immunosorbent assay, and Western blot, and cytokine function in vivo was investigated by monoclonal antibody injection.
Results
B fragilis sphingolipids exacerbated intestinal inflammation. Mice monocolonized with B fragilis lacking sphingolipids exhibited less severe DSS-induced colitis. This amelioration of colitis was associated with increased production of interleukin (IL)-22 by ILC3. Mice colonized with B fragilis lacking sphingolipids following DSS treatment showed enhanced epithelial STAT3 activity, intestinal cell proliferation, and antimicrobial peptide production. Protection against DSS colitis associated with B fragilis lacking sphingolipids was reversed on IL22 blockade. Furthermore, bacterial sphingolipids restricted epithelial IL18 production following DSS treatment and interfered with IL22 production by a subset of ILC3 cells expressing both IL18R and major histocompatibility complex class II.
Conclusions
B fragilis–derived sphingolipids exacerbate mucosal inflammation by impeding epithelial IL18 expression and concomitantly suppressing the production of IL22 by ILC3 cells.
期刊介绍：
"Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology.
CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.
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