Gut microbiota metabolite sensing licenses IEC to cross talk with T cells to inhibit intestinal inflammation

肠道微生物代谢传感许可 IEC 与 T 细胞交互作用以抑制肠道炎症

• 批准号: 10602998
• 负责人: Yingzi Cong
• 金额: $ 55.68万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2023-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602998
• 关键词: Acetates; Affect; Animal Model; Antigens; Butyrates; CD4 Positive T Lymphocytes; Carbohydrates; Cell physiology; Cells; Chromatin; Colitis; Data; Development; Diet; Disease; EZH2 gene; Enzymes; Epigenetic Process; Epithelial Cells; Epithelium; Erythroid; Extrinsic asthma; Fiber; Flagellin; Flavonoids; Gene Expression; Genetic Polymorphism; Histone H3; Histones; Homeostasis; IRF4 gene; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Kinetics; Knockout Mice; Knowledge; Licensing; Lysine; Maintenance; Mediating; Metabolic; Molecular; Mucous Membrane; Mus; Nuclear; Oral; Pathogenesis; Pathway interactions; Patients; Pattern; Physiological; Play; Prevention; Production; Propionates; Regulation; Risk; Role; Spontaneous colitis; Stimulus; T cell response; T-Lymphocyte; Testing; Volatile Fatty Acids; absorption; cell type; comparative; conditional knockout; dysbiosis; feeding; gut bacteria; gut inflammation; gut microbiota; histone methylation; host-microbe interactions; in vivo; interest; intestinal epithelium; intestinal homeostasis; metabolomics; microbiota; microbiota metabolites; new therapeutic target; novel; pathogen; preservation; prevent; small molecule

Project Summary The mechanisms by which gut microbiota regulate intestinal homeostasis and the pathogenesis of inflammatory bowel diseases (IBD) remain unclear. Emerging evidence suggests that the host immune system can sense gut bacterial metabolites in addition to pathogen-associated molecular patterns (PAMP). The recognition of these small molecules can influence the host immune response in the context of disease and inflammation in the gut and beyond. Of particular interest are short-chain fatty acids (SCFA), such as acetate, propionate, and butyrate, which are solely metabolized by gut bacteria from otherwise indigestible carbohydrates, i.e., from fiber-rich diets, and have been shown to alleviate disease in animal models of colitis and allergic asthma. Furthermore, SCFAs are associated with reduced risk of various diseases, including IBD, and dysbiosis in IBD patients has been associated with altered SCFA fermentative pathways. However, the mechanisms involved are still largely unknown. The intestinal epithelial cells (IECs) are the primary cell type in direct contact with stimuli from the luminal microbiota and are critical players in microbe-host interactions. Although it has been shown that SCFA can regulate T cell function, the majority of SCFA are absorbed by epithelial cells in the intestine. Only a small portion of SCFA is available in the free form to directly act on T cells or other mucosal immune cells underneath the epithelium in physiological conditions. Thus, how SCFA regulates mucosal immune cells to contribute to intestinal homeostasis remains unclear. Our preliminary data demonstrated that SCFA has persistent effects on T cell IL-10 production in vivo, which could mediate SCFA protection. The SCFA-induced long-lasting effect is independent of gut microbiota. Interestingly, SCFA inhibits IEC expression of EZH2, a histone-modifying enzyme methylating histone H3 lysine 27, and SCFA-treated IECs promote T cell IL-10 production. By employing untargeted comparative metabolomic analyses, we identified that SCFA drives a significant shift in the levels of IEC metabolites, which promote T cell IL-10 production, indicating a crucial role of IEC sensing SCFA in IEC-T cell crosstalk and maintaining intestinal homeostasis. The central hypothesis of this project is that IEC sensing of SCFA regulates T cell function through metabolic products, which leads to the preservation of intestinal immune homeostasis and inhibition of IBD. We will test our hypothesis in this application to determine (1) how SCFA epigenetically regulates IEC, the role of IEC EZH2 in T cell responses to microbiota, and the maintenance of intestinal homeostasis; (2) which IEC metabolites induced by SCFA are required for promoting T cell IL-10 production and inhibition of colitis; and (3) the role of IEC metabolites in the prevention and treatment of colitis.

项目摘要 肠道微生物群调节肠道内稳态的机制和炎症的发病机制 肠道疾病（IBD）仍不清楚。新出现的证据表明，宿主免疫系统可以感知肠道 细菌代谢物以及病原体相关分子模式（PAMP）。承认这些 在肠道疾病和炎症的背景下，小分子可以影响宿主的免疫应答 以及更远的地方特别感兴趣的是短链脂肪酸（SCFA），例如乙酸酯、丙酸酯和丁酸酯， 其仅由肠道细菌从其他不可消化的碳水化合物代谢，即，从富含纤维的饮食， 并且已经显示在结肠炎和过敏性哮喘的动物模型中减轻疾病。此外，SCFA 与包括IBD在内的各种疾病的风险降低有关，IBD患者的生态失调已经被 与改变的SCFA发酵途径有关。然而，所涉及的机制在很大程度上仍然是 未知肠上皮细胞（IEC）是与来自肠上皮细胞的刺激直接接触的主要细胞类型。 在微生物-宿主相互作用中起关键作用。尽管已经表明SCFA 可以调节T细胞功能，大部分SCFA被肠上皮细胞吸收。只有一小 SCFA的一部分以游离形式直接作用于T细胞或其下的其他粘膜免疫细胞 生理条件下的上皮细胞。因此，SCFA如何调节粘膜免疫细胞， 肠内稳态仍不清楚。我们的初步数据表明，SCFA具有持久的影响， 体内T细胞IL-10产生，其可介导SCFA保护。SCFA诱导的长期效果是 独立于肠道微生物群。有趣的是，SCFA抑制IEC表达EZH 2，一种组蛋白修饰酶， 甲基化组蛋白H3赖氨酸27和SCFA处理的IEC促进T细胞IL-10产生。通过采用 通过非靶向比较代谢组学分析，我们发现SCFA驱动了 IEC代谢物，促进T细胞IL-10的产生，表明IEC传感SCFA在IEC-T中的关键作用。 细胞串扰和维持肠道内稳态。该项目的中心假设是IEC传感 SCFA的含量通过代谢产物调节T细胞功能，从而保护肠道 免疫稳态和IBD抑制。我们将在本申请中测试我们的假设，以确定（1）如何 SCFA表观遗传地调节IEC、IEC EZH 2在T细胞对微生物群的应答中的作用以及维持IEC EZH 2的表达。 （2）SCFA诱导的IEC代谢产物是促进T细胞IL-10所必需的 IEC代谢物在结肠炎预防和治疗中的作用。