Bacterial metabolites controlling Th17 and Treg cells

控制 Th17 和 Treg 细胞的细菌代谢物

• 批准号: 10365478
• 负责人: Jun R. Huh
• 金额: $ 71.87万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365478
• 关键词: Affect; Anti-Inflammatory Agents; Autoimmune; Autoimmune Diseases; Bacteria; Bacterial Genes; Bile Acids; Binding; Cell Differentiation process; Cell physiology; Cells; Cholesterol; Colon; Crohn' s disease; Data; Detergents; Development; Digestion; Digoxin; Disease; Enzymes; Equilibrium; Feces; Foundations; Homeostasis; Human; Immune; Immune response; Immune system; In Vitro; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Ligands; Lithocholic Acid; Liver; Maintenance; Mediating; Molecular; Mus; Natural Products; Nuclear Hormone Receptors; Nuclear Orphan Receptor; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Plants; Play; Production; Publishing; Regulatory T-Lymphocyte; Reporting; Research; Retinoic Acid Receptor; Role; Shapes; Steroids; Systems Development; T cell differentiation; T cell response; T-Lymphocyte; Testing; Tissues; Ulcerative Colitis; Work; adaptive immunity; bacterial metabolism; base; bile acid metabolism; cellular targeting; commensal bacteria; gut bacteria; gut dysbiosis; gut microbes; gut microbiota; immunoregulation; in vivo; insight; intestinal barrier; microbial; microbiota; microorganism; novel; novel therapeutic intervention; novel therapeutics; programs; receptor; response; screening

Abstract Maintaining an equilibrium between inflammatory Th17 cells and anti-inflammatory Treg cells is critical to support intestinal barrier function and tissue homeostasis. Nuclear hormone receptors (NhRs) have been shown to play crucial roles in the development and function of key immune cells, including Th17 and Treg cells. Based on our prior work, we hypothesize that host-produced, bacterially modified steroids bind to host NhRs and modulate T cell differentiation and function. Specifically, we posit that secondary bile acids (microbial metabolites of host-produced primary bile acids) bind to host NhRs and modulate T cell differentiation and function. We previously demonstrated that two bile acid metabolites modulate T cell differentiation: 3-oxo- lithocholic acid (3oxoLCA) inhibits the differentiation of naïve T cells into inflammatory Th17 cells, and isoallo- lithocholic acid (isoalloLCA) enhances the differentiation of naïve T cells into anti-inflammatory Treg cells. Although we determined that 3oxoLCA inhibited Th17 cells by acting as a ligand for RORγt (retinoic acid receptor-related orphan nuclear receptor γ t), it is unknown whether isoalloLCA exerts its Treg cell-modulating activity by acting through NhR(s). In addition, it is likely that there are additional bile acids that modulate T cell responses. In preliminary work, we have identified an abundant bile acid metabolite, iso-lithocholic acid (isoLCA) that inhibits Th17 cell differentiation and function, as well as human gut bacteria that produce isoLCA and isoalloLCA. We have found that the levels of these metabolites are significantly decreased in the feces of human patients with Crohn’s disease compared to healthy controls. We propose to (1) identify human gut bacteria and bacterial genes responsible for the production of isoLCA and isoalloLCA, (2) determine the molecular mechanisms by which these compounds influence Th17 and Treg differentiation and function, and (3) investigate whether gut bacteria producing isoLCA and isoalloLCA affect host immune responses in vivo. Elucidating the pathways that produce immunomodulatory bile acids and their mechanisms of action will open up exciting avenues to study unique regulatory interactions between gut-residing microorganisms and host immune cells. This research will lay the groundwork for the development of new therapies to treat autoimmune diseases, including inflammatory bowel disease.

摘要 维持炎性Th 17细胞和抗炎性Treg细胞之间的平衡对于 支持肠屏障功能和组织稳态。核激素受体（NHR）已被 显示在关键免疫细胞的发育和功能中发挥关键作用，包括Th 17和Treg细胞。 基于我们先前的工作，我们假设宿主产生的、细菌修饰的类固醇与宿主NHR结合 并调节T细胞分化和功能。具体来说，我们认为，二级胆汁酸（微生物 宿主产生的初级胆汁酸的代谢物）与宿主NhR结合并调节T细胞分化， 功能 我们先前证明了两种胆汁酸代谢物调节T细胞分化：3-氧代- 石胆酸（3 oxoLCA）抑制幼稚T细胞分化为炎性Th 17细胞，而异源性 石胆酸（isoalloLCA）增强幼稚T细胞向抗炎性Treg细胞的分化。 虽然我们确定3 oxoLCA通过作为RORγt（维甲酸）的配体抑制Th 17细胞， 受体相关孤儿核受体γ t），目前尚不清楚isoalloLCA是否发挥其调节Treg细胞的作用。 通过NhR（s）起作用的活性。此外，很可能还有额外的胆汁酸调节T细胞增殖。 应答在前期工作中，我们已经确定了丰富的胆汁酸代谢产物，异石胆酸 抑制Th 17细胞分化和功能的异LCA（isoLCA），以及产生isoLCA的人肠道细菌 和isoalloLCA。我们已经发现，这些代谢物的水平显着降低，在粪便中， 克罗恩病患者与健康对照的比较。我们建议（1）识别人类肠道 细菌和负责生产isoLCA和isoalloLCA的细菌基因，（2）确定 这些化合物影响Th 17和Treg分化和功能的分子机制，以及（3） 研究产生isoLCA和isoalloLCA的肠道细菌是否影响体内宿主免疫应答。 阐明产生免疫调节胆汁酸的途径及其作用机制 将开辟令人兴奋的途径来研究肠道微生物与肠道微生物之间独特的调节相互作用 宿主免疫细胞这项研究将为开发新的治疗方法奠定基础。 自身免疫性疾病，包括炎症性肠病。