Bacterial metabolites controlling Th17 and Treg cells

控制 Th17 和 Treg 细胞的细菌代谢物

• 批准号: 10670406
• 负责人: Jun R. Huh
• 金额: $ 70.29万
• 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/10670406
• 关键词: Affect; Anti-Inflammatory Agents; Autoimmune Diseases; Bacteria; Bacterial Genes; Bile Acids; Binding; Cell Differentiation process; Cell physiology; Cells; Cholesterol; Circulation; 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; antagonist; bacterial metabolism; bile acid metabolism; cellular targeting; commensal bacteria; gut bacteria; gut dysbiosis; gut microbes; gut microbiota; immunoregulation; in vivo; inflammatory modulation; insight; intestinal barrier; meter; 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.

抽象的 维持炎症性Th17细胞和抗炎Treg细胞之间的平等第一至关重要 支持肠道屏障功能和组织稳态。核马酮受体（NHR）已经 证明在包括Th17和Treg细胞在内的关键免疫细胞的开发和功能中起着至关重要的作用。 基于我们先前的工作，我们假设宿主生产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。具体而言，我们阳性次级胆汁酸（微生物 宿主产生的原发性胆汁酸的代谢产物）与宿主NHRS结合并调节T细胞分化和 功能。 我们先前证明了两个胆汁酸代谢物调节T细胞分化：3-氧 岩性酸（3Oxolca）抑制幼稚的T细胞分化为炎症性TH17细胞，以及异性含量 岩性酸（Isoallolca）增强了幼稚T细胞为抗炎Treg细胞的分化。 尽管我们确定3Oxolca通过充当RORγT（视黄酸）的配体抑制了Th17细胞 与受体相关的孤儿核受体γt），Isoallolca是否执行其Treg细胞调节尚不清楚 通过NHR作用的活动。另外，可能还有其他调节T细胞的胆汁酸 回答。在初步工作中，我们已经确定了绝对的胆汁酸代谢产物，异硫化胆酸 抑制Th17细胞分化和功能的（孤立）以及产生孤立的人类肠道细菌 和Isoallolca。我们发现，这些代谢物的水平在粪便中显着降低 与健康对照组相比，克罗恩病的人类患者。我们建议（1）识别人类的肠道 细菌和细菌基因负责产生伊斯兰菌和isoallolca，（2）确定 这些化合物影响Th17和Treg分化和功能的分子机制，（3） 研究肠道细菌是否产生分离菌和isoallolca是否会影响体内的宿主免疫反应。 阐明产生免疫调节性胆汁酸及其作用机理的途径 将开辟令人兴奋的途径，以研究肠道微生物和 宿主免疫细胞。这项研究将为开发新疗法的治疗奠定基础 自身免疫性疾病，包括炎症性肠病。

项目成果

Isolation and analyses of lamina propria lymphocytes from mouse intestines.

• DOI: 10.1016/j.xpro.2022.101366
• 发表时间: 2022-06-17
• 期刊: STAR PROTOCOLS
• 作者: Kim, Eunha;Tran, Melissa;Sun, Yanyi;Huh, Jun R.
• 通讯作者: Huh, Jun R.