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.

摘要

项目成果

Isolation and analyses of lamina propria lymphocytes from mouse intestines.

从小鼠肠中分离和分析固定层淋巴细胞。

• 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.