Bacterial metabolites controlling Th17 and Treg cells

摘要 维持炎症 Th17 细胞和抗炎 Treg 细胞之间的平衡对于 支持肠道屏障功能和组织稳态。核激素受体 (NhR) 研究表明，它们在关键免疫细胞（包括 Th17 和 Treg 细胞）的发育和功能中发挥着至关重要的作用。 根据我们之前的工作，我们假设宿主产生的细菌修饰类固醇与宿主 NhR 结合 并调节 T 细胞的分化和功能。具体来说，我们假设次级胆汁酸（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 细胞分化和 功能。 我们之前证明了两种胆汁酸代谢物调节 T 细胞分化：3-oxo- 石胆酸 (3oxoLCA) 抑制幼稚 T 细胞分化为炎症 Th17 细胞，并且异同种异体 石胆酸 (isoalloLCA) 可增强幼稚 T 细胞向抗炎 Treg 细胞的分化。 尽管我们确定 3oxoLCA 通过作为 RORγt（视黄酸）的配体抑制 Th17 细胞，但 受体相关的孤儿核受体 γ t)，目前尚不清楚 isoalloLCA 是否发挥其 Treg 细胞调节作用 通过 NhR 采取行动的活动。此外，可能还存在调节 T 细胞的额外胆汁酸 回应。在前期工作中，我们鉴定了一种丰富的胆汁酸代谢物，异石胆酸 (isoLCA) 抑制 Th17 细胞分化和功能，以及产生 isoLCA 的人类肠道细菌 和 isoalloLCA。我们发现，这些代谢物在粪便中的水平显着降低。 患有克罗恩病的人类患者与健康对照者相比。我们建议（1）识别人类肠道 负责产生 isoLCA 和 isoalloLCA 的细菌和细菌基因，(2) 确定 这些化合物影响 Th17 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宿主体内的免疫反应。 阐明产生免疫调节胆汁酸的途径及其作用机制 将为研究肠道微生物和肠道微生物之间独特的调控相互作用开辟令人兴奋的途径 宿主免疫细胞。这项研究将为开发新疗法奠定基础 自身免疫性疾病，包括炎症性肠病。

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.