Bacterial metabolites controlling Th17 and Treg cells

控制 Th17 和 Treg 细胞的细菌代谢物

基本信息

  • 批准号:
    10365478
  • 负责人:
  • 金额:
    $ 71.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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。

项目成果

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Jun R. Huh其他文献

Brain-wide mapping of immune receptors uncovers a neuromodulatory role of IL-17E and the receptor IL-17RB
大脑范围内免疫受体的图谱揭示了 IL-17E 及其受体 IL-17RB 的神经调节作用
  • DOI:
    10.1016/j.cell.2025.03.006
  • 发表时间:
    2025-04-17
  • 期刊:
  • 影响因子:
    42.500
  • 作者:
    Yunjin Lee;Tomoe Ishikawa;Hyeseung Lee;Byeongjun Lee;Changhyeon Ryu;Irene Davila Mejia;Minjin Kim;Guangqing Lu;Yujin Hong;Mengyang Feng;Hyeyoon Shin;Sylvain Meloche;Richard M. Locksley;Ekaterina Koltsova;Sergei I. Grivennikov;Myriam Heiman;Gloria B. Choi;Jun R. Huh
  • 通讯作者:
    Jun R. Huh
Apoptosis: Sculpture of a fly's head
细胞凋亡:苍蝇头部雕塑
  • DOI:
    10.1038/418926a
  • 发表时间:
    2002
  • 期刊:
  • 影响因子:
    64.8
  • 作者:
    Jun R. Huh;B. Hay
  • 通讯作者:
    B. Hay
Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4sup+/sup T cells
母体肠道细菌通过改变 CD4+T 细胞的染色质景观,在患有神经发育障碍的后代中驱动肠道炎症。
  • DOI:
    10.1016/j.immuni.2021.11.005
  • 发表时间:
    2022-01-11
  • 期刊:
  • 影响因子:
    26.300
  • 作者:
    Eunha Kim;Donggi Paik;Ricardo N. Ramirez;Delaney G. Biggs;Youngjun Park;Ho-Keun Kwon;Gloria B. Choi;Jun R. Huh
  • 通讯作者:
    Jun R. Huh
Gut-innervating nociceptor neurons protect against enteric infection by modulating the microbiota and Peyer’s patch microfold cells
肠道神经伤害感受器神经元通过调节微生物群和派尔氏集结微褶皱细胞来防止肠道感染
  • DOI:
    10.1101/580555
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    0
  • 作者:
    N. Lai;Melissa A. Musser;Felipe A. Pinho;P. Baral;Pingchuan Ma;D. Potts;Zuojia Chen;Donggi Paik;Salima Soualhi;Hailian Shi;Aditya Misra;Kaitlin Goldstein;K. Sivanathan;A. Jacobson;Antonia Wallrapp;Valentina N. Lagomarsino;V. Kuchroo;Roni Nowarski;M. Starnbach;N. Surana;Dingding An;Chuan Wu;Jun R. Huh;M. Rao;I. Chiu
  • 通讯作者:
    I. Chiu
Inflammatory and anti-inflammatory cytokines bidirectionally modulate amygdala circuits regulating anxiety
炎症细胞因子和抗炎细胞因子双向调节调节焦虑的杏仁核回路
  • DOI:
    10.1016/j.cell.2025.03.005
  • 发表时间:
    2025-04-17
  • 期刊:
  • 影响因子:
    42.500
  • 作者:
    Byeongjun Lee;Jeong-Tae Kwon;Yire Jeong;Hannah Caris;Dongsun Oh;Mengyang Feng;Irene Davila Mejia;Xiaoying Zhang;Tomoe Ishikawa;Brianna R. Watson;Jeffrey R. Moffitt;Kwanghun Chung;Jun R. Huh;Gloria B. Choi
  • 通讯作者:
    Gloria B. Choi

Jun R. Huh的其他文献

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{{ truncateString('Jun R. Huh', 18)}}的其他基金

Dissecting the modulatory functions of interleukin-17 in Alzheimer's Disease
剖析 IL-17 在阿尔茨海默病中的调节功能
  • 批准号:
    10590495
  • 财政年份:
    2022
  • 资助金额:
    $ 71.87万
  • 项目类别:
Pregnancy influences maternal immune cell function and fetal brain development
怀孕影响母体免疫细胞功能和胎儿大脑发育
  • 批准号:
    10669604
  • 财政年份:
    2019
  • 资助金额:
    $ 71.87万
  • 项目类别:
Pregnancy influences maternal immune cell function and fetal brain development
怀孕影响母体免疫细胞功能和胎儿大脑发育
  • 批准号:
    10011840
  • 财政年份:
    2019
  • 资助金额:
    $ 71.87万
  • 项目类别:
Pregnancy influences maternal immune cell function and fetal brain development
怀孕影响母体免疫细胞功能和胎儿大脑发育
  • 批准号:
    10437718
  • 财政年份:
    2019
  • 资助金额:
    $ 71.87万
  • 项目类别:
Pregnancy influences maternal immune cell function and fetal brain development
怀孕影响母体免疫细胞功能和胎儿大脑发育
  • 批准号:
    10215459
  • 财政年份:
    2019
  • 资助金额:
    $ 71.87万
  • 项目类别:
Lipid-dependent regulation of human Th17 cell function
人类 Th17 细胞功能的脂质依赖性调节
  • 批准号:
    9176733
  • 财政年份:
    2016
  • 资助金额:
    $ 71.87万
  • 项目类别:
Bacterial metabolites controlling Th17 cells
控制 Th17 细胞的细菌代谢物
  • 批准号:
    9571441
  • 财政年份:
    2016
  • 资助金额:
    $ 71.87万
  • 项目类别:
Lipid-dependent regulation of human Th17 cell function
人类 Th17 细胞功能的脂质依赖性调节
  • 批准号:
    9316588
  • 财政年份:
    2016
  • 资助金额:
    $ 71.87万
  • 项目类别:
Lipid-dependent regulation of human Th17 cell function
人类 Th17 细胞功能的脂质依赖性调节
  • 批准号:
    9582212
  • 财政年份:
    2016
  • 资助金额:
    $ 71.87万
  • 项目类别:
Bacterial metabolites controlling Th17 and Treg cells
控制 Th17 和 Treg 细胞的细菌代谢物
  • 批准号:
    10670406
  • 财政年份:
    2016
  • 资助金额:
    $ 71.87万
  • 项目类别:

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开发作为抗炎剂和砷解毒剂的小分子抑制剂
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开发用作抗炎剂的inlammasome抑制剂
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