Regulation of colonic inflammation by butyrate/niacin receptor Gpr109a

丁酸/烟酸受体 Gpr109a 对结肠炎症的调节

• 批准号: 8766246
• 负责人: Nagendra Singh
• 金额: $ 32.84万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766246
• 关键词: Acetates; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Attention; Bacteria; Binding; Biochemical Pathway; Butyrates; Cell surface; Chronic; Colon; Consumption; Data; Defect; Dendritic Cells; Diet; Dietary Fiber; Environment; G-Protein-Coupled Receptors; Gastrointestinal Diseases; Genes; Health; Inflammation; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-10; Intestines; Ligands; Maintenance; Mediating; Modeling; Niacinamide; Nicotinic Acids; Outcome; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Play; Prevention; Prevention approach; Prevention strategy; Production; Property; Propionates; Rag1 Mouse; Regulation; Regulatory T-Lymphocyte; Role; Signal Pathway; Signal Transduction; Sodium Dextran Sulfate; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Ulcerative Colitis; Volatile Fatty Acids; aldehyde dehydrogenases; arrestin 1; base; clinical application; commensal microbes; gastrointestinal; gut microbiota; in vivo; macrophage; mouse model; novel therapeutics; prevent; promoter; public health relevance; receptor; response; therapy design

DESCRIPTION (provided by applicant): Ulcerative colitis (UC) is a chronic gastrointestinal inflammation with limited prevention or treatment options. Colonic dendritic cells (DCs), and macrophages express anti-inflammatory mechanisms that suppress inflammatory responses in the colon. Loss of these anti-inflammatory mechanisms leads to intestinal inflammation during UC. Therefore, enhancing the anti-inflammatory properties of APCs is an important approach for prevention and treatment of UC. A critical barrier to progress in the field is the identification o mechanisms that mediate induction of anti-inflammatory environment and promotion of colonic health, and most importantly, whether we can we harness these mechanisms to design interventions aimed at prevention and/or treatment of UC. Several studies have demonstrated that dietary fiber and specific gut bacteria suppress intestinal inflammations. Dietary fiber/gut microbiota effectors short chain fatty acids (SCFAs); acetate, propionate and butyrate have been speculated to promote colonic health. Among SCFAs, butyrate has received most attention for its anti-inflammatory effects. Therefore, strategies that stimulate butyrate-mediated anti-inflammatory pathways hold a promising approach to prevent and/or treat UC. Our preliminary data demonstrate that Gpr109a, a G- protein coupled receptor for butyrate (and niacin, vitamin B3) induces expression of IL-10, Aldh1a in colonic APCs and potentiate Treg induction and thus facilitates the suppression of colonic inflammation. Based on these findings, the objectives of current proposal are to identify components of the Gpr109a signaling pathway that mediates induction IL-10 and Aldh1a in colonic APCs, and demonstration that targeting of Gpr109a is an effective strategy for prevention and treatment of colonic inflammation in mouse models. The specific aims of this proposal are as follows: Aim 1 will test that peroxisome proliferator-activated receptor ? (PPAR?) plays an essential role in butyrate/niacin/Gpr109a-mediated induction of IL-10 and Aldh1a in colonic APCs, and induction of Tregs in colon and suppression of colonic inflammation. Aim 2 will demonstrate that Gpr109a signaling mediated activation of PPAR? and induction of IL-10 and Aldh1a in colonic APCs and induction of Tregs in colon is ¿-arrestin-1-dependent. Aim 3 will test the hypothesis that Gpr109a ligand replaces role of dietary fiber in induction of Tregs in colon, protect colon against inflammation under dietary fiber deficiency and has a therapeutic value in prevention and treatment of UC. At successful completion, the proposed studies will uncover that Gpr109a is a key receptor that connects dietary fiber/gut bacteria to the biochemical pathways responsible for suppression of colonic inflammation and maintains a healthy colonic environment and the targeting of Gpr109a/butyrate signaling pathway can be utilized for the prevention and treatment of UC.

描述（由申请方提供）：溃疡性结肠炎（UC）是一种慢性胃肠道炎症，预防或治疗选择有限。 结肠树突状细胞（DC）和巨噬细胞表达抑制结肠炎症反应的抗炎机制。 这些抗炎机制的丧失导致UC期间的肠道炎症。因此，增强APC的抗炎活性是预防和治疗UC的重要途径。该领域进展的关键障碍是确定介导诱导抗炎环境和促进结肠健康的机制，最重要的是，我们是否可以利用这些机制来设计旨在预防和/或治疗UC的干预措施。 一些研究表明，膳食纤维和特定的肠道细菌抑制肠道炎症。 膳食纤维/肠道微生物群效应物短链脂肪酸（SCFA）;乙酸酯、丙酸酯和丁酸酯已被推测促进结肠健康。 在SCFA中，丁酸盐因其抗炎作用而受到最多关注。因此，刺激丁酸盐介导的抗炎途径的策略是预防和/或治疗UC的有希望的方法。我们的初步数据表明，Gpr 109 a，一种丁酸盐（和烟酸，维生素B3）的G蛋白偶联受体，诱导结肠APC中IL-10，Aldh 1a的表达，并增强Treg诱导，从而促进结肠炎症的抑制。基于这些发现，本研究的目的是鉴定Gpr 109 a信号通路中介导结肠APC中IL-10和Aldh 1a诱导的组分，并证明靶向Gpr 109 a是预防和治疗小鼠模型结肠炎症的有效策略。 本建议的具体目的如下：目的1将测试过氧化物酶体增殖物激活受体？(PPAR?)在丁酸盐/烟酸/Gpr 109 a介导的结肠APC中IL-10和Aldh 1a的诱导、结肠中TbR的诱导和结肠炎症的抑制中起重要作用。目的2将证明Gpr 109 a信号介导的激活的过氧化物酶体增殖物激活受体？并且结肠APC中IL-10和Aldh 1a的诱导以及结肠中TdR的诱导是<$arrestin-1依赖的。目的3将验证Gpr 109 a配体取代膳食纤维在结肠中诱导Treg的作用，保护结肠免受膳食纤维缺乏下的炎症，并对预防和治疗UC具有治疗价值的假设。在成功完成后，拟议的研究将揭示Gpr 109 a是一种关键受体，将膳食纤维/肠道细菌与负责抑制结肠炎症的生化途径联系起来，并维持健康的结肠环境，并且Gpr 109 a/丁酸信号通路的靶向可用于预防和治疗UC。