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: 8926412
• 负责人: Nagendra Singh
• 金额: $ 33.06万
• 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/8926412
• 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; Diarrhea; Diet; Dietary Fiber; Environment; G-Protein-Coupled Receptors; Gastrointestinal Diseases; Genes; Health; Inflammation; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-10; Ligands; Maintenance; Mediating; Modeling; Niacinamide; Nicotinic Acids; Outcome; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Play; Prevention; Prevention approach; Prevention strategy; 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; commensal microbes; gastrointestinal; gut microbiota; in vivo; macrophage; mouse model; novel therapeutics; prevent; promoter; 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 γ (PPARγ) 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 PPARγ and induction of IL-10 and Aldh1a in colonic APCs and induction of Tregs in colon is ß-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（由应用提供）：溃疡性结肠炎（UC）是一种慢性胃肠道感染，预防或治疗方案有限。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期间肠道感染。因此，增强APC的抗炎特性是预防和治疗UC的重要方法。该领域进步的一个关键障碍是识别O机制，该机制介导了抗炎环境的诱导和促进结肠健康，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。几项研究表明，饮食纤维和特定的肠道细菌抑制肠道感染。饮食纤维/肠道菌群影响短链脂肪酸（SCFA）；据推测，乙酸盐，丙酸和丁酸酯是为了促进菌落健康。在SCFA中，丁酸酯因其抗炎作用而受到最大关注。因此，刺激丁理介导的抗炎途径的策略采取了预防和/或治疗UC的希望方法。我们的初步数据表明，GPR109A是一种用于丁酸酯（和烟酸，维生素B3）的G蛋白偶联受体，可诱导结肠APC中IL-10，ALDH1A的表达，并诱导潜在的TREG诱导，从而促进结肠炎症的抑制。基于这些发现，当前建议的目标是确定介导诱导IL-10和ALDH1A的GPR109A信号传导途径的组成部分，并证明靶向GPR109A是针对小鼠模型中结肠炎症的预防和治疗的有效策略。该提案的具体目的如下：AIM 1将测试过氧化物体增生剂激活的受体γ（PPARγ）在丁酸/烟酸/GPR109A介导的结肠APC中的IL-10和ALDH1A的引入以及结肠和抑制的Tregs引入的丁酸/烟酸/GPR109A介导的引入。 AIM 2将证明GPR109A信号传导介导的PPARγ激活以及在结肠APC中引入IL-10和ALDH1A，并且在结肠中的Tregs解释是ß-arrestin-1依赖性。 AIM 3将检验以下假设：GPR109A配体取代Treg饮食纤维诱导在结肠中的作用，保护结肠免受饮食纤维缺乏下的感染，并在预防和治疗UC方面具有治疗价值。成功完成后，拟议的研究将发现GPR109A是一个关键的接收者，它将饮食纤维/肠道细菌与负责抑制结肠炎症的生化途径联系起来，并可以维持健康的结肠环境，并保持GPR109A/Butyrate信号传导途径可用于预防和治疗UC。