Regulation of colonic inflammation by butyrate/niacin receptor Gpr109a

描述（由申请人提供）：溃疡性结肠炎（UC）是一种慢性胃肠道炎症，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期间的肠道炎症。因此，增强APCs的抗炎特性是预防和治疗UC的重要途径。该领域进展的一个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。几项研究表明，膳食纤维和特定的肠道细菌可以抑制肠道炎症。膳食纤维/肠道微生物效应物短链脂肪酸（SCFAs）；据推测，醋酸盐、丙酸盐和丁酸盐可促进结肠健康。在scfa中，丁酸盐因其抗炎作用而受到广泛关注。因此，刺激丁酸介导的抗炎途径是预防和/或治疗UC的有希望的方法。我们的初步数据表明，丁酸（烟酸、维生素B3）的G蛋白偶联受体Gpr109a在结肠APCs中诱导IL-10、Aldh1a的表达，增强Treg的诱导，从而促进结肠炎症的抑制。基于这些发现，本研究的目标是鉴定介导结肠apc中IL-10和Aldh1a诱导的Gpr109a信号通路的组分，并在小鼠模型中证明靶向Gpr109a是预防和治疗结肠炎症的有效策略。本课题的具体目的如下：Aim 1将检测过氧化物酶体增殖激活受体γ (PPARγ)在丁酸盐/烟酸/ gpr109a介导的结肠APCs中诱导IL-10和Aldh1a，诱导结肠Tregs和抑制结肠炎症中发挥重要作用。Aim 2将证明Gpr109a信号介导的PPARγ激活和结肠APCs中IL-10和Aldh1a的诱导以及结肠中treg的诱导依赖于ß-arrestin-1。Aim 3将验证Gpr109a配体取代膳食纤维诱导结肠Tregs的作用，在膳食纤维缺乏的情况下保护结肠免受炎症的影响，在预防和治疗UC方面具有治疗价值。如果顺利完成，本研究将揭示Gpr109a是膳食纤维/肠道细菌与抑制结肠炎症的生化途径连接并维持健康结肠环境的关键受体，靶向Gpr109a/丁酸盐信号通路可用于UC的预防和治疗。

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.