Regulation of colonic inflammation by butyrate/niacin receptor Gpr109a

描述(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会导致UC时的肠道炎症。因此，加强APC的抗炎作用是防治UC的重要途径。在这一领域取得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，我们是否能够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/肠道微生物区系效应短链脂肪酸(SCFAs)；醋酸盐、丙酸盐和丁酸盐被认为促进结肠健康。在超临界脂肪酸中，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通路的策略是预防和/或治疗UC的一种有前途的方法。我们的初步数据表明，丁酸(和烟酸、维生素B3)的G蛋白偶联受体Gpr109a可诱导结肠APC表达IL-10、Aldh1a，并增强Treg的诱导，从而促进结肠炎症的抑制。基于这些发现，目前的建议的目的是确定Gpr109a信号通路的组成部分，介导诱导结肠APC中IL-10和Aldh1a的产生，并证明靶向Gpr109a是预防和治疗小鼠模型结肠炎的有效策略。该提案的具体目的如下：目的1将验证过氧化物酶体增殖物激活受体γ(PPARγ)在丁酸/烟酸/GPR109a介导的诱导结肠APC中IL-10和Aldh1a，以及在结肠中诱导Treg和抑制结肠炎中起重要作用。目的2证明GPR109a信号通路介导的PPARγ的激活、IL-10和Aldh1a的诱导以及结肠Tregs的诱导依赖于P-arrestin-1。目的验证Gpr109a配体替代膳食纤维在结肠Tregs诱导中的作用，保护膳食纤维缺乏状态下的结肠炎性反应，对UC的预防和治疗有一定的治疗价值。在成功完成后，拟议的研究将发现Gpr109a是一个关键的受体，它将膳食纤维/肠道细菌连接到负责抑制结肠炎症的生化途径，并维持健康的结肠环境，靶向Gpr109a/丁酸信号通路可用于预防和治疗UC。

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.