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GPR120 regulation of intestinal IgA responses and gut IgA-coated bacteria

GPR120 对肠道 IgA 反应和肠道 IgA 包被细菌的调节

基本信息

批准号：
10176396
负责人：
JIAREN SUN
金额：
$ 19.75万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10176396
关键词：
16S ribosomal RNA sequencing Agonist Antibodies B-Lymphocytes Bacteria Binding Cell physiology Colitis Data Diabetes Mellitus Diet Dietary Component Dietary Fats Dietary Fatty Acid Disease Energy-Generating Resources G-Protein-Coupled Receptors Gene Expression Gene Expression Profile Homeostasis Immune Immune response Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin Switch Recombination In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Insulin Resistance Intestinal Mucosa Intestines Knowledge Mediating Metabolic Diseases Molecular Mucous Membrane Mus Nonesterified Fatty Acids Nutrient Obesity Pathogenesis Pathway interactions Patients Play Production Regulation Role Secretory Immunoglobulin A Signaling Molecule Surface T-Lymphocyte Testing Transforming Growth Factor beta autocrine cytokine dietary feeding gut bacteria gut microbiota inflammatory disease of the intestine intestinal homeostasis lipid biosynthesis long chain fatty acid magnetic cell separation microbiota new therapeutic target novel preservation receptor response therapeutic target

项目摘要

Abstract Increasing evidence suggests that the interactions between diet and the gut microbiota may play a critical role in promoting or alleviating intestinal inflammation. However, little is known about the mechanisms involved. Free fatty acids provide important energy sources as dietary nutrients, and act as signaling molecules in various cellular processes. Most notable among the free fatty acids targets are mammalian G protein-coupled receptors (GPR). GPR120 (also known as free fatty acid receptor 4, FFAR4) has been identified as a bona fide receptor for long-chain fatty acids (LCFA) from dietary products and has a critical role in various physiological homeostasis mechanisms such as adipogenesis. Its agonists are suggested as therapeutic targets for diabetes, metabolic disorders, and inflammatory diseases. However, the mechanisms involved are still largely unknown. Intestinal mucosal surfaces are protected by a first-line defense mediated by secretory Immunoglobulin A (SIgA), which has been shown to be critical in mucosal immune defense. Intestinal IgA can be produced by both T cell- dependent and T cell-independent pathways, however, the relative importance of each and how they are regulated are still largely unclear. Although both are enriched in the intestines, there is a significant knowledge gap regarding how LCFA regulate intestinal IgA responses as well as the role of the LCFA-IgA axis in the regulation of host responses to microbiota and intestinal homeostasis. In this application, we will test the hypothesis that GPR120 promotes intestinal IgA responses to microbiota through either substituting for TGFβ, which is a critical cytokine in induction of B cell production of IgA, or through promoting TGFβ production by B cells to enhance IgA production, leading to the preservation of intestinal immune homeostasis by regulating the function and composition of gut microbiota. Aim 1 will define the molecular mechanisms by which GPR120 promotes intestinal IgA responses, and Aim 2 will determine whether GPR120-mediated intestinal production of IgA alters gut microbiota to contribute to intestinal homeostasis. If successful, this project will potentially provide a novel therapeutic target for treatment of patients with inflammatory bowel disease.

摘要越来越多的证据表明，饮食和肠道微生物群之间的相互作用可能起着关键作用促进或减轻肠道炎症。然而，人们对所涉及的机制知之甚少。免费脂肪酸作为膳食营养素提供重要的能量来源，并在各种疾病中充当信号分子。细胞过程在游离脂肪酸靶点中最值得注意的是哺乳动物G蛋白偶联受体（GPR）。GPR 120（也称为游离脂肪酸受体4，FFAR 4）已被鉴定为真正的受体长链脂肪酸（LCFA）的膳食产品，并在各种生理稳态的关键作用脂肪生成等机制。它的激动剂被建议作为糖尿病、代谢性疾病和糖尿病的治疗靶点。疾病和炎性疾病。然而，所涉及的机制在很大程度上仍然是未知的。肠粘膜表面受到分泌型免疫球蛋白A（SIgA）介导的第一线防御的保护，已经显示在粘膜免疫防御中是关键的。肠道伊加可以由T细胞和淋巴细胞产生。依赖性和T细胞非依赖性途径，然而，每一个的相对重要性，以及它们是如何监管在很大程度上仍不明确。虽然两者都是在肠道中富集，但有一个重要的知识关于LCFA如何调节肠道伊加反应以及LCFA-IgA轴在肠道免疫反应中的作用，调节宿主对微生物群和肠道内稳态的反应。在本应用程序中，我们将测试假设GPR 120通过替代TGFβ，其是诱导B细胞产生伊加或通过促进B细胞产生TGFβ的关键细胞因子细胞，以提高伊加的生产，从而导致肠道免疫稳态的保护，通过调节肠道微生物群的功能和组成。目的1将定义GPR 120 促进肠道伊加应答，Aim 2将确定GPR 120介导的肠道IgA产生是否伊加改变肠道微生物群以促进肠道内稳态。如果成功，该项目将提供用于治疗炎症性肠病患者的新治疗靶点。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

STING controls intestinal homeostasis through promoting antimicrobial peptide expression in epithelial cells.

DOI：
10.1096/fj.202001524r
发表时间：
2020-11
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Yu Y;Yang W;Bilotta AJ;Yu Y;Zhao X;Zhou Z;Yao S;Xu J;Zhou J;Dann SM;Li Y;Cong Y
通讯作者：
Cong Y

The disruption of intestinal homeostasis when foods are colored red.

当食物呈红色时，肠道稳态会受到破坏。

DOI：
10.1038/s41423-022-00875-0
发表时间：
2022
期刊：
Cellular & molecular immunology
影响因子：
24.1
作者：
Yang,Wenjing;Cong,Yingzi
通讯作者：
Cong,Yingzi

GPR120 promotes neutrophil control of intestinal bacterial infection.

DOI：
10.1080/19490976.2023.2190311
发表时间：
2023-01
期刊：
Gut microbes
影响因子：
12.2
作者：
通讯作者：

Th17 Cell-Derived Amphiregulin Promotes Colitis-Associated Intestinal Fibrosis Through Activation of mTOR and MEK in Intestinal Myofibroblasts.

Th17 细胞衍生的双调蛋白通过激活肠肌成纤维细胞中的 mTOR 和 MEK 促进结肠炎相关的肠纤维化。

DOI：
10.1053/j.gastro.2022.09.006
发表时间：
2023
期刊：
Gastroenterology
影响因子：
29.4
作者：
Zhao,Xiaojing;Yang,Wenjing;Yu,Tianming;Yu,Yu;Cui,Xiufang;Zhou,Zheng;Yang,Hui;Yu,Yanbo;Bilotta,AnthonyJ;Yao,Suxia;Xu,Jimin;Zhou,Jia;Yochum,GregoryS;Koltun,WalterA;Portolese,Austin;Zeng,Defu;Xie,Jingwu;Pinchuk,IrynaV;
通讯作者：

IL-21 Promotes Intestinal Memory IgA Responses.