Role of the environmental sensor, AhR on colitis

环境传感器 AhR 对结肠炎的作用

• 批准号: 10685372
• 负责人: Mitzi Nagarkatti
• 金额: $ 49.44万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-27 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685372
• 关键词: 3-Dimensional; ARNT gene; ATAC-seq; Affect; Anti-Inflammatory Agents; Antiinflammatory Effect; Aryl Hydrocarbon Receptor; Attenuated; Binding; Biological Assay; Broccoli - dietary; CD4 Positive T Lymphocytes; Cabbage - dietary; Cauliflower; Cells; Chromatin; Chronic; Clinical; Colitis; Colon; Colonic inflammation; Complex; Crohn' s disease; DNA; DNA Methylation; Data; Defensins; Dietary Factors; Dietary Indole; Dietary Phytochemical; Dioxins; Disease; Disease model; Electrophoretic Mobility Shift Assay; Elements; Environmental Pollutants; Environmental Risk Factor; Epigenetic Process; Epithelial Cells; Epithelium; FOXP3 gene; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Histone Acetylation; Histone Deacetylase Inhibitor; Histone Deacetylation; Human; IL17 gene; Immune response; Immune system; Immunomodulators; Immunosuppression; Indole-3-Carbinol; Inflammation; Inflammatory Bowel Diseases; Intestines; Knockout Mice; Ligands; Ligation; Mediating; MicroRNAs; Modeling; Mus; Pathogenesis; Pathway interactions; Patients; Peptides; Persons; Plants; Play; Prevention; Property; Protein Family; Quantitative Reverse Transcriptase PCR; Receptor Activation; Regulation; Regulatory T-Lymphocyte; Reporter; Resistance; Response Elements; Role; Surface; T cell differentiation; T-Lymphocyte; Testing; Tissues; Ulcerative Colitis; antagonist; antimicrobial peptide; aryl hydrocarbon receptor ligand; beta-Defensins; chromatin remodeling; comparison control; dextran sulfate sodium induced colitis; epigenetic regulation; gut dysbiosis; gut microbiota; histone modification; immunoregulation; intestinal barrier; intestinal epithelium; microbial; microbial colonization; microbial products; microbiota; murine colitis; novel; pollutant; prevent; promoter; sensor; transcription factor; villin

The environmental sensor, aryl hydrocarbon receptor (AhR) serves as a ligand for pollutants as well as for plant, microbial and endogenous compounds. Following AhR ligation, the activated AhR regulates gene expression through the binding of AhR/ARNT complex to specific DNA motifs known as Dioxin Response Elements (DREs). Studies from our lab and elsewhere have shown that some AhR ligands have potent immunosuppressive properties. Inflammatory bowel disease (IBD) results from chronic inflammation in the gastrointestinal tract that affects 1.5 million people in the US. The pathogenesis of IBD involves complex interactions between gut microbiota, immune response, environmental and dietary factors, and genetic/epigenetic regulation. Recently, we made an exciting observation that the AhR ligand and plant product, I3C ameliorates colitis in mice, which was associated with anti-inflammatory effects, regulation of gut dysbiosis, and enhanced expression of β-defensins (mBD1,2,3) by Colonic Epithelial Cells (CEC). β-defensins constitute antimicrobial peptides (AMPs) that resist microbial colonization of epithelial surfaces in the colonic tissue. β- defensins may also mediate anti-inflammatory effects. In fact, studies have shown defective expression of intestinal AMPs particularly defensins in IBD patients. We were excited to uncover DREs in the promoters of mouse β-defensins (mBD1, 2, and 3). In the current study, we will test the central hypothesis that dietary indoles (I3C) attenuate colitis through AhR activation leading to increased expression of mBDs by CECs via pathways involving DREs, and/or epigenetic regulation resulting in modulation of microbiota and prevention of epithelial barrier damage. Furthermore, we propose that mBDs induced by I3C play a critical role in restoring healthy gut microbiota, preventing intestinal barrier damage and suppressing colonic inflammation through induction of Tregs. Aim 1 will test the mechanisms of mBD induction by dietary indoles. We will use reporter assay, promoter bashing and electrophoretic mobility shift assay to determine whether I3C activated AhR directly binds to the DREs to induce mBDs. We will also determine the effect of I3C on the mBD expression by using AhR cKO mice with AhR deletion in IEC, ILC3 and Tregs. In Aim 2, we will study epigenetic regulation of β-defensins by dietary indoles. To that end, we will test whether I3C regulates mBD expression by altering histone modification and decreasing DNA methylation. We will specifically determine if I3C regulates the SATB1-mediated histone deacetylation and chromatin remodeling. In Aim 3, we will test whether administration of mBDs offers protection from colitis by regulating gut dysbiosis, preventing CEC barrier damage, enhancing Treg subsets and decreasing Th17 subpopulations to attenuate colonic inflammation. Finally, we will use mBD KO mice to test whether mBDs are required for I3C-mediated protection from colitis. The proposed studies are highly significant because they will identify novel mechanisms through which dietary indoles suppress colitis by altering the microbiota, through activation of AhR leading to increased expression of host-derived AMPs, specifically β-defensins.

环境传感器，芳烃受体（AhR）作为污染物的配体，以及