Role and Regulation of the AhR-IL22 axis in I3C-mediated protection against colitis

AhR-IL22 轴在 I3C 介导的结肠炎保护中的作用和调节

• 批准号: 10220532
• 负责人: Philip Brandon Busbee
• 金额: $ 22.31万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220532
• 关键词: Affect; Aryl Hydrocarbon Receptor; Bacteroides; Butyrates; Cells; Chronic; Colitis; Colon; Complex; DNA; Dependence; Dioxins; Disease; Epigenetic Process; Epithelial Cells; Etiology; Genes; Gram-Negative Bacteria; Immune; Indole-3-Carbinol; Indoles; Inflammation; Inflammatory Bowel Diseases; Large Intestine; Lymphoid; Mediating; MicroRNAs; Modification; Patients; Phase; Play; Production; Regulation; Response Elements; Role; Severity of illness; Source; Symptoms; T-Lymphocyte; aryl hydrocarbon receptor ligand; cost; cruciferous vegetable; cytokine; dietary supplements; dysbiosis; effective therapy; gut microbiome; interleukin-22; metabolome; metabolomics; microbial; prevent; protective effect; receptor expression

Colitis is an inflammatory bowel disorder (IBD) characterized by chronic inflammation of the large intestine or colon. This disease, affecting over 1 million people and costing over a billion dollars/year in the US alone, has a complex etiology and to date, there are few and effective treatment options to patients. In the current study, we demonstrate that in TNBS-induced colitis, a natural indole product found in numerous cruciferous vegetables (Indole-3-carbinol, or I3C) and ligand for the aryl hydrocarbon receptor (AhR) is effective at preventing symptoms of colitis. Most notably, I3C was able to prevent colitis-associated dysbiosis and increase colonic butyrate. Specifically, I3C prevented increases in colitis-associated gram-negative bacteria (e.g. Bacteroides acidifaciens), while also increasing butyrate producing Roseburia. IL-22 was found to be significantly increased after I3C treatment, and neutralization of this cytokine prevented I3C from reducing disease severity and altering the gut microbiome and metabolome. In the current proposal, the central hypothesis is I3C mediates its beneficial effects through regulation of cross talk immune cells and colonic epithelial cells (CECs) by activation of AhR and depends on IL-22 production to mediate its protective effects during colitis. The aims of this study will be as follows: 1.) Dependency of AhR in I3C-mediated protective effects will be investigated using conditional KO of AhR on immune cells (T cells and innate lymphoid type 3 cells/ILC3s) or CECs, both of which express AhR. These studies will determine if I3C-mediated effects are dependent on AhR expression in immune cells and/or CECs in preventing colitis and altering disease-associated microbial dysbiosis and the metabolomic profile,. Focus on the impact AhR plays in regulating I3C-mediated modulation of IL-22 will be performed to identify AhR-specific dioxin response elements (DREs) on IL-22 and IL-22 promoting genes. 2.) Additionally, studies will be conducted to determine the cell source of IL-22 production and investigate epigenetic modifications( microRNA/miRNA and DNA methlyation) affecting IL-22, which could be mediated by I3C treatment during colitis.

结肠炎是一种炎症性肠病(IBD)，以大肠或结肠的慢性炎症为特征。这种疾病影响了100多万人，仅在美国每年就花费超过10亿美元，病因复杂，到目前为止，患者几乎没有有效的治疗选择。在目前的研究中，我们证明了在TNBS诱导的结肠炎中，在许多十字花科蔬菜中发现的一种天然吲哚产物(吲哚-3-甲醇或I3C)和芳烃受体(AhR)的配体在预防结肠炎症状方面是有效的。最值得注意的是，I3C能够预防结肠炎相关的生物失调，并增加结肠丁酸盐。具体地说，I3C防止了结肠炎相关革兰氏阴性细菌(例如酸性杆菌)的增加，同时也增加了丁酸盐的产生。发现I3C治疗后IL-22显著增加，这种细胞因子的中和阻止了I3C减轻疾病严重程度和改变肠道微生物组和代谢组。在目前的提议中，中心假说是I3C通过激活AhR调节串扰免疫细胞和结肠上皮细胞(CECs)而介导其有益作用，并依赖于IL-22的产生来介导其在结肠炎中的保护作用。这项研究的目的如下：1)将使用AhR对免疫细胞(T细胞和固有淋巴类型3细胞/ILC3)或CEC的条件KO来研究AhR在I3C介导的保护作用中的依赖性，这两种细胞都表达AhR。这些研究将确定I3C介导的作用是否依赖于免疫细胞和/或CEC中AhR的表达，以预防结肠炎和改变与疾病相关的微生物失调和代谢组谱。重点是AhR在调节I3C介导的IL-22调节中所起的作用，以确定AhR特异的二恶英反应元件(DRE)对IL-22和IL-22促进基因的影响。2.)此外，还将进行研究，以确定IL-22产生的细胞来源，并调查影响IL-22的表观遗传修饰(microRNA/miRNA和DNA甲基化)，这可能是通过I3C治疗在结肠炎期间介导的。