Mechanisms underlying sex differences in the pathogenesis of IBD

描述（由申请方提供）：最近报告了炎症性肠病（IBD）严重程度的性别差异，克罗恩病（CD）（特发性IBD之一）女性患者可能比男性患者经历更严重的疾病表现，并且在青春期、妊娠期和产后期间出现与激素激增相关的症状活动。虽然确切的病因目前尚不清楚，但公认IBD是由对环境因素（例如，肠道微生物群落）。然而，IBD性别差异的潜在机制是一个研究不足的研究领域，关于遗传学、宿主免疫以及肠道微环境的协调如何导致性别差异，特别是在克罗恩病患者中，人们知之甚少。基于我们广泛的初步数据，本提案的中心假设是肠道微生物配体通过TLR 9信号传导促进粘膜Treg群体中的表型和功能多样性，这有助于实验CD中的性别差异，例如在SAMP小鼠（CD样回肠炎的自发模型）和CD患者中观察到的差异。这一假设将通过执行两个特定的测试来检验。 目的：1）确定肠道微生物群对粘膜Treg群体/亚群的表型和功能特性的性别差异的影响，和2）确定关于TLR 9活化如何特异性地导致性别相关的肠道炎症的机制。拟议的研究旨在阐明自发性实验性克罗恩病样回肠炎性别差异的潜在机制，并确定潜在的早期疾病途径，从而开发新的性别靶向策略，以改善这种毁灭性疾病患者的治疗。 公共卫生相关性：克罗恩病（Crohn's disease，CD）是一种特发性炎症性肠病（idiopathic inflammatory bowel disease，IBD），其特征是胃肠道的慢性、复发性炎症，通常认为其是遗传易感个体对环境因素的不受控制的免疫应答所致。最近的证据表明，CD存在明显的性别差异，女性比男性表现出更严重的疾病表现，这与青春期、妊娠期和产后期间的激素激增有关;然而，一般而言，粘膜免疫的性别差异，特别是IBD，是一个研究不足的领域。本提案将研究一种潜在的机制，即肠道微生物配体促进粘膜Treg群体的表型和功能多样性，这有助于慢性肠道炎症发病机制的性别差异，例如在IBD中观察到的差异。

DESCRIPTION (provided by applicant): Gender disparity has been recently reported for the severity of inflammatory bowel disease (IBD), with female patients with Crohn's disease (CD), one of the idiopathic IBDs, likely to experience more severe disease manifestations compared to males, and with symptom activity associated with hormonal surges during puberty, pregnancy and the post-partum period. Although the precise etiology is currently unknown, it is well accepted that IBD results from a dysregulated immune response to environmental factors (e.g., gut microflora) in genetically-predisposed individuals. However, the mechanism(s) underlying sex differences in IBD is an understudied area of investigation and little is known regarding how the orchestration of genetics, host immunity, as well as the gut microenvironment leads to gender disparity, specifically in Crohn's patients. Based on our extensive preliminary data, the central hypothesis of the present proposal is that gut microbial ligands signaling through TLR9 promote phenotypic and functional diversity in mucosal Treg populations that contribute to sex differences in experimental CD, such as that observed in SAMP mice, a spontaneous model of CD-like ileitis, and in patients with CD. This hypothesis will be tested by performing two specific aims: 1) Determine the impact of the gut microbiota on sex differences in the phenotypic and functional properties of the mucosal Treg population/subpopulations, and 2) Determine the mechanism(s) as to how TLR9 activation specifically results in sex-associated gut inflammation. The proposed studies are designed to elucidate potential mechanism(s) underlying sex differences in spontaneous, experimental Crohn's-like ileitis, and identify potential, early diseas pathways that can lead to the development of novel, gender-targeted strategies to improve treatment of patients suffering from this devastating disease. PUBLIC HEALTH RELEVANCE: Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases (IBD)s, is characterized by a chronic, relapsing inflammation of the GI tract that is generally thought to result from uncontrolled immune responses to environmental factors in genetically predisposed individuals. Recent evidence shows that clear gender disparity in CD exists, with females displaying more severe disease manifestations than males that is associated with hormonal surges during puberty, pregnancy and the post-partum period; however, sex differences in mucosal immunity, in general, and IBD, in particular, is an understudied area of investigation. The present proposal will investigate one potential mechanism that gut microbial ligands promote phenotypic and functional diversity in mucosal Treg populations that contribute to sex differences in the pathogenesis of chronic intestinal inflammation, such as that observed in IBD.