Altered Bacterial Bile Acid Metabolism as a Driver of CVID Enteropathy

细菌胆汁酸代谢的改变是 CVID 肠病的驱动因素

• 批准号: 10227914
• 负责人: Jason L Kubinak
• 金额: $ 20.31万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227914
• 关键词: Address; Adoptive Transfer; Antibodies; Automobile Driving; Bile Acids; Body Weight decreased; Chronic; Chronic diarrhea; Common Variable Immunodeficiency; Complication; Data; Diagnosis; Dietary Fats; Health; Human; Hydrolase; IgA Deficiency; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; In Vitro; Inflammation; Laboratory mice; Malabsorption Syndromes; Metabolic Diseases; Metabolism; Modeling; Mucous Membrane; Mus; Pathologic; Patients; Phase; Phenotype; Play; Regulation; Role; Shapes; Testing; absorption; bile acid metabolism; bile salts; commensal bacteria; congenital immunodeficiency; dietary manipulation; dietary supplements; dysbiosis; experimental study; gastrointestinal symptom; hypogammaglobulinemia; in vivo Model; microbial community; microbiome; microbiota; mouse model; mutant

Antibody deficiency is the most frequently diagnosed form of primary immunodeficiency in humans. Common variable immunodeficiency (CVID) is the most severe form of antibody deficiency and is characterized as hypogammaglobulinemia (low IgG) with an accompanying deficit in IgA and/or IgM titers. In both humans and laboratory mouse models, IgA deficiency has been associated with alterations to the composition and function of symbiotic microbial communities (a.k.a. the microbiota) in the gut, and emerging data from CVID patients indicate that a similar association exists. Up to 50% of CVID patients will develop gastrointestinal symptoms, and the major complication of CVID is CVID enteropathy. CVID enteropathy most often presents as chronic diarrhea and weight loss due to an underlying intestinal malabsorption. The pathophysiological mechanism driving CVID enteropathy is not known but pathological alterations to the microbiota ('dysbiosis') could be a key factor. Bile acids (BAs) are secreted into the gut where they play a crucial role in the emulsification of dietary lipids that facilitates their absorption. The microbiome plays a central role in shaping BA composition in the gut. Thus, dysbiosis caused by gut antibody deficiency may drive CVID enteropathy and associated metabolic disease by influencing BA metabolism in the gut. The objective of Specific Aim #1 is to test that intestinal malabsorption is an IgA-dependent phenotype using adoptive transfer models in antibody deficient recipients. The objective of Specific Aim #2 is to specifically test that bacterial bile salt hydrolase (bsh) activity results in enhanced BA deconjugation that drives malabsorption in antibody deficient mice. Mono-colonization experiments in germfree Ig-deficient mice using WT and bsh-null mutant strain of commensal bacteria will be used to address this hypothesis. The objective of Specific Aim #3 is to determine the impact of altered BA pools on host metabolism using a mixture of in vitro and in vivo models. Collectively, these experiments are the first to address the role of mucosal IgA deficiency in the context of CVID on the regulation of bacterial BA metabolism and its effect on host health. Several approaches will be utilized to assess the feasibility of treating malabsorption and chronic inflammation through dietary manipulation of the microbiome.

抗体缺乏是人类原发性免疫缺陷最常见的诊断形式。常见变异型免疫缺陷 (CVID) 是最严重的抗体缺陷形式，其特征是低丙种球蛋白血症（低 IgG），伴有 IgA 和/或 IgM 滴度缺陷。在人类和实验室小鼠模型中，IgA 缺乏与肠道共生微生物群落（又称微生物群）的组成和功能的改变有关，来自 CVID 患者的新数据表明存在类似的关联。高达50%的CVID患者会出现胃肠道症状，CVID的主要并发症是CVID肠病。 CVID 肠病最常表现为慢性腹泻和由于潜在的肠道吸收不良而导致的体重减轻。导致 CVID 肠病的病理生理机制尚不清楚，但微生物群的病理改变（“菌群失调”）可能是一个关键因素。胆汁酸 (BA) 被分泌到肠道中，在膳食脂质的乳化过程中发挥着至关重要的作用，从而促进其吸收。微生物组在塑造肠道 BA 组成方面发挥着核心作用。因此，肠道抗体缺乏引起的菌群失调可能通过影响肠道内的 BA 代谢而导致 CVID 肠病和相关代谢疾病。具体目标 #1 的目的是使用抗体缺陷受体的过继转移模型来测试肠道吸收不良是一种 IgA 依赖性表型。具体目标#2 的目的是专门测试细菌胆汁盐水解酶 (bsh) 活性导致 BA 解偶联增强，从而导致抗体缺陷小鼠吸收不良。使用共生细菌的 WT 和 bsh-null 突变株在无菌 Ig 缺陷小鼠中进行单定植实验将用于解决这一假设。具体目标 #3 的目标是使用体外和体内模型的混合来确定改变的 BA 池对宿主代谢的影响。总的来说，这些实验首次探讨了 CVID 背景下粘膜 IgA 缺乏对细菌 BA 代谢调节的作用及其对宿主健康的影响。将采用多种方法来评估通过饮食控制微生物组来治疗吸收不良和慢性炎症的可行性。