Altered Bacterial Bile Acid Metabolism as a Driver of CVID Enteropathy

抗体缺乏症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）是最严重的抗体缺乏形式，其特征为低丙种球蛋白血症（低IgG），伴有伊加和/或IgM滴度缺陷。在人类和实验室小鼠模型中，伊加缺乏症与共生微生物群落的组成和功能的改变有关（也称为IgA缺乏症）。肠道中的微生物），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体重减轻，原因是潜在的肠道吸收不良。驱动CVID肠病的病理生理学机制尚不清楚，但微生物群的病理学改变（“生态失调”）可能是一个关键因素。胆汁酸（BA）被分泌到肠道中，在乳化促进吸收的膳食脂质中起着至关重要的作用。微生物组在形成肠道中的BA组成中起着核心作用。因此，由肠道抗体缺乏引起的生态失调可能通过影响肠道中的BA代谢来驱动CVID肠病和相关代谢疾病。具体目标#1的目的是在抗体缺陷受体中使用过继转移模型检测肠道吸收不良是否为IgA依赖性表型。具体目标#2的目的是专门测试细菌胆盐水解酶（bsh）活性导致BA去缀合增强，从而导致抗体缺陷小鼠吸收不良。将使用无菌Ig缺陷小鼠中的WT和bsh无效突变体菌株的大肠杆菌单菌落实验来解决这一假设。具体目标#3的目的是使用体外和体内模型的混合物确定改变的BA合并液对宿主代谢的影响。总的来说，这些实验是第一个解决粘膜伊加缺乏症在CVID背景下对细菌BA代谢调节的作用及其对宿主健康的影响。将利用几种方法来评估通过饮食操纵微生物组治疗吸收不良和慢性炎症的可行性。

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.