Altered Bacterial Bile Acid Metabolism as a Driver of CVID Enteropathy

抗体缺陷是人类最常见的原发免疫缺陷诊断形式。常见可变型免疫缺陷(CVID)是最严重的抗体缺陷形式，其特征是低丙种球蛋白血症(低免疫球蛋白血症)，并伴有IgA和/或IgM滴度缺陷。在人类和实验小鼠模型中，IgA缺乏症都与共生微生物群落的组成和功能改变有关(又名。肠道中的微生物区系)，以及来自CVID患者的新兴数据表明，存在类似的关联。高达50%的CVID患者会出现胃肠道症状，而CVID的主要并发症是CVID肠病。CVID肠病最常见的表现为慢性腹泻和因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，但微生物区系的病理变化(‘失调’)可能是一个关键因素。胆汁酸(BA)被分泌到肠道中，在饮食脂肪的乳化过程中起着关键作用，从而促进它们的吸收。微生物群对肠道中BA成分的形成起着核心作用。因此，肠道抗体缺乏引起的生物失调可能通过影响肠道中BA的代谢而导致CVID肠病和相关的代谢性疾病。具体目标#1的目的是利用抗体缺陷受体的过继转移模型来检验肠道吸收不良是一种依赖于IgA的表型。具体目标#2的目的是专门测试细菌胆盐水解酶(BSH)的活性是否能增强BA的去卷曲能力，从而导致抗体缺陷小鼠吸收不良。使用WT和BSH-零共生菌突变株在无菌免疫球蛋白缺陷小鼠中的单一定植实验将被用于解决这一假说。具体目标#3的目的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。总而言之，这些实验是第一次在CVID的背景下讨论粘膜IgA缺乏对细菌BA代谢的调节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作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.