Altered Bacterial Bile Acid Metabolism as a Driver of CVID Enteropathy

抗体缺乏是人类原发性免疫缺陷最常见的诊断形式。常见变异性免疫缺陷（CVID）是最严重的抗体缺乏形式，其特征是低γ -球蛋白血症（低IgG）伴有IgA和/或IgM滴度的缺陷。在人类和实验室小鼠模型中，IgA缺乏与肠道中共生微生物群落（又称微生物群）的组成和功能的改变有关，并且来自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，由于潜在的肠道吸收不良。驱动CVID肠病的病理生理机制尚不清楚，但微生物群的病理改变（“生态失调”）可能是一个关键因素。胆汁酸（BAs）分泌到肠道中，在促进吸收的膳食脂质的乳化中起着至关重要的作用。微生物组在肠道BA组成的形成中起着核心作用。因此，肠道抗体缺乏引起的生态失调可能通过影响肠道BA代谢来驱动CVID肠病及相关代谢性疾病。Specific Aim #1的目的是在抗体缺乏受体中使用过继转移模型来测试肠道吸收不良是一种iga依赖性表型。Specific Aim #2的目的是专门测试细菌胆盐水解酶（bsh）活性是否会导致抗体缺陷小鼠的BA解缀合作用增强，从而导致吸收不良。利用WT和共生菌bsh-null突变株在无菌igg缺陷小鼠中的单定殖实验将用于验证这一假设。Specific Aim #3的目的是通过体外和体内混合模型确定改变的BA池对宿主代谢的影响。总的来说，这些实验首次解决了CVID背景下粘膜IgA缺乏对细菌BA代谢调节及其对宿主健康影响的作用。几种方法将被用来评估通过饮食控制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.