Altered Bacterial Bile Acid Metabolism as a Driver of CVID Enteropathy

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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.