Date of Award

Spring 2021

Document Type

Open Access Dissertation

Department

Biomedical Science

First Advisor

Jason L. Kubinak

Abstract

Mucosal antibodies maintain gut homeostasis by promoting spatial segregation between host tissues and luminal microbes. Antibody-deficiency is the most common form of primary immunodeficiency observed in humans. In antibody-deficient humans, abnormal composition of the gut microbiota ('dysbiosis') is associated with chronic inflammatory responses and gastrointestinal complications. However, the mechanisms by which dysbiosis promotes inflammatory disease are poorly defined. In the studies described in this dissertation, we utilize CD19-/- mice as a model of antibody deficiency to test the hypothesis that antibody deficiency negatively impacts gut physiology under steady-state conditions. Chapter #1 is an overview of B cell development and how mucosal humoral immunity influences host-microbiota interactions. Also, primary antibody deficiency forms in humans are summarized and an overview of the influence of gut microbiota on host bile acid metabolism is provided. In chapter #2 we demonstrate the antibody deficiency in CD19-/- mice is associated with defective anti-commensal IgA responses and the outgrowth of anaerobic bacteria in the gut and results in an intestinal lipid malabsorption. Administration of the metronidazole or gluten-free diet rescues CD19-/- mice from disease indicating that small intestine (SI) enteropathy is a microbiota-dependent and a gluten-sensitive. Whether and how mucosal antibody disruption influence gut health through modulation of microbiota composition is unclear. In Chapter #3, we use CD19-/- mouse model to demonstrate that a relationship exists between dysbiosis, defects in host bile acid homeostasis, and SI enteropathy. SI enteropathy in CD19-/- mice is associated with alterations in the SI luminal bile acid conjugation and pool. Manipulation of bile acid availability, adoptive transfer of functional B cells, and ablation of bacterial bile salt hydrolase activity all influence the severity of SI enteropathy in CD19-/- mice.

Collectively, results from our experiments support that mucosal antibody deficiency results in non-infectious pathological outcomes specific to the SI and that disruption to host bile acid pools may be a novel axis of gastrointestinal disease. These results complement emerging data derived from human studies that have recently linked IgA deficiency with non-infectious chronic inflammatory conditions. Finally, our experiments support a model whereby mucosal humoral immune responses limit inflammatory disease of the small bowel by regulating bacterial metabolism of host bile acids.

Available for download on Monday, May 15, 2023

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