Differential and synergistic roles of mucosal immunoglobulins in the regulation of microbiota homeostasis and metabolism

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

The symbiotic relationship between microbiota (MB) and the human host is a key component of health and its dysregulation is associated with many disease states, including inflammatory, cardiovascular, and autoimmune diseases. Homeostatic regulation of gut microbial communities and their metabolic products is achieved by several host mucosal immune mechanisms, most critically, the production of secretory IgA (sIgA) that directly coat large fractions of the MB. Until recently it has been believed that sIgA is the only secretory immunoglobulin (sIg) involved in the maintenance of MB homeostasis. However, this paradigm is now being challenged by findings showing that sIgM also coats a large proportion of the human MB, often in association with sIgA. The goal of this proposal is to determine the unique and synergistic physical and functional consequences derived from the targeting of MB by different sIg isotypes. Upon sIgA binding, bacteria undergo agglutination, motility arrest, and enchained growth (EGrowth), processes that ultimately dictate whether bacteria are physically excluded from the mucosal barrier or colonize it. In addition, sIgA binding to MB regulates bacterial gene expression and metabolite production, thus further contributing to the sIgA functional properties. While sIgA effects on MB are beginning to be deciphered, the effects of sIgM coating and the potential synergies between sIgM and sIgA have never been investigated. In contrast to humans and fish, laboratory mice lack sIgM-coated MB thus precluding the use of this animal model in studies involving sIgM-MB interactions. Using our highly tractable fish model, we have established that both sIgT (a functional homolog of sIgA) and sIgM coat their gut MB (either alone or in combination). Moreover, we have generated new preliminary data that support our central hypothesis that MB coating by sIgT and/or sIgM has unique, complementary, and synergistic functional consequences on the modulation of several key processes critical for MB homeostasis, including MB agglutination, EG, motility, gene expression and metabolism. To address this hypothesis, we will first evaluate the differential and synergistic effects of sIgT and sIgM binding to MB on agglutination, EGrowth, motility and colonization followed by evaluation of the effect of sIgM and sIgT binding on MB metatranscriptome, gene expression and metabolism. We will then explore sIgs-mediated modulation of bacterial gene expression through novel superoxide-dependent and independent mechanisms, evaluate regulation of bacterial antibiotic production upon sIgs coating of MB, and explore where are MB-specific sIgM generated in the host while assessing whether sIgM and sIgT recognize the same or different MB molecules. The proposed work has the potential to uncover novel mechanisms by which sIg-coating of MB play unique and synergistic roles in physically regulating MB colonization or clearance, and in modulating gene expression as well as enhancing or limiting the metabolic influence of MB on the host. Moreover, the knowledge derived from this paradigm shifting research will be used in future projects to identify, design and evaluate MB- and sIg-targeted interventions for critical human diseases associated with dysregulation of the microbiome such as Chron’s disease, inflammatory bowel disease, and colorectal cancer.