Understanding the role of intestinal immunoglobulin A in utilization of a dietary polysaccharide by the model gut symbiont bacteroides thetaiotaomicron VPI-5482 [electronic resource]

Intestinal IgA is one of the major host factors that shapes our gut microbiota composition and functionality. However, the actual mechanisms involved in the IgA-commensal interaction remain understudied. Our current work uses a model gut commensal, Bacteroides thetaiotaomicron VPI-5482 (Bt), in a gnotobiotic mouse model system to identify Bt antigens that prime a specific gut IgA response. Our study shows that the gut IgA targets a diverse set of bacterial proteins involved in a variety of functions that are thought to be important for bacterial colonization, survival and competition in the host intestine. Our IgA screen identified Bt proteins involved in utilization of dietary fructans that allow Bt to thrive in the gut lumen, when fructans are present in the host diet. Specifically, we identified the outer membrane machinery (OMM) involved in degradation and uptake of β2-6 fructans to be an active target of specific IgA. Biochemical and genetic analysis of this operon in closely related Bacteroides thetaiotaomicron strains demonstrated that the genes encoding the OMM determines fructan specificity, and thus the type of fructan that is utilized by a given organism. Further, comparative genomic analysis of the fructan utilization loci in closely related Bacteroides spp., revealed that the OMM is variably conserved. Using gene transfer experiments we were able to establish that the OMM acts as functional unit that can be transferred among closely related Bacteroides, which allows gain of a new specificity by the recipient organism. Our study further demonstrated that the OMM determines bacterial competitiveness in the gut in presence of specific fructans. Inquiry into the role of IgA in targeting this OMM demonstrated that specific IgA causes reduced expression of the fructan operon in presence of dietary fructans. We propose that this mechanism should allow the host to prevent bacterial overgrowth in presence of specific fructans. Our study thus highlights a novel mechanism by which the host regulates the growth of gut commensals, and could serve as an important pathway to control the gut microbial composition in the wake of dietary disturbances. Further our study also demonstrated that the natural, polyreactive IgA secreted in the mouse gut showed weak binding to Bt antigens. Analysis of the fructan operon expression in presence of this natural IgA indicated that the operon was upregulated in the early stages of bacterial colonization, even in absence of specific fructans. We propose that the natural IgA acts as a cue for Bt to non-specifically upregulate its nutrient utilization pathways in order to compete in the high bacterial density environment that it normally faces in a conventional host gut. Our current works sheds new light on the mechanism by which the gut IgA controls bacterial functionality in the gut lumen in order to maintain gut homeostasis.

Keywords: Microbiology and Immunology.
Advisor: Sonnenburg Justin
Boyd Scott
Idoyaga Juliana advisor. Thesis advisor
Schneider David (David Samuel)