GENETIC ANALYSIS OF MUCIN UTILIZATION BY AKKERMANSIA MUCINIPHILA AND ITS IMPACT ON HOST PHYSIOLOGY

ABSTRACTMicrobes that inhabit the mucin layer that separates epithelial surfaces from thebulk of microbial contents of the gastrointestinal tract (GI) play a critical role inmaintaining the metabolic and immunological health of their host. For instance,the mucolytic, gram negative, obligate anaerobic bacterium Akkermansiamuciniphila is associated with protection from high-fat induced obesity.Concomitantly, the abundance of this microbe decreases in humans on westernstyle diets. Importantly, in mouse models of diet-induced obesity, experimentalcolonization with A. mucinophila leads to lower rates of weight gain and glucoseresistance. In addition, A. muciniphila contributes to dampening inflammation byenhancing mucin production and promoting intestinal barrier integrity throughenhanced formation of epithelial cell junctions. Not surprisingly, A. muciniphila isbeing considered as a potential commercial probiotic.Unfortunately, the molecular mechanisms underlying the interactions betweenAkkermansia, its host, and associated microbial communities are largelyunknown In this application, we propose to apply genetic methods we recentlydeveloped to characterize the process of mucin acquisition and degradation byA. mucinipihila, develop new ex vivo colonization models to test the impact of A.muciniphila exposure on epithelial cell physiology and function, and define therole that mucin metabolism plays in Akkermansia colonization of mice and itsimpact on GI ecology.The proposed work will generate new genetic tools and host model systems withwhich to understand the molecular basis of how this emerging beneficial microbeexerts its health-promoting effects on its host, and aid in the engineering of A.muciniphila strains with enhanced probiotic functions.