Friday, April 4, 2025
4/4/2025
Mechanism of Colonization Resistance - PROJECT SUMMARY Antibiotic treatment impairs colonization resistance, thereby increasing the risk of infection with Enterobacteriaceae that are frank (e.g. non-typhoidal Salmonella serovars) or opportunistic (e.g. carbapenem-resistant Enterobacteriaceae) pathogens. However, how the host contributes to colonization resistance against pathogenic Enterobacteriaceae remains incompletely understood. The host uses “habitat filters” to select for microbial traits permitting survival and growth in the host, thereby shaping composition, spatial organization and size of microbial communities. Our goal is to elucidate how the host contributes to colonization resistance against pathogenic Enterobacteriaceae and to develop approaches aimed at restoring this nonspecific immune function during antibiotic therapy. We hypothesize that a mechanistic understanding of how the host contributes to colonization resistance against pathogenic Enterobacteriaceae will facilitate the development of drugs that target host signaling pathways to strengthen colonization resistance. We will test different aspects of our hypothesis in two specific aims. Specific Aim 1 will identify resources that a shift in epithelial metabolism provides for pathogenic Enterobacteriaceae to overcome niche modification by microbiota-derived short-chain fatty acids. Specific Aim 2 will provide a proof-of-principle for the idea drugs targeting the host can strengthen colonization resistance, thus making it possible to preserve this nonspecific immune function during active antibiotic therapy. Successful completion of the proposed work will provide mechanistic insights into a key function of the microbiome, which will be of wide appeal among researchers interested in microbial pathogenesis, microbiota research, and intestinal biology.
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