Microbiota-Immune Interactions and Host Defense in Sepsis
Date
2023-04-18
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Abstract
Gut microbial dysbiosis is associated with increased susceptibility to infectious diseases, including systemic infection and sepsis. While the impact of the microbiota on intestinal homeostasis is well recognized, gut commensals also influence several processes in extraintestinal niches, including host defense against systemic infection. This thesis aimed to study the microbiota-immune interactions that promote host defense against bacterial sepsis at a cellular and molecular level. Using gnotobiotic mouse models and resonant scanning confocal intravital microscopy, I demonstrated that mice devoid of gut commensals show defective intravascular immune responses against staphylococcal sepsis. In germ-free mice, impaired Kupffer cell-mediated bacterial capture and neutrophil trafficking in the liver contribute to increased bacterial dissemination and host mortality. Gut microbiota-dependent regulation of intravascular immunity is dynamic and partly rescued by replenishing gut-derived D-lactate, indicating this bacterial metabolite mediates the crosstalk between the gut microbiota and the liver microenvironment. D-lactate enhances bacterial clearance by Kupffer cells and primes the liver endothelium to respond robustly to inflammatory stimuli, leading to increased neutrophil adherence after infection. Altogether, this thesis uncovers a line of communication between the gut microbiota and the liver microenvironment that is pivotal for intravascular immune defense against sepsis.
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Keywords
Microbiota, Sepsis, Intravascular immunity, Liver, Systemic infection
Citation
Zucoloto, A. (2023). Microbiota-immune interactions and host defense in sepsis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.