Role of mast cells in endomicrobial sepsis revisited: Mast cell-deficient mice show normal immunological protection

Kit-mutant mice are highly susceptible to polymicrobial sepsis elicited by cecal ligation and puncture (CLP). This vulnerability has been attributed to the mast cell deficiency of Kit mutants, suggesting key roles of mast cells in antibacterial defense. We show that mice lacking mast cells but wild-type for Kit are as resistant to sepsis as mast cell-proficient mice, excluding mast cells as protective factor. Induction of sepsis by direct injection of intestinal microbiota instead of surgical gut perforation revealed comparable protective responses of Kit-deficient and Kit wild-type mice, indicating intact antibacterial immunity in the absence of Kit. Notably, cecal contents of Kit-mutant mice contained 1000-fold greater Escherichia coli colony-forming units compared to wild-type mice. Consistently, 16S rRNA gene sequencing revealed a broad compositional shift characterized by enrichment of Enterobacteriaceae and other taxa associated with inflammatory intestinal states, in keeping with intestinal dysmotility in Kit-mutant mice. Thus, upon intestinal puncture, overrepresentation of pathogenic bacteria led to a more severe infection of Kit mutants compared to wild-type controls. Hence, the susceptibility of Kit-mutant mice to sepsis is caused by enteral dysbiosis, not mast cell deficiency. These findings highlight the importance of considering genotype-dependent effects on endogenous microbiota composition in CLP models. Collectively, our results show that immunological resistance to sepsis is independent of mast cells.