Susceptibility of Kit-mutant mice to sepsis caused by enteral dysbiosis, not mast cell deficiency

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 important roles of mast cells in defense against bacteria. We show here 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 protection of Kit-deficient and Kit wild-type mice, indicating normal bacterial immune defense in the absence of Kit. Notably, compared to wild-type mice, we observed more that 1000-fold greater E. coli colony-forming units in the cecal content of Kit-mutant mice, consistent with dysbiosis from gastrointestinal pathophysiology. Thus, upon intestinal puncture, this vast overrepresentation of pathogenic bacteria led to incomparable infections, likely explaining the apparent susceptibility of Kit-mutants. These findings highlight the importance of considering potential effects of genetic mutations on endogenous microbiota composition in cecal ligation and puncture studies of mutant mice. Collectively, our results suggest that the susceptibility of Kit-mutant mice to sepsis is associated with their enteral dysbiosis rather than mast cell-deficiency.