Susceptibility ofKit-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 ofKitmutants, suggesting important roles of mast cells in defense against bacteria. We show here that mice lacking mast cells but wild-type forKitare 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 ofKit-deficient andKitwild-type mice, indicating normal bacterial immune defense in the absence of Kit. Notably, compared to wild-type mice, we observed more that 1000-fold greaterE. colicolony-forming units in the cecal content ofKit-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 ofKit-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 ofKit-mutant mice to sepsis is associated with their enteral dysbiosis rather than mast cell-deficiency.