Protein malnutrition facilitates intestinal colonization with highly resistant Klebsiella pneumoniae through disrupted intestinal microbial metabolism

Pediatric infections with highly resistant Klebsiella pneumoniae (HR-Kp) disproportionately affect low-income countries where childhood malnutrition is prevalent. Malnutrition is an identified risk factor for infection with HR-Kp and other antimicrobial-resistant Enterobacterales, but the mechanistic underpinnings of this link and independence from other common exposures, like antibiotics, in children are unclear. Using a murine model of pediatric malnutrition, we found that mice fed a protein-deficient diet (PD) were more susceptible to colonization with HR-Kp at a 4-log lower challenge inoculum and developed a 3-log higher intestinal burden in comparison to adequately nourished mice. HR-Kp colonization in PD-fed mice persisted beyond 5 weeks, and colonization was transmitted to diet-matched cage mates. Antibiotic treatment resulted in similar HR-Kp colonization burdens regardless of diet, suggesting that nutrition-dependent colonization risk is driven by altered intestinal microbiota. Despite reduced dietary protein intake, intestinal amino acid content was maintained in PD-fed mice, supporting optimal HR-Kp growth. Furthermore, secondary bile acids, prototypic intestinal microbiota-derived molecules, were reduced in PD-fed mice, demonstrated an inverse correlation with HR-Kp burden in vivo , and partially inhibited the growth of HR-Kp in vitro . Collectively, these findings reveal a role for dietary protein intake in determining nutrition-dependent colonization resistance to HR-Kp.