Protein Malnutrition Facilitates Intestinal Colonization with Highly Resistant Klebsiella pneumoniae

Pediatric infections with Highly Resistant Enterobacterales (HRE), including Klebsiella pneumoniae resistant to 3^rd-generation cephalosporins and/or carbapenems, disproportionately affect low- and middle-income countries where malnutrition is prevalent. The underlying mechanisms linking malnutrition to HRE colonization in children have not been established. In this study we developed a mouse model of pediatric malnutrition and intestinal colonization with clinical isolates of carbapenem-resistant K. pneumoniae (CR-Kp). Juvenile mice fed a protein-deficient diet (PD) were more susceptible to intestinal colonization after inoculation with human-derived strains of CR-Kp, demonstrating a 3-4 log higher colonization burden in comparison to mice fed a control diet (CD). Colonization in PD-fed mice persisted for up to 6 weeks and CR-Kp were transmitted between PD-fed but not CD-fed cage mates. Antibiotic treatment resulted in similar CR-Kp colonization burdens regardless of diet, suggesting that nutrition-dependent colonization resistance is reliant on an intact microbiota. Secondary bile acids, a product of resident intestinal microbiota, were reduced in PD-fed and antibiotic treated mice and demonstrated an inverse correlation with CR-Kp burden. Secondary bile acids directly inhibited CR-Kp growth in vitro, suggesting that a loss of these inhibitory metabolites may mediate malnutrition-induced susceptibility to HRE colonization.