Lactobacillus derived small RNAs protect against Klebsiella pneumoniae infection

Abstract Carbapenem‐resistant Klebsiella pneumoniae (CRKP) is a major multidrug‐resistant pathogen with limited treatment options. Plant‐derived natural products have broad biological activities, but their protective effects against extraintestinal multidrug‐resistant bacterial infections remain poorly understood. Herein, we show that selected plant‐derived natural products protect mice against CRKP pulmonary infection by remodeling the gut microbiota. Fecal microbiota transplantation and microbiota‐depletion experiments demonstrated that this protection was microbiota dependent, with Lactobacillus emerging as a key genus associated with reduced pulmonary bacterial burden. Among four isolated Lactobacillus species, Lactobacillus murinus ( L. murinus ) conferred the strongest protection against CRKP infection. Mechanistically, L. murinus ‐derived membrane vesicles (MVs) delivered the small RNA mim‐miR‐21a‐5p to pulmonary macrophages, where it targeted PDCD4 and activated the Nrf2/SOD2 antioxidant pathway. This signaling cascade preserved mitochondrial oxidative phosphorylation, promoted an M2‐like macrophage phenotype, and ultimately restricted CRKP infection. Consistent with these findings, intestinal Lactobacillus , particularly L. murinus , was reduced in patients with CRKP infection compared with healthy controls. Collectively, our findings reveal a mechanism by which plant‐derived natural products enhance host resistance to CRKP through microbiota remodeling and identify L. murinus ‐derived small RNAs and membrane vesicles as key mediator of this gut‐lung protective axis.