Poria cocos Polysaccharide Alleviates Multidrug-Resistant Klebsiella pneumoniae-Induced Acute Lung Injury by Modulating the Gut-Lung Axis via Gut Microbiota Remodeling

Abstract

The emergence and spread of multidrug-resistant Klebsiella pneumoniae (MDR-KP), which leads to acute lung injury (ALI) and severe pneumonia, poses a huge challenge to clinical treatment and public health. Non-antibiotic strategies have recently garnered significant attention as promising avenues for combating antibiotic resistance. In this study, whole-genome sequencing of an MDR-KP strain isolated from a deceased goat revealed key genetic features underlying its pathogenicity, including 31 resistance genes mediating broad-spectrum resistance to 14 antibiotic classes, 71 pathogen-host interaction genes supporting cross-organ infection, and 66 virulence factors enhancing colonization and immune evasion. Importantly, this clinically isolated strain was found to be pathogenic to both mice and chickens. Poria cocos polysaccharide (PCP) is a natural immunomodulator, but its effects on MDR-KP-induced ALI have not been explored. Herein, we investigated the protective effect of oral PCP and its dependence on gut microbiota remodeling using murine models of intranasal MDR-KP infection and antibiotic-induced pseudo-germ-free mice. Results showed that PCP pretreatment significantly alleviated MDR-KP-induced ALI by reducing pulmonary bacterial load (P < 0.01) and suppressing TNF-α and IL-1β levels in bronchoalveolar lavage fluid (P < 0.05). Mechanistically, PCP restored intestinal barrier function by upregulating tight junction proteins (Occludin, Claudin-1) and mucosal defense factors (SIgA, MUC-2), and reversed gut dysbiosis by restoring microbial diversity and enriching beneficial taxa. These protective effects were largely attenuated in pseudo-germ-free mice, suggesting that the protection offered by PCP against MDR-KP-induced ALI is dependent on the gut microbiota. In conclusion, oral PCP alleviates MDR-KP-induced ALI through a gut microbiota-mediated pathway by remodeling the gut microbiota, reinforcing intestinal barrier integrity, and regulating the gut-lung axis, providing a novel gut-targeted therapeutic strategy against drug-resistant KP infections.