Gut Commensal Klebsiella pneumoniae Extracellular Vesicles Shape a Liver Microenvironment Conducive to Gut‐Liver Bacterial Translocation and Pro‐Tumorigenic Processes

Bacterial extracellular vesicles (EVs) are emerging mediators of host-microbe communication; however, their role in human disease remains unclear. Here, we identify two bacterial small tRNAs (tsRNAs) enriched in gut commensal Klebsiella pneumoniae-derived EVs (KpEVs) that are markedly elevated in the serum of patients with hepatocellular carcinoma (HCC). These tsRNAs suppress the production of nitric oxide (NO) by macrophages, a critical antitumor molecule. Notably, KpEVs reach the liver more efficiently than bacterial cells, thus facilitating bacterial translocation from the gut by inducing distinctive immunosuppressive macrophages. Mechanistically, KpEVs drive an M2-like macrophage phenotype, enhance phagocytosis, and inhibit both NO production and caspase-1-dependent pyroptosis during infection. The results show that KpEVs shape a liver microenvironment promoting gut-liver bacterial translocation, which may also influence HCC progression. Our study uncovers a previously unrecognized strategy by which K. pneumoniae exploits EVs to modulate host immunity of distant organs, highlighting tsRNAs as potential biomarkers and therapeutic targets.