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.
Tsubaki et al. (Thu,) studied this question.