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

Two bacterial small tRNA-derived RNAs (tsRNAs) enriched in Klebsiella pneumoniae-derived EVs (KpEVs) are markedly elevated in the serum of patients with hepatocellular carcinoma (HCC).

• The tsRNAs were identified as enriched specifically in KpEVs compared to other bacterial EV preparations.
• Serum levels of these two tsRNAs were significantly elevated in HCC patients relative to controls.
• The tsRNAs were characterized as potential biomarkers for HCC based on their elevated serum concentrations.

KpEV-associated tsRNAs suppress the production of nitric oxide (NO) by macrophages, impairing a critical antitumor molecule.

• NO production by macrophages was inhibited following exposure to KpEVs carrying the identified tsRNAs.
• NO is described as a 'critical antitumor molecule' whose suppression may contribute to pro-tumorigenic processes.
• The mechanism involved tsRNA-mediated modulation of macrophage function rather than direct bacterial action.

KpEVs reach the liver more efficiently than intact bacterial cells, facilitating gut-to-liver bacterial translocation.

• KpEVs demonstrated greater hepatic delivery efficiency compared to K. pneumoniae bacterial cells in experimental models.
• KpEVs were found to facilitate bacterial translocation from the gut to the liver by inducing immunosuppressive macrophages.
• This preferential liver accumulation of EVs over bacteria suggests EVs act as advance mediators conditioning the liver environment.

KpEVs drive an M2-like macrophage phenotype that enhances phagocytosis while inhibiting antimicrobial and inflammatory killing mechanisms.

• KpEV exposure induced polarization toward an M2-like macrophage phenotype.
• KpEVs enhanced phagocytic activity of macrophages.
• KpEVs simultaneously inhibited NO production by macrophages.
• KpEVs inhibited caspase-1-dependent pyroptosis during bacterial infection, suppressing an inflammatory cell death pathway.

KpEVs shape a liver microenvironment that promotes gut-liver bacterial translocation and may also influence HCC progression.

• The immunosuppressive macrophage phenotype induced by KpEVs in the liver creates conditions permissive for bacterial translocation.
• The liver microenvironment shaped by KpEVs is described as 'conducive to gut-liver bacterial translocation and pro-tumorigenic processes.'
• The study suggests KpEVs represent a previously unrecognized strategy by which K. pneumoniae modulates host immunity of distant organs.

K. pneumoniae exploits EVs as a mechanism to modulate host immunity in distant organs, with tsRNAs identified as potential biomarkers and therapeutic targets.

• The EV-mediated immunomodulation represents a 'previously unrecognized strategy' used by gut commensal K. pneumoniae.
• tsRNAs are highlighted as 'potential biomarkers and therapeutic targets' based on their elevation in HCC patient serum and their functional role in NO suppression.
• The study characterizes this as host-microbe communication mediated by bacterial EVs acting systemically beyond the gut.