Klebsiella pneumoniae T6SS exacerbates gut inflammation promoting tumorigenesis.

Dysbiosis and bacterial pathobionts contribute to inflammation in IBD and CRC, yet the molecular drivers of this process remain unclear. We identify the Klebsiella pneumoniae type VI secretion system (T6SS) as a key promoter of intestinal inflammation and tumor progression. Metagenomic analyses revealed enrichment of T6SS encoding genes in the gut microbiota of IBD patients during inflammatory flares. In zebrafish and mouse models, K. pneumoniae T6SS activity exacerbated inflammation and promoted colorectal tumor growth. Mechanistically, T6SS firing enhanced the secretion of LPS via outer membrane vesicles (OMVs), driving NF-κB activation and interferon signalling in host cells. In vivo, T6SS-dependent inflammation was associated with the expansion of regulatory T-cell subsets and an immunosuppressive tumor microenvironment. These findings redefine the T6SS as a microbial determinant of host inflammation and cancer progression, highlighting T6SS inhibition as a potential therapeutic approach for IBD and CRC.