Fusobacterium periodonticum promotes colorectal tumorigenesis via decanoic acid-driven neutrophil chemotaxis

Gut microbiota dysbiosis and immune dysregulation are closely associated with the development of colorectal cancer. Identifying the mechanistic links among specific microbial species, metabolites, and immune responses is crucial for uncovering novel insights into its pathogenesis. Here we show, through metagenomic and metabolomic analyses of clinical cohorts, that Fusobacterium periodonticum is significantly enriched in colorectal cancer patients and strongly correlated with elevated decanoic acid levels. Single-cell transcriptomic results further reveal tissue-specific neutrophil enrichment in colorectal cancer tissues, characterized by high CXCL8 expression and activation of neutrophil-related immune pathways. Cellular experiments demonstrate that decanoic acid induces late apoptosis/necrosis of neutrophils, enhances their chemotaxis through a pertussis toxin-sensitive G-protein-dependent mechanism, and upregulates genes involved in leukocyte migration and tumorigenesis. Mouse models further confirm that F. periodonticum colonization increases intestinal dysplasia and decanoic acid levels, and that decanoic acid intervention promotes tumor progression by facilitating neutrophil infiltration and modulating the local immune microenvironment. Our study reveals an important role of F. periodonticum in colorectal tumorigenesis via decanoic acid-medicated neutrophil chemotaxis, providing mechanistic insights into the pathogenesis of colorectal cancer.