Periodontitis-Associated Circulating EVs Promote Colorectal Cancer Progression via Carnosine-Mediated Acidosis...

Colorectal cancer (CRC) is the third most common malignancy worldwide. Epidemiological studies have suggested a positive association between periodontitis (PD) and CRC risk; however, the mechanistic basis underlying this relationship remains unclear. Extracellular vesicles (EVs) represent an important mode of systemic communication and may mediate the distal effects between PD and CRC. PD model was established in Apc^+/- mice with spontaneous intestinal tumorigenesis. Tumour onset, burden, and progression were evaluated in the colorectum and small intestine. Circulating EVs were isolated from the plasma of PD or sham mice and characterised. The functional contribution of EVs was assessed using pharmacological inhibition of EV release and MC38 syngeneic tumour models. Metabolomic profiling, RNA sequencing, and in vitro functional assays were performed to investigate EV cargo and underlying mechanisms. PD significantly accelerated CRC onset and increased tumour number and size in Apc^+/- mice. Inhibition of EV release by GW4869 attenuated PD-driven tumour progression, indicating a critical role of periodontitis-associated EVs (PDEVs). PDEVs promoted tumour growth and induced an immunosuppressive tumour microenvironment in MC38 transplanted tumours. Metabolomic analysis revealed marked enrichment of carnosine in PDEVs. Under acidic conditions, EV-delivered carnosine alleviated intracellular acidosis, preserved lysosomal positioning and acidification, and promoted proliferation, migration, and epithelial-mesenchymal transition of MC38 cells. Collectively, circulating EV-mediated metabolic communication pathway linking PD to CRC progression. By delivering carnosine, PDEVs support malignant phenotypes and facilitate tumour adaptation to acidic stress. Circulating EV-associated carnosine may represent a potential biomarker and a candidate target for modulating CRC progression in high-risk populations.