High-Fat Diet-Induced Gut Microbiota Disruption Promotes Colorectal Cancer Lymphatic Metastasis via Propionate/GPR41 Signaling

Objective: High-fat diets (HFD) are known to affect the gut microbiome structure and potentially promote the development and metastasis of colorectal cancer (CRC). This study aims to elucidate the molecular mechanisms through which gut microbiome dysbiosis, mediated by the propionate/GPR41 signaling pathway, promotes lymphangiogenesis and lymph node (LN) metastasis in CRC, providing new insights for CRC treatment. Methods: Microbial diversity and composition in rectal cancer were compared between CRC patients and healthy controls using 16s rRNA sequencing. Key genes related to short-chain fatty acid metabolism, HFD, and gut microbiota were identified. In vitro assays assessed CRC cell proliferation, migration, invasion, and lymphangiogenesis. A CRC mouse model on an HFD was used to measure fecal propionate levels and analyze GPR41 expression in tumors. In vivo fluorescence imaging was employed to track cancer cell migration and lymph node metastasis. Results: HFD-induced microbial dysbiosis led to a significant reduction in SCFA-producing bacteria and an increase in pro-inflammatory species. This dysbiosis contributed to the suppression of propionate’s protective effects. Propionate inhibited CRC cell proliferation, migration, and invasion under HFD conditions by activating the GPR41 pathway. Silencing GPR41 reversed these inhibitory effects, highlighting the key role of GPR41 in mediating propionate’s anti-tumor effects. In vivo experiments further confirmed that propionate suppressed HFD-enhanced CRC lymphatic metastasis through the GPR41 signaling pathway, linking microbial dysbiosis with the modulation of cancer progression. Conclusion: This study reveals that HFD promotes CRC lymphangiogenesis and LN metastasis through gut microbiota dysbiosis and suppression of the propionate-activated GPR41 signaling pathway. These findings highlight the therapeutic potential of targeting the propionate/GPR41 axis , offering a promising strategy for developing novel anticancer therapies.