High-salt diet decreases FOLFOX efficacy via gut bacterial tryptophan metabolism in colorectal cancer

BackgroundFOLFOX is the recommended chemotherapy regimen for colorectal cancer (CRC), but its response rate remains low. Our previous studies have established a close relationship between gut microbiota and the anti-CRC effect of FOLFOX, though the underlying mechanisms remain unclear. Diet has been confirmed as a key factor influencing gut microbiota, and high-salt diets, representative of western dietary habits, has been shown to affect gut microbiota, immune function, and the risk of developing CRC. However, the impact of high-salt diets on the anti-CRC efficacy of FOLFOX remains unstudied. Therefore, we aimed to investigate the effect and mechanism of high-salt diets on the anti-CRC effect of FOLFOX.MethodsWe performed 16 S rRNA sequencing and T500 targeted metabolomics analysis on fecal samples from CRC patients and healthy adults. A CRC orthotopic xenograft mouse model was used to study the effect of a high-salt diet on FOLFOX's anti-CRC efficacy. 16 S rRNA sequencing and non-targeted metabolomics were conducted on mouse fecal samples. Flow cytometry was used to assess immune cell infiltration in tumor and paracancerous tissues. A mouse macrophage conditioned medium system, with tryptophan metabolites, was employed to annotate the functional metabolites, followed by in vivo verification using the orthotopic xenograft mouse model.ResultsThe structure and metabolic profiles of gut microbiota are significantly different between 9 healthy adults and 6 CRC patients. A high-salt diet significantly reduced the efficacy of FOLFOX in mice, with notable changes in gut microbiota and related metabolites. Correlation analysis revealed a significant relationship between gut microbiota, tryptophan metabolites and FOLFOX efficacy. Flow cytometry indicated that a high-salt diet altered macrophage infiltration (CD45+F4/80+) in both the tumor and paracancerous tissues. In vitro experiments confirmed that the tryptophan metabolite SK reduced FOLFOX efficacy, while IPA enhanced it through macrophage-conditioned medium. In vivo, we verified that under a high-salt diet, SK inhibited the efficacy of FOLFOX, while IPA promoted it.ConclusionA high-salt diet reduces the anti-CRC efficacy of FOLFOX through gut bacterial tryptophan metabolism mediated macrophage immunomodulation.