Role of Gut Microbiota-Derived Metabolites in Modulating Immune Responses in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is a leading cause of global cancer mortality, with its incidence rising due to environmental and lifestyle factors. The gut microbiota influence CRC pathogenesis through the production of bioactive metabolites that modulate the host immune response. This case-control study integrated metabolomic and immunohistochemical analyses to investigate this relationship. We found that CRC patients (n=30) exhibited a significant dysregulation of key metabolites compared to healthy controls (n=30), with fecal butyrate depleted from 52.4 ± 14.2 µg/g to 31.5 ± 11.8 µg/g (p<0.0001) and serum deoxycholic acid (DCA) elevated from 1.2 ± 0.5 µM to 3.1 ± 1.2 µM (p<0.0001). These systemic metabolite levels were strongly correlated with the tumor immune architecture: serum butyrate showed a strong positive correlation with cytotoxic CD8⁺ T-cell density (r = +0.712, p<0.0001) and a negative correlation with immunosuppressive Tregs (r = -0.501, p=0.002), while DCA correlated negatively with CD8⁺ T-cells (r = -0.654, p<0.0001) and positively with Tregs (r = +0.598, p<0.0001). Critically, this metabolomic profile directly impacted patient survival; those with high serum butyrate had a 72% 5-year overall survival rate compared to 48% for those with low levels (HR 0.41, p=0.006). Our findings directly link a dysregulated gut metabolome, characterized by low butyrate/high DCA, to an immunosuppressive tumor microenvironment and poorer clinical outcomes, highlighting these metabolites as promising non-invasive prognostic biomarkers and potential therapeutic targets.