Colorectal Cancer-Associated Microbiome Remodeling Implicates Host Microbial Metabolite–Receptor Axes

Background/Objectives: Colorectal neoplasia is accompanied by reproducible changes in the gut microbiome and fecal metabolome, but the receptor systems through which altered microbial metabolic outputs may interface with the host remain incompletely defined. We investigated whether disease-associated microbial functional remodeling converges on metabolite–sensing receptor axes that could prioritize mechanistic and pharmacological hypotheses across the adenoma-to-carcinoma sequence. Methods: We analyzed 1534 publicly available stool shotgun metagenomes from 11 colorectal neoplasia cohorts, including 624 controls, 209 adenomas and 701 colorectal cancers (CRCs). Study-adjusted species and unstratified MetaCyc pathway models were combined with stage-pattern classification and mapping of microbial pathways to predefined metabolite–receptor axes. Findings were examined in two independent fecal metabolomics datasets. Results: CRC was associated with 68 species and 249 unstratified pathways at false discovery rate q < 0.05. Among CRC-associated features, 17 species and 36 pathways were adenoma-concordant, whereas 37 species and 170 pathways were CRC-specific. Of 136 pathways mapped to seven receptor-linked ligand classes, 79 were FDR-supported. Nucleotide/purinergic metabolism contained 39 FDR-supported pathways, predominantly lower in CRC, whereas fatty-acid/short-chain fatty acid signaling contained 21 FDR-supported pathways, predominantly higher in CRC. Independent fecal metabolomics showed the strongest axis-level convergence for these two axes. Conclusions: Colorectal neoplasia is associated with reproducible microbial functional remodeling that can be organized into biologically defined metabolite–receptor axes. Fatty-acid/SCFA and nucleotide/purinergic pathways emerge as the leading candidates for prospective functional and pharmacological investigation. The analysis prioritizes testable host–microbiome signaling modules but does not establish metabolite flux, receptor activation or therapeutic efficacy.