Integrated Metabolomic and Metagenomic Profiling Reveals Distinct Microbial-Metabolic Signatures in the Adenoma-Carcinoma Sequence of Colorectal Cancer.
Colorectal cancer (CRC) arises via the stepwise adenoma-carcinoma sequence (ACS). Gut microbial dysbiosis and host metabolic reprogramming jointly correlate with CRC onset and advancement, yet their stage-specific crosstalk across ACS remains largely unclear. Limited multi-omics research on microbial-metabolic interactions throughout ACS hinders the development of early diagnostic biomarkers and preventive strategies. Here, we combined untargeted mucosal metabolomics and fecal shotgun metagenomic sequencing in 36 participants, covering healthy controls, ACS, and CRC patients. We systematically analyzed microbial composition, functions, differential metabolites, and enriched pathways and integrated multi-omics data to screen stage-specific signatures. Distinct gut microbial profiles and progressive functional shifts toward pathogenicity and abnormal carbohydrate metabolism were observed along ACS. Mucosal metabolism was continuously disrupted, with prominent alterations in taurine-hypotaurine, sphingolipid, and bile acid pathways. Core differential metabolites showed excellent diagnostic performance. Microbe-metabolite interactions were progressively enhanced to form a concerted pro-tumor axis. This study characterizes unique ACS-stage microbial-metabolic features. Dysregulated metabolic pathways and key microbe-metabolite crosstalk are closely associated with CRC progression, offering novel non-invasive biomarkers and premalignant intervention targets.