Gut microbial metabolites in inflammation-associated colorectal cancer: mechanisms and therapeutic implications

Colitis-associated colorectal cancer (CAC) represents the most severe malignant complication of inflammatory bowel disease (IBD), characterized by high invasiveness, frequent recurrence, and poor prognosis. Recent studies have revealed that gut microbial metabolites are involved in the initiation and progression of CAC through a “metabolite-signaling pathway-epigenetics” regulatory network, demonstrating a remarkable dual modulatory role. Protective metabolites, such as short-chain fatty acids (SCFAs), tryptophan derivatives (e.g., indole compounds), and vitamin B2, exert anti-inflammatory, antioxidant, intestinal barrier-enhancing, and oncogenic pathway-suppressing effects. In contrast, pathogenic metabolites promote carcinogenesis. Prominent among such metabolites are secondary bile acids e.g., deoxycholic acid (DCA), trimethylamine N-oxide (TMAO), and high concentrations of hydrogen sulfide (H2S). These metabolites activate nuclear factor κB (NF-κB), stimulate the release of pro-inflammatory cytokines, induce DNA damage, and disrupt immune homeostasis. Conversely, elevated plasma TMAO levels are closely associated with poor survival outcomes, with high-risk individuals showing significantly increased risks of all-cause mortality and recurrence. This review systematically summarizes the microbial origins, dual mechanisms in CAC, and potential therapeutic value of several key gut microbiota-derived metabolites, including SCFAs, succinate, secondary bile acids, TMAO, tryptophan metabolites, polyamines, H2S, and vitamin B2. Based on current evidence, intervention strategies are primarily focused on regulating microbial metabolic balance via probiotics/prebiotics, increasing precursor supply of beneficial metabolites through dietary fiber supplementation, reconstructing gut homeostasis via microbiota transplantation, and developing metabolite analogs or chelators for targeted intervention. Although gut microbial metabolites offer new paradigms for early diagnostic biomarkers and targeted therapies in CAC, clinical translation still faces several challenges, including interindividual microbial heterogeneity, establishment of causal relationships between metabolites and disease, and optimization of clinical intervention pathways, which require further research breakthroughs.