The microbiota-metabolite-immune axis in colorectal cancer: mechanistic insights and emerging clinical applications.

Colorectal cancer (CRC) results from a complex interplay of host genetics, environmental factors, and gut microbiota. Increasing evidence suggests that intestinal microorganisms significantly affect the initiation and progression of CRC through metabolic and immunological reprogramming. Dysbiosis, defined as an imbalance between beneficial and harmful microbial species, leads to chronic inflammation, genotoxic stress, and disruption of epithelial homeostasis. Microbial metabolites, such as short-chain fatty acids, secondary bile acids, and tryptophan derivatives, function as signaling molecules that influence epithelial proliferation, apoptosis, and immune cell activity. These metabolites regulate essential oncogenic and inflammatory pathways, including Wnt/β-catenin, NF-κB, and STAT3, and alter the tumor microenvironment by affecting regulatory T cells (Tregs), Th17 cells, macrophages, and myeloid-derived suppressor cells. Specific bacteria, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli, illustrate how particular microbes can promote tumorigenesis through metabolite-mediated signaling and immune modulation. This review summarizes recent advances in understanding how gut microbiota and their metabolites contribute to colorectal carcinogenesis by influencing inflammatory signaling, epithelial homeostasis, and tumor immune responses. These mechanistic insights highlight the microbiota-metabolite-immune axis as a crucial driver of CRC initiation and progression. The increasing recognition that microbial alterations occur alongside early neoplastic changes and affect tumor behavior emphasizes their translational potential. Although further validation in large, well-controlled clinical settings is necessary, microbiome- and metabolite-based markers could enhance current strategies for the early detection, risk assessment, and therapeutic guidance of CRC. Ultimately, deepening our understanding of the intricate interactions between intestinal microbes, host metabolism, and immune regulation will facilitate the development of microbiome-informed approaches for CRC monitoring and intervention in the future.