Gut microbiota regulation of the IL-6/STAT3 pathway: Linking hematopoiesis to colorectal cancer progression.

BACKGROUND AND AIM: Chronic gut microbiota-driven inflammation fuels colorectal cancer (CRC) progression, but how microbial signals influence systemic immunity and tumor growth remains poorly defined. This review synthesizes evidence on gut microbiota regulation of the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway as the central mechanistic link connecting intestinal dysbiosis, altered hematopoiesis, and CRC progression. Other inflammatory pathways and therapies are discussed only as they intersect with this core axis. METHODS: A structured search of PubMed, Web of Science, and Scopus (January 2015-December 2024) was performed using CRC, microbiota, IL-6, and STAT3 terms. Included studies provided direct evidence from human CRC tissues, CRC cell lines, or relevant animal models. RESULTS: Pathobionts such as Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis directly activate STAT3, whereas beneficial commensals like Clostridium butyricum suppress IL-6/STAT3 signaling. Microbial metabolites-including tryptophan derivatives, short-chain fatty acids, and 4-hydroxybenzeneacetic acid-fine-tune STAT3 activation via host receptors (e.g., aryl hydrocarbon receptor, GPR43). Beyond local effects, chronic IL-6/STAT3 signaling systemically reprograms hematopoiesis: gut-derived inflammatory signals reach the bone marrow, activating STAT3 in hematopoietic stem and progenitor cells and skewing differentiation toward myeloid lineages. This drives expansion of immunosuppressive polymorphonuclear myeloid-derived suppressor cells that infiltrate tumors, inhibit cytotoxic T cell and natural killer cell activity, and enable immune evasion. CONCLUSION: The microbiota-IL-6/STAT3 interface establishes a gut-bone marrow-tumor axis linking dysbiosis to altered hematopoiesis and CRC progression. Integrative strategies targeting this axis hold promise but require further safety evaluation.