Divergent Colorectal Cancer Risks Following Metabolic Bariatric Surgery: Anatomical Remodeling and the Genotoxic Microenvironment

Metabolic bariatric surgery (MBS) reduces overall cancer incidence, yet colorectal cancer (CRC) risk diverges by procedure. Roux-en-Y gastric bypass (RYGB) has been associated with increased long-term CRC risk (HR 1.55 at 10–14 years), whereas sleeve gastrectomy (SG) shows no equivalent elevation, though shorter follow-up (mean 4.5 vs. 8.5 years) precludes definitive conclusions. This review develops a biologically plausible mechanistic framework for these divergent outcomes. RYGB-induced anatomical bypass and accelerated transit are proposed to drive distal substrate overload, with an associated shift of the colonic microbiome toward proteolytic fermentation. The proposed genotoxic luminal environment is characterized by convergent actions of secondary bile acids, tyramine, and hydrogen sulfide, compounded by butyrate depletion. By preserving gastrointestinal continuity, SG is hypothesized to avoid these alterations. These considerations support integrating baseline CRC risk into surgical selection and procedure-specific surveillance after RYGB.