Westernized diet related arachidonic acid metabolism expands DNA error-prone growth factor-dependent colonic quiescent stem cells in adolescent mice

Given the association between early-onset colorectal cancer (eoCRC) and insulin resistance (IR), we investigated the effects of westernized diet (WD)-induced IR on intestinal stem cells (ISCs) by in-depth phenotyping three adolescent mouse models of escalating WD-driven IR. WD-related hyperlipidaemia and hyperglycaemia enhanced ω6-polyunsaturated fatty acid (PUFA) metabolism, while inhibiting glucose metabolism, resulting in colonic epithelial cell (EC) energy deficiency, hypoproliferation, and quiescent ISCs (qISC) expansion. WD-induced systemic IR provoked colonic EC IR, reduced ω6-PUFA metabolism, which was compensated by aberrated triglyceride metabolism and growth factor receptor signalling, causing hyperproliferation of expanded qISCs. Combined with single-cell transcriptomic data and colonic 3D-organoid analysis we revealed that the ω6-PUFA arachidonic acid inhibited glucose uptake, favouring colonic EC IR driven expansion of the lipid-dependent inherently DNA-mismatch prone qISC compartment in expense of the insulin-dependent LGR5 ⁺ ISCs. Overall, our findings may open new alleys for targeted nutritional interventions in eoCRC prevention.