Lea Christiansen, Mohab Ragab, Laura Nickel, Annika Sünderhauf, Lina Jegodzinski, Maren Hicken, Heidi Schlichting, Rudrik Weikamp, Franziska Schmelter, Daniel Margis, Stefan Mertel, Ines Richerzhagen, Henrike Wenk, Luise Pötter, Sebastian Tornow, Nele Buchmann, Daniel Vondran, Clarissa Gottschild, Annika Raschdorf, Larissa Nogueira de Almeida, OUTLIVE-CRC consortium, Axel Künstner, Hauke Busch, Timo Gemoll, Christian D Sadik, Darko Castven, Jens U Marquardt, Senad Divanovic, Walter Raasch, Christian Sina, Stefanie Derer
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.