EXCESS DIETARY SUGAR ALTERS COLONOCYTE METABOLISM AND IMPAIRS THE EARLY PROLIFERATIVE RESPONSE TO DAMAGE

Abstract The colonic epithelium requires continuous renewal by crypt resident intestinal stem cells (ISCs) and transit amplifying (TA) to maintain barrier integrity, especially after inflammatory damage. An important regulator of ISC TA cell function is dietary metabolites which can affect their proliferative capacity. Over the last 150 years, diet high-income countries contains increasing amounts simple sugars, such as sucrose, but whether excess sugar affects ISCs directly unknown. We used a combination 3-dimensional colonoids mouse model colon damage/repair (DSS colitis) demonstrate direct effect on transcriptional, metabolic, regenerative functions cells. that high conditions limit murine human colonoid development, associated with reduction in expression key gene signatures. Further, high-glucose led accumulation glycolytic metabolite pyruvate colonoids, concomitant decrease ATP, suggesting impaired fuel metabolism. Treatment DCA, forces into TCA cycle, restored growth, ATP levels, proliferation Similarly, DSS treatment mice fed massive irreparable damage was independent microbiota its metabolites. Metabolic analyses from high-sucrose-fed revealed increased potential without commensurate increase aerobic respiration. Rather, has mitochondrial content, levels further demonstrating oxidative phosphorylation Finally, we demonstrated reduced number daughter Taken together, our results indicate short-term, sucrose modulate metabolism inhibit ISC/TA proliferation. This knowledge may inform diets better support acute injury, seen patients an flare Ulcerative Colitis.