Intestinal adaptations increase basolateral intestinal glucose uptake and glycolysis in a mouse model of Cystic Fibrosis

The gastrointestinal manifestations of Cystic Fibrosis (CF) are a continued source of morbidity and mechanistic uncertainty despite recent advances in CF care. We sought to characterize intestinal glucose demand in a mouse model of CF to better understand CF intestinal disease. We assessed in vivo systemic glucose uptake from circulation, including intestinal glucose demand, using 18 F-Fluorodeoxyglucose Positron Emission Tomography (PET) imaging studies in wildtype (WT) and CF mice. RNA-Sequencing studies with complementary assessments of protein expression and functional metabolism were performed to identify the responsible glucose transporter and relevant metabolic pathways. Lastly, morphologic and histologic differences between the CF and WT small intestine were investigated. Increased glucose uptake from circulation to CF intestine was detected with the most prominent increases seen in CF jejunum and ileum. Increased mRNA and protein expression of GLUT1 was evident in whole intestinal tissue and isolated crypts suggesting GLUT1 is responsible for mediating the increased glucose uptake from the blood supply. We found transcriptional and functional enrichment of glycolysis in the CF jejunum and ileum. Proliferative intestinal adaptations, including increased intestinal length and weight, in addition to increased villi length and crypt depth, were observed in CF mice. The increased intestinal glucose uptake from circulation and increased glycolysis, in combination with the morphologic and histologic changes in the CF intestine, are suggestive of a proliferative adaptive response and increased intestinal glucose demand in CF. This work may yield novel markers of CF disease status and new therapeutic approaches.