Epithelial Hexokinase 2 expression is a marker for intestinal inflammation

Abstract

BackgroundInflammation is characterized by a metabolic switch promoting glycolysis and lactate production. Hexokinases (HK) catalyze the first reaction of glycolysis and inhibition of epithelial HK2 protected from colitis in mice. HK2 expression has been described as elevated in patients with intestinal inflammation, however there is conflicting data from few cohorts especially with severely inflamed individuals, thus systematic studies linking disease activity with HK2 levels are needed. MethodsWe examined the relationship between HK2 expression and inflammation severity using bulk transcriptome data derived from the mucosa of thoroughly phenotyped patients suffering from intestinal inflammation of two independent cohorts. Analyzing publicly available single cell RNA sequencing data and performing immunofluorescence on colonic biopsies of unrelated patients with intestinal inflammation confirmed the RNA-based findings on cellular and protein level. ResultsHK2 expression gradually increased from mild to intermediate inflammation, yet strongly declined at high inflammation scores. Expression of epithelial marker genes also declined at high inflammation scores, whereas that of candidate immune marker genes increased, indicating a cellular remodeling of the mucosa during inflammation with an infiltration of HK2-negative immune cells and a loss of the apical epithelium - the main site of HK2 expression. Normalizing for the enterocyte loss clearly identified epithelial HK2 expression as gradually increasing with disease activity and remaining elevated at high inflammation scores. HK2 protein expression was mostly restricted to brush border enterocytes and these cells along with HK2 levels vanished with increasing disease severity. ConclusionsOur findings clearly define dysregulated epithelial HK2 expression as an indicator of disease activity in intestinal inflammation and suggest targeted HK2-inhibition as a potential therapeutic avenue.