Therapeutic targeting of hexokinase in intestinal inflammation

Introduction

Inflammation is characterized by changes in metabolic activity, in particular glucose metabolism. Hexokinase (HK) catalyzes the first step of glycolysis limiting its pace. During phase I of miTarget, we found that epithelial HK2 expression is upregulated in the inflamed mucosa of patients with intestinal inflammation and correlates with disease severity (1). We further revealed that, in mice, ablation of HK2 in intestinal epithelial cells (IEC) protects from colitis congruent with suppressed cell death and altered mitochondrial function, and that the microbial metabolite butyrate inhibits HK2 by signaling through histone deacetylase 8 (HDAC8) and thereby protects from acute inflammation (2). Thus, targeting HK2 through microbiome manipulation presents as an attractive therapeutic approach during intestinal inflammation.

Aims

We now aim to build upon these findings by elucidating the precise molecular mechanism how HK2-inhibition protects from inflammation, investigating the transcriptional regulatory landscape how the microbiome controls HK2 via butyrate and HDAC8, and testing newly identified specific HK2 inhibitors as well as pro- and prebiotics for their potential to modulate colitis susceptibility in mice as trials with butyrate in IBD patients had to be discontinued due to side-effects related to its chemical nature.

Outlook

This project promises to reveal druggable molecular targets in the microbiome-HK2 axis that then can be translated into the clinic to treat intestinal inflammation.