Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis

Finn Hinrichsen, Jacob Hamm, Magdalena Westermann, Lena Schröder, Kensuke Shima, Neha Mishra, Alesia Walker, Nina Sommer, Kenneth Klischies, Daniela Prasse, Johannes Zimmermann, Sina Kaiser, Dora Bordoni, Antonella Fazio, Georgios Marinos, Georg Laue, Simon Imm, Valentina Tremaroli, Marijana Basic, Robert HäslerRuth A. Schmitz, Stefan Krautwald, Andrea Wolf, Bärbel Stecher, Philippe Schmitt-Kopplin, Christoph Kaleta, Jan Rupp, Fredrik Bäckhed, Philip Rosenstiel, Felix Sommer*

*Corresponding author for this work
1 Citation (Scopus)


Hexokinases (HK) catalyze the first step of glycolysis limiting its pace. HK2 is highly expressed in gut epithelium, contributes to immune responses, and is upregulated during inflammation. We examined the microbial regulation of HK2 and its impact on inflammation using mice lacking HK2 in intestinal epithelial cells (Hk2ΔIEC). Hk2ΔIEC mice were less susceptible to acute colitis. Analyzing the epithelial transcriptome from Hk2ΔIEC mice during colitis and using HK2-deficient intestinal organoids and Caco-2 cells revealed reduced mitochondrial respiration and epithelial cell death in the absence of HK2. The microbiota strongly regulated HK2 expression and activity. The microbially derived short-chain fatty acid (SCFA) butyrate repressed HK2 expression via histone deacetylase 8 (HDAC8) and reduced mitochondrial respiration in wild-type but not in HK2-deficient Caco-2 cells. Butyrate supplementation protected wild-type but not Hk2ΔIEC mice from colitis. Our findings define a mechanism how butyrate promotes intestinal homeostasis and suggest targeted HK2-inhibition as therapeutic avenue for inflammation.

Original languageEnglish
JournalCell Metabolism
Issue number12
Pages (from-to)2355-2366.e8
Publication statusPublished - 07.12.2021

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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