2. Academic Validation
  3. Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis

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

  • Cell Metab. 2021 Dec 7;33(12):2355-2366.e8. doi: 10.1016/j.cmet.2021.11.004.
Finn Hinrichsen 1,  Jacob Hamm 1,  Magdalena Westermann 1,  Lena Schröder 1,  Kensuke Shima 2,  Neha Mishra 1,  Alesia Walker 3,  Nina Sommer 1,  Kenneth Klischies 1,  Daniela Prasse 4,  Johannes Zimmermann 5,  Sina Kaiser 1,  Dora Bordoni 1,  Antonella Fazio 1,  Georgios Marinos 5,  Georg Laue 1,  Simon Imm 1,  Valentina Tremaroli 6,  Marijana Basic 7,  Robert Häsler 8,  Ruth A Schmitz 4,  Stefan Krautwald 9,  Andrea Wolf 10,  Bärbel Stecher 11,  Philippe Schmitt-Kopplin 3,  Christoph Kaleta 5,  Jan Rupp 2,  Fredrik Bäckhed 12,  Philip Rosenstiel 1,  Felix Sommer 13
Affiliations

Affiliations

  • 1 Institute of Clinical Molecular Biology, University of Kiel, 24105 Kiel, Germany.
  • 2 Department of Infectious Diseases and Microbiology, University of Lübeck, 23538 Lübeck, Germany.
  • 3 Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, German Research Centre for Environmental Health (GmbH), 85764 Neuherberg, Germany.
  • 4 Institute of General Microbiology, University of Kiel, 24118 Kiel, Germany.
  • 5 Institute of Experimental Medicine, University of Kiel, 24105 Kiel, Germany.
  • 6 The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345 Gothenburg, Sweden.
  • 7 Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany.
  • 8 Institute of Clinical Molecular Biology, University of Kiel, 24105 Kiel, Germany; Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
  • 9 Department of Nephrology and Hypertension, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
  • 10 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 11 Max von Pettenkofer Institute of Hygiene and Medical Microbiology, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany; German Center for Infection Research (DZIF), partner site LMU Munich, Munich Germany.
  • 12 The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345 Gothenburg, Sweden; Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
  • 13 Institute of Clinical Molecular Biology, University of Kiel, 24105 Kiel, Germany. Electronic address: [email protected].
PMID: 34847376 DOI: 10.1016/j.cmet.2021.11.004
Abstract

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.

Keywords

HK2; butyrate; hexokinase; immunometabolism; inflammation; intestinal epithelial cell; microbiota.

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