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Hinrichsen, F.* ; Hamm, J.* ; Westermann, M.* ; Schröder, L.* ; Shima, K.* ; Mishra, N.* ; Walker, A. ; Sommer, N.* ; Klischies, K.* ; Prasse, D.* ; Zimmermann, J.* ; Kaiser, S.* ; Bordoni, D.* ; Fazio, A.* ; Marinos, G.* ; Laue, G.* ; Imm, S.* ; Tremaroli, V.* ; Basic, M.* ; Häsler, R.* ; Schmitz, R.A.* ; Krautwald, S.* ; Wolf, A.* ; Stecher, B.* ; Schmitt-Kopplin, P. ; Kaleta, C.* ; Rupp, J.* ; Bäckhed, F.* ; Rosenstiel, P.* ; Sommer, F.*

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

Cell Metab. 33, 2355-2366.e8 (2021)

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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 (Hk2^ΔIEC). Hk2^ΔIEC mice were less susceptible to acute colitis. Analyzing the epithelial transcriptome from Hk2^ΔIEC 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 Hk2^ΔIEC mice from colitis. Our findings define a mechanism how butyrate promotes intestinal homeostasis and suggest targeted HK2-inhibition as therapeutic avenue for inflammation.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Hk2 ; Butyrate ; Hexokinase ; Immunometabolism ; Inflammation ; Intestinal Epithelial Cell ; Microbiota; Chain Fatty-acids; Permeability Transition; Cyclophilin-d; Gut Microbiota; Ulcerative-colitis; Escherichia-coli; Gene-expression; Stem-cells; In-vitro; Butyrate

ISSN (print) / ISBN 1550-4131

e-ISSN 1932-7420

Journal Cell Metabolism

Quellenangaben Volume: 33, Issue: 12, Pages: 2355-2366.e8

Publisher Elsevier

Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Analytical BioGeoChemistry (BGC)

Grants German Center for Infection Research (DZIF)
German Research Foundation (DFG) through Research Training Group "Genes, Environment, and Inflammation"
German Research Foundation (DFG) through Research Unit FOR5042 "miTarget-The Microbiome as a Target in Inflammatory Bowel Dis-eases"
German Research Foundation (DFG) through Collaborative Research Centre CRC1182 "Origin and Function of Metaorganisms"
German Research Foundation (DFG) through Excellence Cluster EXS2167 "Precision Medicine in Chronic Inflammation"
German Research Foundation (DFG) through Excellence Cluster EXC306 "Inflammation at Interfaces"
Federal Ministry of Education and Research (BMBF) iTREAT SP5 project
SH Excellence Chair Program
DFG CRC1371 "Micro-biome Signatures"
European Research Council (EVOGUTHEALTH)
German Research Foundation (DFG)