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

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

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
chain fatty-acids
permeability transition
cyclophilin-d
gut
microbiota
ulcerative-colitis
escherichia-coli
gene-expression
stem-cells
in-vitro
butyrate
Cell Biology
Endocrinology & Metabolism

Hamm, J. (author)
Westermann, M. (author)
Schroder, L. (author)
Shima, K. (author)
Mishra, N. (author)
Walker, A. (author)
Sommer, N. (author)
Klischies, K. (author)
Prasse, D. (author)
Zimmermann, J. (author)
Kaiser, S. (author)
Bordoni, D. (author)
Fazio, A. (author)
Marinos, G. (author)
Laue, G. (author)
Imm, S. (author)
Tremaroli, Valentina,1978Gothenburg University,Göteborgs universitet,Center for Cardiovascular and Metabolic Research (CMR),Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory(Swepub:gu)xtreva (author)
Basic, M. (author)
Hasler, R. (author)
Schmitz, R. A. (author)
Krautwald, S. (author)
Wolf, A. (author)
Stecher, B. (author)
Schmitt-Kopplin, P. (author)
Kaleta, C. (author)
Rupp, J. (author)
Bäckhed, Fredrik,1973Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Center for Cardiovascular and Metabolic Research (CMR),Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xbafre (author)
Rosenstiel, P. (author)
Sommer, F. (author)
Göteborgs universitetCenter for Cardiovascular and Metabolic Research (CMR) (creator_code:org_t)

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NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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