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 Häsler; Ruth A. Schmitz; Stefan Krautwald; Andrea Wolf; Bärbel Stecher; Philippe Schmitt-Kopplin; Christoph Kaleta; Jan Rupp; Fredrik Bäckhed; Philip Rosenstiel; Felix Sommer

doi:10.1016/j.cmet.2021.11.004

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 af dette arbejde

Bäckhed Group

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

71 Citationer (Scopus)

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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 (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.

Originalsprog	Engelsk
Tidsskrift	Cell Metabolism
Vol/bind	33
Udgave nummer	12
Sider (fra-til)	2355-2366.e8
ISSN	1550-4131
DOI	https://doi.org/10.1016/j.cmet.2021.11.004
Status	Udgivet - 2021

Bibliografisk note

Funding Information:
This work was supported by the German Research Foundation (DFG) through the individual grant SO1141/10-1 , the Research Training Group “Genes, Environment, and Inflammation” ( RTG1743 ), the Research Unit FOR5042 “miTarget - The Microbiome as a Target in Inflammatory Bowel Diseases” (projects P5, P3, and Z), the Collaborative Research Centre CRC1182 “Origin and Function of Metaorganisms” (projects C2 and A1), the Excellence Clusters EXS2167 “Precision Medicine in Chronic Inflammation,” and EXC306 “Inflammation at Interfaces,” the Federal Ministry of Education and Research (BMBF) iTREAT SP5 project and via the SH Excellence Chair Program to Philip Rosenstiel. This work was further supported by the DFG CRC1371 “Microbiome Signatures,” the European Research Council (EVOGUTHEALTH; grant no. 865615 ), and the German Center for Infection Research (DZIF).

Publisher Copyright:
© 2021 Elsevier Inc.

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10.1016/j.cmet.2021.11.004

FulltextIndsendt manuskript, 13,2 MBLicens: Ikke-specificeret

Citationsformater

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., ... Sommer, F. (2021). Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis. Cell Metabolism, 33(12), 2355-2366.e8. https://doi.org/10.1016/j.cmet.2021.11.004

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, RA, Krautwald, S, Wolf, A, Stecher, B, Schmitt-Kopplin, P, Kaleta, C, Rupp, J, Bäckhed, F, Rosenstiel, P & Sommer, F 2021, 'Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis', Cell Metabolism, bind 33, nr. 12, s. 2355-2366.e8. https://doi.org/10.1016/j.cmet.2021.11.004

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title = "Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis",

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.",

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author = "Finn Hinrichsen and Jacob Hamm and Magdalena Westermann and Lena Schr{\"o}der and Kensuke Shima and Neha Mishra and Alesia Walker and Nina Sommer and Kenneth Klischies and Daniela Prasse and Johannes Zimmermann and Sina Kaiser and Dora Bordoni and Antonella Fazio and Georgios Marinos and Georg Laue and Simon Imm and Valentina Tremaroli and Marijana Basic and Robert H{\"a}sler and Schmitz, {Ruth A.} and Stefan Krautwald and Andrea Wolf and B{\"a}rbel Stecher and Philippe Schmitt-Kopplin and Christoph Kaleta and Jan Rupp and Fredrik B{\"a}ckhed and Philip Rosenstiel and Felix Sommer",

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AU - Hinrichsen, Finn

AU - Hamm, Jacob

AU - Westermann, Magdalena

AU - Schröder, Lena

AU - Shima, Kensuke

AU - Mishra, Neha

AU - Walker, Alesia

AU - Sommer, Nina

AU - Klischies, Kenneth

AU - Prasse, Daniela

AU - Zimmermann, Johannes

AU - Kaiser, Sina

AU - Bordoni, Dora

AU - Fazio, Antonella

AU - Marinos, Georgios

AU - Laue, Georg

AU - Imm, Simon

AU - Tremaroli, Valentina

AU - Basic, Marijana

AU - Häsler, Robert

AU - Schmitz, Ruth A.

AU - Krautwald, Stefan

AU - Wolf, Andrea

AU - Stecher, Bärbel

AU - Schmitt-Kopplin, Philippe

AU - Kaleta, Christoph

AU - Rupp, Jan

AU - Bäckhed, Fredrik

AU - Rosenstiel, Philip

AU - Sommer, Felix

PY - 2021

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N2 - 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.

AB - 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.

KW - butyrate

KW - hexokinase

KW - HK2

KW - immunometabolism

KW - inflammation

KW - intestinal epithelial cell

KW - microbiota

U2 - 10.1016/j.cmet.2021.11.004

DO - 10.1016/j.cmet.2021.11.004

M3 - Journal article

C2 - 34847376

AN - SCOPUS:85120446938

SN - 1550-4131

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SP - 2355-2366.e8

JO - Cell Metabolism

JF - Cell Metabolism

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ER -