Hexokinase – regulator of host-microbiota interactions?

Background and current state of research
Originally hexokinase (HK) has been known for its metabolic role acting as a pace-maker enzyme in glycolysis. HK2, which is one of the five HK isoforms, was recently found to be involved in inflammation and cancer (Patra et al. 2013 Cancer Cell). In macrophages and dendritic cells, HK binds N-Acetylglucosamine (NAG) which is a component of Peptidoglycan in bacterial cell walls. In the following the NLRP3-inflammosome gets activated and mediates the expression of proinflammatory cytokines such as IL1-ß and IL-18 (Wolf et al. 2016 Cell). Recently, it was also found that the microbiome regulates the expression of Hk2 in intestinal epithelial cells (IEC) (Sommer et al. 2015 Genome Biology). We also identified a gram-negative bacterium as a specific inductor of HK. This led us to the assumption that species-specific mechanisms exist that regulate Hk2 expression and thereby affect intestinal physiology.

Our goals
Our goal is to understand the interactions between the intestinal microbiome and HK. We aim to identify bacterial species and factors, which influence the expression of this enzyme. Afterwards we may be able to, for example, characterize beneficial types of bacteria and their mode of action.

How to get there
To identify bacterial species that interact with HK, we will analyze the microbiome of knockout and control wildtype mice by 16S RNA amplicon sequencing. Additionally, we will investigate the regulation of HK using multiple in vitro approaches and test the functional relevance using in vivo models of inflammation, carcinogenesis and metabolic disease.

Our findings
Deleting hexokinase 2 (HK2) specifically in the intestinal epithelium protected from acute colitis by suppressing cell death and altering mitochondrial function. The microbiome regulates HK2 expression via SCFAs targeting HDAC8. The SCFA butyrate ameliorates intestinal inflammation by downregulating HK2.
For more details see our latest published manuscript: Link to article

Mitochondrial Function and Microbial Metabolites as Central Regulators of Intestinal Immune Responses and Cancer. Weber-Stiehl S, Järke L, Castrillón-Betancur JC, Gilbert F, Sommer F. Front Microbiol. 2022 Jun 29;13:919424. doi: 10.3389/fmicb.2022.919424. eCollection 2022. PMID: 35847099
Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis. 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. Cell Metab. 2021 Dec 7;33(12):2355-2366.e8. doi: 10.1016/j.cmet.2021.11.004. Epub 2021 Nov 29. PMID: 34847376
Patra et al. “Hexokinase 2 Is Required for Tumor Initiation and Maintenance and Its Systemic Deletion Is Therapeutic in Mouse Models of Cancer” Cancer Cell 24, pages 213–220, August 12, 2013.
Sommer et al. „Site-specific Programming of the Host Epithelial Transcriptome by the Gut Microbiota”. Genome Biology. 2015 Mar 28;16:62. doi: 10.1186/s13059-015-0614-4.
Wolf et al. “Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan.” Cell 166, pages 624–630 , July 28, 2016.

Saskia Weber-Stiehl
Andre Geisler
Lea Hueber
Lea Järke

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