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| Status |
Public on Dec 01, 2021 |
| Title |
Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Hexokinases (HK) catalyze the first step of glycolysis and thereby limit its pace. HK2 is highly expressed in the gut epithelium, plays a role in immune responses and is upregulated in inflammation and ulcerative colitis 1-3. Here, we examined the microbial regulation of HK2 and its impact on intestinal inflammation by generating mice lacking HK2 specifically in intestinal epithelial cells (Hk2∆IEC). Hk2∆IEC mice were less susceptible to acute intestinal inflammation upon challenge with dextran sodium sulfate (DSS). Analyzing the epithelial transcriptome from Hk2∆IEC mice during acute colitis revealed downregulation of cell death signaling and mitochondrial dysfunction dependent on loss of HK2. Using intestinal organoids derived from Hk2∆IEC mice and Caco-2 cells lacking HK2, we identified peptidyl-prolyl cis-trans isomerase (PPIF) as a key target of HK2-mediated regulation of mitochondrial permeability and repression of cell-death during intestinal inflammation. The microbiota strongly regulated HK2 expression and activity. The microbially-derived short-chain fatty acid (SCFA) butyrate repressed HK2 expression and oral supplementation protected wildtype but not Hk2∆IEC mice from DSS colitis. Our findings define a novel mechanism how butyrate may act as a protective factor for intestinal barrier homeostasis and suggest targeted HK2 inhibition as a promising therapeutic avenue in intestinal inflammation.
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| Overall design |
RNA-seq of colon tissue of WT and Hk2∆IEC mice at days 0, 3 and 7 during DSS colitis
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| |
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| Contributor(s) |
Sommer F, Hamm J, Hinrichsen F, Mishra N, Rosenstiel P |
| Citation(s) |
34847376 |
| |
| Submission date |
Sep 16, 2020 |
| Last update date |
Dec 08, 2021 |
| Contact name |
Neha Mishra |
| E-mail(s) |
n.mishra@ikmb.uni-kiel.de
|
| Organization name |
Institute of Clinical Molecular Biology
|
| Lab |
Cell biology Lab
|
| Street address |
Rosalind-Franklin-Str. 12
|
| City |
Kiel |
| ZIP/Postal code |
24105 |
| Country |
Germany |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (38)
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| Relations |
| BioProject |
PRJNA663789 |
| SRA |
SRP282566 |
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