Bacterial metabolite butyrate links mitochondrial metabolism and cell death in colitis via repression of Hk2

Doctoral Researcher

Associated Doctoral Researcher

Background and current state of research

Speaker of the project group is: Finn Hinrichsen

In 2020, doctoral researchers from at least two or more RTG projects working in different disciplines could apply for extra funding for a small interdiciplinary project within the RTG.

The aim of this offer is

  • to enhance the scientific collaboration within the RTG,
  • to widen interdisciplinary skills of the doctoral researchers and
  • to provide the doctoral researchers the opportunity to practice
    • writing a proposal,
    • working as a team,
    • coordinating a small own research project (one of the junior researchers helds the position of the project leader).

Four proposals have been submitted and reviewed by two external reviewers and two members of the supervisory board. The results were pretty clear, all of the proposals received good scores. However, there were two first places and two second places. Both 1st and 2nd winners were close from the score. Therefore, the overall funding budget was devided between the four groups giving all of them the chance to make this experience.

Under the header "Our goals" you find more information about this mini-proposal.

Our goals

Hexokinase (HK) 2 catalyzes the first step of glycolysis and thereby limits its pace. We previously showed that Hk2ΔIEC mice lacking HK2 specifically in intestinal epithelial cells (IECs) were less susceptible to acute dextran sodium sulfate (DSS)-induced colitis and apoptosis was reduced in the colon epithelium as assessed by TUNEL staining and RNA-sequencing. In HK2-deficient ΔHk2 Caco-2 cells cyclophilin D was verified as the key target of HK2-mediated repression of pro-apoptotic signaling during intestinal inflammation. We further identified bacteria and microbial metabolites modulating HK2 in gnotobiotic mice and epithelial cell lines. Specifically, butyrate was a potent repressor of HK2 and oral supplementation protected WT but not Hk2ΔIEC mice from colitis. We here aim to elucidate the mechanism how butyrate alleviates colitis via downregulation of HK2 in three independent work pack-ages. In WP1 we will determine the functional effect of butyrate on mitochondrial activity by Seahorse analysis. WP2 will focus on identifying the molecular mitochondrial components involved in the interaction between HK2 and butyrate. WP3 aims to uncover target genes regulated by butyrate.

Project leader: Finn Hinrichsen

Project budget: 35.000 €

Running time: April - December 2020

also members of the project team are:

Anna Schaade (doctoral researcher in Medicine, since 04.2020)

Lena Schröder (MSc student)