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Yersiniabactin-producing adherent-invasive Escherichia coli exploit host glycolysis to drive macrophage HIF-1α

Marlus S Pedrosa1, Ju-Hyun Ahn1, John D Sears1

  • 1Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Science Advances
|July 23, 2026
PubMed

Insights

Yersiniabactin-producing E. coli drives Crohn's disease fibrosis by activating hypoxia-inducible factor 1-alpha (HIF-1α) in macrophages. Targeting host glycolysis may limit this activation and disease progression.

Area of Science:

  • Microbiology
  • Immunology
  • Gastroenterology

Background:

  • Adherent-invasive Escherichia coli (AIEC) producing yersiniabactin (Ybt) are linked to intestinal fibrosis in Crohn's disease (CD).
  • Ybt disrupts host metal homeostasis and activates hypoxia-inducible factor 1-alpha (HIF-1α) in macrophages.
  • Metabolic reprogramming, including elevated glycolysis, is characteristic of CD.

Purpose of the Study:

  • To investigate the role of host glycolysis in Ybt-mediated HIF-1α activation by AIEC.
  • To elucidate the molecular mechanisms linking Ybt, glycolysis, and HIF-1α stabilization.

Main Methods:

  • Utilized a murine model of CD and AIEC infection.
  • Investigated the impact of glycolysis inhibition on HIF-1α activation and signaling pathways.
  • Analyzed Akt-mTOR pathway activation and HIF-1α translation and nuclear localization.

Main Results:

  • HIF-1α stabilization by Ybt+ AIEC requires active host glycolysis, independent of Hif1a transcription or LPS.
  • Host metabolic activity, not solely bacterial load, drives HIF-1α activation.
  • Ybt+ AIEC activates the Akt-mTOR pathway, promoting HIF-1α translation; glycolysis inhibition disrupts this.

Conclusions:

  • Host glycolysis is essential for Ybt-mediated HIF-1α activation in macrophages by AIEC.
  • Targeting host glycolysis presents a potential therapeutic strategy to limit AIEC-driven fibrosis in CD.

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