Yersiniabactin-producing adherent-invasive <i>Escherichia coli</i> exploit host glycolysis to drive macrophage HIF-1α stabilization.

Abstract

The siderophore yersiniabactin (Ybt) produced by a subset of intestinal adherent-invasive <i>Escherichia coli</i> (AIEC) drive intestinal fibrosis in murine model of Crohn's disease (CD). This is linked to the Ybt-induced disruption of host metal homeostasis and activation of the hypoxia-inducible factor 1-alpha (HIF-1α) in macrophages. Elevated glycolytic activity has been documented in both intestinal tissues and macrophages from patients with CD, indicating that metabolic reprogramming is a characteristic feature of the disease. Here, we show that HIF-1α stabilization by Ybt⁺ AIEC requires active host glycolysis. This effect is independent of <i>Hif1a</i> transcription and lipopolysaccharide stimulation and is not solely explained by intracellular bacterial load but instead relies on host metabolic activity. Mechanistically, Ybt⁺ AIEC activated the Akt-mTOR pathway to support HIF-1α translation. Inhibition of glycolysis suppressed this signaling axis, reducing HIF-1α translation and nuclear localization. Given the association between Ybt⁺ AIEC and fibrosis in CD, these findings suggest that targeting host glycolysis may limit AIEC-driven macrophage HIF-1α activation and fibrotic progression in CD patients.