Siderophore-mediated zinc acquisition enhances enterobacterial colonization of the inflamed gut Original paper

What was studied?

This experimental study tested whether E. coli Nissle 1917 uses yersiniabactin as a zincophore to support siderophore-mediated zinc acquisition, resist host calprotectin, and colonize the inflamed gut. The authors combined zinc-limited growth assays, targeted gene deletions in zinc transport and yersiniabactin loci, native electrospray metabolomics, and NMR to confirm direct zinc binding, and mouse colitis models to assess competitive fitness in vivo. They compared E. coli Nissle with Salmonella Typhimurium under calprotectin pressure, showed pH-dependent metal preference for yersiniabactin, and used exogenous purified yersiniabactin to rescue growth of zinc-transport–deficient mutants. They then quantified colonization advantages in dextran sodium sulfate colitis, and contrasted results in germ-free and calprotectin-deficient mice to define the inflammation and calprotectin dependence of the mechanism.

Who was studied?

The work used E. coli Nissle 1917 and Salmonella typhimurium strains, including double mutants lacking ZnuABC and ZupT and triple mutants additionally lacking irp2 or ybtX. The in vivo models were female C57BL/6 mice with dextran sodium sulfate colitis, germ-free Swiss Webster mice without inflammation, and S100a9−/− mice lacking calprotectin. Competitive indices from feces and cecal content quantified fitness. Host inflammation markers and histopathology confirmed comparable colitis across groups. No human participants were enrolled.

Most important findings

E. coli Nissle outgrew Salmonella Typhimurium under calprotectin, even when high-affinity zinc transporters were deleted, indicating an additional route for zinc uptake. Yersiniabactin directly bound zinc, with greater relative zinc preference at higher pH, and exogenous yersiniabactin rescued zinc-transport–deficient growth, while enterobactin did not. Deleting irp2 or ybtX in the zinc-transport–deficient background caused severe zinc-limited growth defects that zinc supplementation corrected, implicating yersiniabactin as a functional zincophore. In dextran sodium sulfate colitis, wild-type E. coli Nissle gained large competitive advantages over mutants lacking zinc transport or yersiniabactin functions, and these advantages disappeared in germ-free or calprotectin-deficient mice, proving inflammation and calprotectin dependence.

Together, these results define a microbiome signature for Enterobacteriaceae blooms in inflammation: presence of the yersiniabactin locus and ybtX, resistance to calprotectin-mediated zinc sequestration, pH-tuned zinc affinity, and enhanced colonization of the inflamed colon. Because many commensal and pathogenic Enterobacteriaceae carry yersiniabactin, this signature links metal capture with competitive dominance over obligate anaerobes during dysbiosis.

Key implications

Clinicians should view E. coli Nissle benefits in inflammation as context dependent and metal linked. Zinc availability and calprotectin shape colonization. Probiotics or pathogens with yersiniabactin may gain a selective advantage in colitis, potentially altering community structure. This mechanism suggests biomarker candidates for microbiome signatures and therapeutic targets in metal competition, but translation to human outcomes requires clinical trials.