Targeting catecholate siderophore systems enables precision depletion of gut enterobacteria during colitis

Abstract

Adherent-invasive Escherichia coli (AIEC) is frequently isolated from the dysbiotic gut microbiome in inflammatory bowel disease and is implicated in disease progression, highlighting its potential as a therapeutic target. Here we show that iron acquisition is essential for AIEC colonization of the inflamed gut. Mechanistically, four catecholate siderophore receptors act redundantly to support AIEC growth under iron-limited conditions and during colitis. Immunization of colitis-prone Il10-/- mice against catecholate siderophores reduced intestinal AIEC colonization, particularly its association with the mucosa, while largely preserving overall gut microbiome composition. Longitudinal metagenomic profiling identified immunization-associated shifts in Akkermansiaceae and Lactobacillaceae, and experiments in gnotobiotic Il10-/- mice demonstrated that Limosilactobacillus reuteri, a member of the Lactobacillaceae, limited AIEC colonization, whereas Akkermansiaceae exacerbated disease. Our findings establish catecholate siderophore-mediated iron acquisition as a therapeutic target in AIEC and provide proof-of-principle that virulence-targeted immunization can selectively antagonize a disease-associated bacterium while preserving the gut microbiota

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BibTeX RIS

BibTeX

@misc{norton2026targeting,
  title = {{Targeting catecholate siderophore systems enables precision depletion of gut enterobacteria during colitis}},
  author = {G. J. Norton and A. M. Dudek and R. R. Gerner and C. Guo and V. Castillo and F. A. Argueta and C. J. Beebout and G. Kanyabi and J. Drushell and G. T. Walker and C.-Y. Hsu and S. Bessho and S.-P. Nuccio and H. Chu and K. Zengler and E. M. Nolan and M. Raffatellu},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.02.756324},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.02.756324v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Targeting catecholate siderophore systems enables precision depletion of gut enterobacteria during colitis
AU  - G. J. Norton
AU  - A. M. Dudek
AU  - R. R. Gerner
AU  - C. Guo
AU  - V. Castillo
AU  - F. A. Argueta
AU  - C. J. Beebout
AU  - G. Kanyabi
AU  - J. Drushell
AU  - G. T. Walker
AU  - C.-Y. Hsu
AU  - S. Bessho
AU  - S.-P. Nuccio
AU  - H. Chu
AU  - K. Zengler
AU  - E. M. Nolan
AU  - M. Raffatellu
PY  - 2026
DA  - 2026/10/02
PB  - bioRxiv
DO  - 10.64898/2026.10.02.756324
UR  - https://www.biorxiv.org/content/10.64898/2026.10.02.756324v1
AB  - Adherent-invasive Escherichia coli (AIEC) is frequently isolated from the dysbiotic gut microbiome in inflammatory bowel disease and is implicated in disease progression, highlighting its potential as a therapeutic target. Here we show that iron acquisition is essential for AIEC colonization of the inflamed gut. Mechanistically, four catecholate siderophore receptors act redundantly to support AIEC growth under iron-limited conditions and during colitis. Immunization of colitis-prone Il10-/- mice against catecholate siderophores reduced intestinal AIEC colonization, particularly its association with the mucosa, while largely preserving overall gut microbiome composition. Longitudinal metagenomic profiling identified immunization-associated shifts in Akkermansiaceae and Lactobacillaceae, and experiments in gnotobiotic Il10-/- mice demonstrated that Limosilactobacillus reuteri, a member of the Lactobacillaceae, limited AIEC colonization, whereas Akkermansiaceae exacerbated disease. Our findings establish catecholate siderophore-mediated iron acquisition as a therapeutic target in AIEC and provide proof-of-principle that virulence-targeted immunization can selectively antagonize a disease-associated bacterium while preserving the gut microbiota
ER  -

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