Abstract
Enterohemorrhagic Escherichia coli (EHEC) is a severe foodborne pathogen that can lead to hemolytic uremic syndrome. However, antibiotics are contraindicated for EHEC treatment due to toxin release and gut microbiota disruption. Here we report a dual‑mechanism therapeutic strategy combining an engineered Escherichia coli Nissle 1917 strain (EcN3) with 2′‑fucosyllactose (2‑FL) delivered via multicompartment microspheres (MCMs). EcN3 expresses α‑L‑fucosidase to hydrolyze 2‑FL into lactose and fucose. Lactose enhances glucuronic acid utilization, limiting a preferred nutrient of EHEC, whereas fucose activates FusKR signaling to suppress virulence gene expression. MCMs confer gastric protection and enable targeted colonic release, ensuring coordinated activity. In female mouse models and infant rabbit models of Citrobacter rodentium and EHEC infection, this system reduces intestinal colonization, virulence gene expression and epithelial damage without inducing Shiga toxin production. Moreover, MCMs-based strategy preserves the relative abundance of Lactobacillus, and promotes intestinal integrity. This targeted strategy presents a viable alternative to antibiotics, addressing EHEC pathogenesis and antibiotic resistance.
Data availability
The raw sequencing data of 16S rRNA gene sequencing in this study have been deposited in the Genome Sequence Archive (GSA) at the BIG Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences, under accession code CRA024889. The metabolomic data have been uploaded into the Open Archive for Miscellaneous Data under accession Number: OMIX013933. The relevant experimental data and metadata generated in this study are provided in the manuscript, Supplementary Information, and Source Data file. Source data are provided with this paper.
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Acknowledgements
This study was supported by National Natural Science Foundation of China (NSFC) Grants 825B2066 (to R.L.), 32170144 (to T.W.), 32470146 (to T.W.), 32100144 (to Y.L.), 32201183 (to G.T.), 82502737 (to X.L.); and National Key R&D Program of China grant 2024YFE0198900 (to Y.L.); Scientific Research Project of Tianjin Municipal Education Commission Grants 2024ZXZD016 (to M.Z.); China Postdoctoral Science Foundation Grant 2025M772657 (to X.L.); China Postdoctoral Science Foundation-Tianjin Joint Support Program Grant 2025T024TJ (to X.L.); Postdoctoral Fellowship Program of China Postdoctoral Science Foundation Grant GZC20251763 (to X.L.).
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Y.L., T.W., G.T., and Y.S. designed the research; G.M., R.L., X.L., J.W.(Jialin Wu), Y.N., and S.W. performed the research; G.M., R.L., X.L., Z.C., X.Q., Q.W., J.W.(Junyue Wang), J.Q., M.Z., and Y.P. analyzed the data; and Y.L., G.M., R.L., X.L., and J.W.(Jialin Wu) wrote the manuscript. All authors gave final approval for the version to be published.
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Ma, G., Liu, R., Li, X. et al. Engineered bacterial therapy suppresses Enterohemorrhagic Escherichia coli through metabolic competition and virulence silencing. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69126-4
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DOI: https://doi.org/10.1038/s41467-026-69126-4
