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Engineering probiotics to inhibit Clostridioides difficile infection by dynamic regulation of intestinal metabolism

Author

Listed:
  • Elvin Koh

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • In Young Hwang

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Hui Ling Lee

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Ryan De Sotto

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Jonathan Wei Jie Lee

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Yung Seng Lee

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • John C. March

    (Cornell University)

  • Matthew Wook Chang

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

Abstract

Clostridioides difficile infection (CDI) results in significant morbidity and mortality in hospitalised patients. The pathogenesis of CDI is intrinsically related to the ability of C. difficile to shuffle between active vegetative cells and dormant endospores through the processes of germination and sporulation. Here, we hypothesise that dysregulation of microbiome-mediated bile salt metabolism contributes to CDI and that its alleviation can limit the pathogenesis of CDI. We engineer a genetic circuit harbouring a genetically encoded sensor, amplifier and actuator in probiotics to restore intestinal bile salt metabolism in response to antibiotic-induced microbiome dysbiosis. We demonstrate that the engineered probiotics limited the germination of endospores and the growth of vegetative cells of C. difficile in vitro and further significantly reduced CDI in model mice, as evidenced by a 100% survival rate and improved clinical outcomes. Our work presents an antimicrobial strategy that harnesses the host-pathogen microenvironment as the intervention target to limit the pathogenesis of infection.

Suggested Citation

  • Elvin Koh & In Young Hwang & Hui Ling Lee & Ryan De Sotto & Jonathan Wei Jie Lee & Yung Seng Lee & John C. March & Matthew Wook Chang, 2022. "Engineering probiotics to inhibit Clostridioides difficile infection by dynamic regulation of intestinal metabolism," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31334-z
    DOI: 10.1038/s41467-022-31334-z
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    References listed on IDEAS

    as
    1. Yen-Lin Huang & Christophe Chassard & Martin Hausmann & Mark von Itzstein & Thierry Hennet, 2015. "Sialic acid catabolism drives intestinal inflammation and microbial dysbiosis in mice," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    2. In Young Hwang & Elvin Koh & Adison Wong & John C. March & William E. Bentley & Yung Seng Lee & Matthew Wook Chang, 2017. "Engineered probiotic Escherichia coli can eliminate and prevent Pseudomonas aeruginosa gut infection in animal models," Nature Communications, Nature, vol. 8(1), pages 1-11, April.
    3. Katharine M. Ng & Jessica A. Ferreyra & Steven K. Higginbottom & Jonathan B. Lynch & Purna C. Kashyap & Smita Gopinath & Natasha Naidu & Biswa Choudhury & Bart C. Weimer & Denise M. Monack & Justin L., 2013. "Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens," Nature, Nature, vol. 502(7469), pages 96-99, October.
    4. Masanori Funabashi & Tyler L. Grove & Min Wang & Yug Varma & Molly E. McFadden & Laura C. Brown & Chunjun Guo & Steven Higginbottom & Steven C. Almo & Michael A. Fischbach, 2020. "A metabolic pathway for bile acid dehydroxylation by the gut microbiome," Nature, Nature, vol. 582(7813), pages 566-570, June.
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    Cited by:

    1. Mairead K. Heavey & Anthony Hazelton & Yuyan Wang & Mitzy Garner & Aaron C. Anselmo & Janelle C. Arthur & Juliane Nguyen, 2024. "Targeted delivery of the probiotic Saccharomyces boulardii to the extracellular matrix enhances gut residence time and recovery in murine colitis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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