IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31334-z.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31334-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-31334-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    4. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. K. E. Huus & T. T. Hoang & A. Creus-Cuadros & M. Cirstea & S. L. Vogt & K. Knuff-Janzen & P. J. Sansonetti & P. Vonaesch & B. B. Finlay, 2021. "Cross-feeding between intestinal pathobionts promotes their overgrowth during undernutrition," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. James D Brunner & Nicholas Chia, 2020. "Minimizing the number of optimizations for efficient community dynamic flux balance analysis," PLOS Computational Biology, Public Library of Science, vol. 16(9), pages 1-20, September.
    3. Bennett W. Fox & Maximilian J. Helf & Russell N. Burkhardt & Alexander B. Artyukhin & Brian J. Curtis & Diana Fajardo Palomino & Allen F. Schroeder & Amaresh Chaturbedi & Arnaud Tauffenberger & Cheste, 2024. "Evolutionarily related host and microbial pathways regulate fat desaturation in C. elegans," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Ren Dodge & Eric W. Jones & Haolong Zhu & Benjamin Obadia & Daniel J. Martinez & Chenhui Wang & Andrés Aranda-Díaz & Kevin Aumiller & Zhexian Liu & Marco Voltolini & Eoin L. Brodie & Kerwyn Casey Huan, 2023. "A symbiotic physical niche in Drosophila melanogaster regulates stable association of a multi-species gut microbiota," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Vinod Nikhra, 2019. "Therapeutic Potential of Gut Microbiome Manipulation: Concepts in Fecal Microbiota Transplantation," Current Research in Diabetes & Obesity Journal, Juniper Publishers Inc., vol. 11(1), pages 1-9, June.
    6. Maximilian J. Helf & Bennett W. Fox & Alexander B. Artyukhin & Ying K. Zhang & Frank C. Schroeder, 2022. "Comparative metabolomics with Metaboseek reveals functions of a conserved fat metabolism pathway in C. elegans," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    7. Brian D. Huang & Thomas M. Groseclose & Corey J. Wilson, 2022. "Transcriptional programming in a Bacteroides consortium," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    8. Naomi Ohta & Bo Norby & Guy H Loneragan & Javier Vinasco & Henk C den Bakker & Sara D Lawhon & Keri N Norman & Harvey M Scott, 2019. "Quantitative dynamics of Salmonella and E. coli in feces of feedlot cattle treated with ceftiofur and chlortetracycline," PLOS ONE, Public Library of Science, vol. 14(12), pages 1-17, December.
    9. Alexander Y. G. Yip & Olivia G. King & Oleksii Omelchenko & Sanjana Kurkimat & Victoria Horrocks & Phoebe Mostyn & Nathan Danckert & Rohma Ghani & Giovanni Satta & Elita Jauneikaite & Frances J. Davie, 2023. "Antibiotics promote intestinal growth of carbapenem-resistant Enterobacteriaceae by enriching nutrients and depleting microbial metabolites," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    10. Betz, Ulrich A.K. & Arora, Loukik & Assal, Reem A. & Azevedo, Hatylas & Baldwin, Jeremy & Becker, Michael S. & Bostock, Stefan & Cheng, Vinton & Egle, Tobias & Ferrari, Nicola & Schneider-Futschik, El, 2023. "Game changers in science and technology - now and beyond," Technological Forecasting and Social Change, Elsevier, vol. 193(C).
    11. Mengci Li & Shouli Wang & Yitao Li & Mingliang Zhao & Junliang Kuang & Dandan Liang & Jieyi Wang & Meilin Wei & Cynthia Rajani & Xinran Ma & Yajun Tang & Zhenxing Ren & Tianlu Chen & Aihua Zhao & Chen, 2022. "Gut microbiota-bile acid crosstalk contributes to the rebound weight gain after calorie restriction in mice," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    12. Austin G. Rottinghaus & Aura Ferreiro & Skye R. S. Fishbein & Gautam Dantas & Tae Seok Moon, 2022. "Genetically stable CRISPR-based kill switches for engineered microbes," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    13. Giuliano Bonanomi & Mohamed Idbella & Ahmed M. Abd-ElGawad, 2021. "Microbiota Management for Effective Disease Suppression: A Systematic Comparison between Soil and Mammals Gut," Sustainability, MDPI, vol. 13(14), pages 1-16, July.
    14. Vinod Nikhra, 2019. "Therapeutic Potential of Gut Microbiome Manipulation: Concepts in Fecal Microbiota Transplantation," Current Research in Diabetes & Obesity Journal, Juniper Publishers Inc., vol. 11(1), pages 9-17, June.
    15. Chang Ge & Zheng Yu & Huakang Sheng & Xiaolin Shen & Xinxiao Sun & Yifei Zhang & Yajun Yan & Jia Wang & Qipeng Yuan, 2022. "Redesigning regulatory components of quorum-sensing system for diverse metabolic control," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31334-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.