1. Immunology and Inflammation
  2. Medicine
Download icon

Bacterial-fungal interactions in the neonatal gut influence asthma outcomes later in life

  1. Rozlyn CT Boutin  Is a corresponding author
  2. Charisse Petersen
  3. Sarah E Woodward
  4. Antonio Serapio-Palacios
  5. Tahereh Bozorgmehr
  6. Rachelle Loo
  7. Alina Chalanuchpong
  8. Mihai Cirstea
  9. Bernard Lo
  10. Kelsey E Huus
  11. Weronika Barcik
  12. Meghan B Azad
  13. Allan B Becker
  14. Piush J Mandhane
  15. Theo J Moraes
  16. Malcolm R Sears
  17. Padmaja Subbarao
  18. Kelly M McNagny
  19. Stuart E Turvey
  20. Brett Finlay  Is a corresponding author
  1. University of British Columbia, Canada
  2. University of Manitoba, Canada
  3. University of Alberta, Canada
  4. The Hospital for Sick Children, Canada
  5. McMaster University, Canada
Short Report
  • Cited 0
  • Views 1,665
  • Annotations
Cite this article as: eLife 2021;10:e67740 doi: 10.7554/eLife.67740

Abstract

Bacterial members of the infant gut microbiota and bacterial-derived short-chain fatty acids (SCFAs) have been shown to be protective against childhood asthma, but a role for the fungal microbiota in asthma etiology remains poorly defined. We recently reported an association between overgrowth of the yeast Pichia kudriavzevii in the gut microbiota of Ecuadorian infants and increased asthma risk. In the present study, we replicated these findings in Canadian infants and investigated a causal association between early life gut fungal dysbiosis and later allergic airway disease (AAD). In a mouse model, we demonstrate that overgrowth of P. kudriavzevii within the neonatal gut exacerbates features of type-2 and -17 inflammation during AAD later in life. We further show that P. kudriavzevii growth and adherence to gut epithelial cells are altered by SCFAs. Collectively, our results underscore the potential for leveraging inter-kingdom interactions when designing putative microbiota-based asthma therapeutics.

Data availability

Data Availability: All data generated or analyzed during this study are included in the manuscript and supporting files. Sequencing data have been deposited in the NCBI SRA under accession code SUB7276684 (https://www.ncbi.nlm.nih.gov/sra/PRJNA624902).

The following data sets were generated

Article and author information

Author details

  1. Rozlyn CT Boutin

    Michael Smith Laboratories, Microbiology & Immunology, University of British Columbia, Vancouver, Canada
    For correspondence
    rozlyn.boutin@msl.ubc.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1598-0104
  2. Charisse Petersen

    Michael Smith Laboratories, Microbiology & Immunology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Sarah E Woodward

    Michael Smith Laboratories, Microbiology & Immunology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6688-0595
  4. Antonio Serapio-Palacios

    Michael Smith Laboratories, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Tahereh Bozorgmehr

    Michael Smith Laboratories, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Rachelle Loo

    Michael Smith Laboratories, Microbiology & Immunology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Alina Chalanuchpong

    Michael Smith Laboratories, Microbiology & Immunology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Mihai Cirstea

    Michael Smith Laboratories, Microbiology & Immunology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4900-6385
  9. Bernard Lo

    The Biomedical Research Centre, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Kelsey E Huus

    Michael Smith Laboratories, Microbiology & Immunology, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  11. Weronika Barcik

    Michael Smith Laboratories, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. Meghan B Azad

    Children's Hospital Research Institute of Manitoba, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada
    Competing interests
    The authors declare that no competing interests exist.
  13. Allan B Becker

    Children's Hospital Research Institute of Manitoba, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada
    Competing interests
    The authors declare that no competing interests exist.
  14. Piush J Mandhane

    Department of Pediatrics, School of Public Health, University of Alberta, Edmonton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  15. Theo J Moraes

    The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  16. Malcolm R Sears

    Department of Medicine, McMaster University, Hamilton, Canada
    Competing interests
    The authors declare that no competing interests exist.
  17. Padmaja Subbarao

    The Hospital for Sick Children, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  18. Kelly M McNagny

    Department of Biomedical Engineering, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4737-3499
  19. Stuart E Turvey

    Department of Pediatrics, University of British Columbia, Vancouver, Canada
    Competing interests
    The authors declare that no competing interests exist.
  20. Brett Finlay

    Michael Smith Laboratories, Microbiology & Immunology, University of British Columbia, Vancouver, Canada
    For correspondence
    bfinlay@msl.ubc.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5303-6128

Funding

Canadian Institutes of Health Research (Project Grant PJT-148484)

  • Brett Finlay

Canadian Institutes of Health Research (Foundation Grant FDN-159935)

  • Brett Finlay

AllerGen (12CHILD)

  • Meghan B Azad
  • Allan B Becker
  • Piush J Mandhane
  • Theo J Moraes
  • Malcolm R Sears
  • Padmaja Subbarao
  • Stuart E Turvey
  • Brett Finlay

Canadian Institutes of Health Research (Doctoral: Vanier Canada Graduate Scholarships)

  • Rozlyn CT Boutin

Vancouver Coastal Health-Canadian Institutes of Health Research (UBC MD/PhD Studentship Award)

  • Rozlyn CT Boutin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were in accordance with the University of British Columbia Animal Care Committee guidelines and approved by the UBC Animal Care Committee (protocols A17-0322 and A13-0344).

Human subjects: The CHILD Cohort Study protocols were approved by the human clinical research ethics boards at all universities and institutions directly involved with the CHILD cohort (McMaster University, University of British Columbia, the Hospital for Sick Children, University of Manitoba, and University of Alberta). Work in the Finlay/Turvey labs is conducted under the ethics certificate number H07-03120.

Reviewing Editor

  1. Antonis Rokas, Vanderbilt University, United States

Publication history

  1. Received: February 21, 2021
  2. Accepted: April 7, 2021
  3. Accepted Manuscript published: April 20, 2021 (version 1)
  4. Version of Record published: April 26, 2021 (version 2)
  5. Version of Record updated: April 27, 2021 (version 3)

Copyright

© 2021, Boutin et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,665
    Page views
  • 228
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Hao Gu et al.
    Research Article

    Vaccination strategies for rapid protection against multidrug-resistant bacterial infection are very important, especially for hospitalized patients who have high risk of exposure to these bacteria. However, few such vaccination strategies exist due to a shortage of knowledge supporting their rapid effect. Here, we demonstrated that a single intranasal immunization of inactivated whole cell of Acinetobacter baumannii elicits rapid protection against broad A. baumannii-infected pneumonia via training of innate immune response in Rag1-/- mice. Immunization-trained alveolar macrophages (AMs) showed enhanced TNF-α production upon restimulation. Adoptive transfer of immunization-trained AMs into naive mice mediated rapid protection against infection. Elevated TLR4 expression on vaccination-trained AMs contributed to rapid protection. Moreover, immunization-induced rapid protection was also seen in Pseudomonas aeruginosa and Klebsiella pneumoniae pneumonia models, but not in Staphylococcus aureus and Streptococcus pneumoniae model. Our data reveal that a single intranasal immunization induces rapid and efficient protection against certain Gram-negative bacterial pneumonia via training AMs response, which highlights the importance and the possibility of harnessing trained immunity of AMs to design rapid-effecting vaccine.

    1. Immunology and Inflammation
    Anders Laustsen et al.
    Tools and Resources Updated

    Plasmacytoid dendritic cells (pDCs) constitute a rare type of immune cell with multifaceted functions, but their potential use as a cell-based immunotherapy is challenged by the scarce cell numbers that can be extracted from blood. Here, we systematically investigate culture parameters for generating pDCs from hematopoietic stem and progenitor cells (HSPCs). Using optimized conditions combined with implementation of HSPC pre-expansion, we generate an average of 465 million HSPC-derived pDCs (HSPC-pDCs) starting from 100,000 cord blood-derived HSPCs. Furthermore, we demonstrate that such protocol allows HSPC-pDC generation from whole-blood HSPCs, and these cells display a pDC phenotype and function. Using GMP-compliant medium, we observe a remarkable loss of TLR7/9 responses, which is rescued by ascorbic acid supplementation. Ascorbic acid induces transcriptional signatures associated with pDC-specific innate immune pathways, suggesting an undescribed role of ascorbic acid for pDC functionality. This constitutes the first protocol for generating pDCs from whole blood and lays the foundation for investigating HSPC-pDCs for cell-based immunotherapy.