Bacterial-fungal interactions in the neonatal gut influence asthma outcomes later in life
- University of British Columbia, Canada
- University of Manitoba, Canada
- University of Alberta, Canada
- The Hospital for Sick Children, Canada
- McMaster University, Canada
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).
Article and author information
Author details
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.
Reviewing Editor
- Antonis Rokas, Vanderbilt University, United States
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.
Version history
- Received: February 21, 2021
- Accepted: April 7, 2021
- Accepted Manuscript published: April 20, 2021 (version 1)
- Version of Record published: April 26, 2021 (version 2)
- 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
-
- 2,947
- views
-
- 424
- downloads
-
- 25
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Bacterial-fungal interactions in the neonatal gut influence asthma outcomes later in life
eLife 10:e67740.
https://doi.org/10.7554/eLife.67740
Further reading
-
- Immunology and Inflammation
- Medicine
Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
-
- Immunology and Inflammation
Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
