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Elevated faecal 12,13-diHOME concentration in neonates at high risk for asthma is produced by gut bacteria and impedes immune tolerance

Nature Microbiology volume 4, pages 1851–1861 (2019)Cite this article

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An Author Correction to this article was published on 06 September 2019

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Abstract

Neonates at risk of childhood atopy and asthma exhibit perturbation of the gut microbiome, metabolic dysfunction and increased concentrations of 12,13-diHOME in their faeces. However, the mechanism, source and contribution of this lipid to allergic inflammation remain unknown. Here, we show that intra-abdominal treatment of mice with 12,13-diHOME increased pulmonary inflammation and decreased the number of regulatory T (Treg) cells in the lungs. Treatment of human dendritic cells with 12,13-diHOME altered expression of PPARγ-regulated genes and reduced anti-inflammatory cytokine secretion and the number of Treg cells in vitro. Shotgun metagenomic sequencing of neonatal faeces indicated that bacterial epoxide hydrolase (EH) genes are more abundant in the gut microbiome of neonates who develop atopy and/or asthma during childhood. Three of these bacterial EH genes (3EH) specifically produce 12,13-diHOME, and treatment of mice with bacterial strains expressing 3EH caused a decrease in the number of lung Treg cells in an allergen challenge model. In two small birth cohorts, an increase in the copy number of 3EH or the concentration of 12,13-diHOME in the faeces of neonates was found to be associated with an increased probability of developing atopy, eczema or asthma during childhood. Our data indicate that elevated 12,13-diHOME concentrations impede immune tolerance and may be produced by bacterial EHs in the neonatal gut, offering a mechanistic link between perturbation of the gut microbiome during early life and atopy and asthma during childhood.

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Fig. 1: Peritoneal treatment with 12,13-diHOME exacerbates lung inflammation in mice challenged with CRA.
Fig. 2: 12,13-diHOME acts through PPARγ on DCs to decrease the number of Tregs.
Fig. 3: Neonatal gut-microbiome-derived EH genes from B. bifidum and E. faecalis produce 12,13-diHOME and decrease the number of lung Treg cells in mice challenged with CRA.
Fig. 4: Increased concentrations of 12,13-diHOME and the 3EH genes in neonatal stool are associated with the development of childhood atopy, eczema and/or asthma in two US cohorts.

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Data availability

Metagenomic data generated in this study are available in the EMBLI repository as PRJEB24006 (https://www.ebi.ac.uk/ena/). Further datasets and materials are available from the corresponding author on reasonable request.

Code availability

Datasets and R scripts used for statistical analysis and figures are available on GitHub (https://github.com/srlevan/).

Change history

  • 06 September 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

We thank the WHEALS and TIPS study participants; A. Iavarone and the mass spectrometry facility and genomic sequencing laboratory at QB3 Berkeley (http://qb3.berkeley.edu/), O. Rosenberg, B. Vogelstein and B. Spiegelman for plasmid donations and N. Lukacs for assessment of the manuscript. This research was funded by NIH/NIAID award AI089473.

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    Sophia R. Levan, Kelsey A. Stamnes, Din L. Lin, Ariane R. Panzer, Elle Fukui, Kathryn McCauley, Kei E. Fujimura & Susan V. Lynch

  2. Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA

    Michelle McKean

  3. Section of Allergy–Immunology, Augusta University, Augusta, GA, USA

    Dennis R. Ownby

  4. Department of Internal Medicine, Division of Allergy and Immunology, Henry Ford Health System, Detroit, MI, USA

    Edward M. Zoratti

  5. Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    Homer A. Boushey

  6. Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA

    Michael D. Cabana

  7. Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA

    Christine C. Johnson

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Contributions

S.R.L. designed the study, performed immune assays, animal models, metagenomic analysis, biochemical assays, mass spectrometry and statistical analyses, and developed the manuscript. K.A.S. assisted with animal models, performed all microscopy analysis and contributed to the manuscript. D.L.L. assisted with animal models and human immune assays. A.R.P. assisted with animal models and manuscript editing. K.E.F. and K.M. assisted with metagenomic and statistical analysis. E.F. assisted with microscopy. D.R.O., E.M.Z. and C.C.J. provided WHEALS cohort samples and data. M.M. and M.D.C. provided TIPS cohort samples and data. H.A.B. contributed to manuscript development. S.V.L. designed and supervised the study and developed the manuscript.

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Correspondence to Susan V. Lynch.

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Competing interests

S.V.L. is co-founder of Siolta Therapeutics Inc., and serves as both a consultant and a member of its Board of Directors. Furthermore, the Regents of the University of California, UCSF have filed a provisional patent application (Application number 62/637,175) on behalf of S.V.L. and S.R.L. relating to the methods and compositions of EH genes.

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Levan, S.R., Stamnes, K.A., Lin, D.L. et al. Elevated faecal 12,13-diHOME concentration in neonates at high risk for asthma is produced by gut bacteria and impedes immune tolerance. Nat Microbiol 4, 1851–1861 (2019). https://doi.org/10.1038/s41564-019-0498-2

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