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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $5.17 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Datasets and R scripts used for statistical analysis and figures are available on GitHub (https://github.com/srlevan/).
Havstad, S. et al. Atopic phenotypes identified with latent class analyses at age 2 years. J. Allergy Clin. Immunol. 134, 722–727 (2014).
Yamamoto-Hanada, K., Yang, L., Narita, M., Saito, H. & Ohya, Y. Influence of antibiotic use in early childhood on asthma and allergic diseases at age 5. Ann. Allergy Asthma Immunol. 119, 54–58 (2017).
Chu, S. et al. Cesarean section without medical indication and risks of childhood allergic disorder, attenuated by breastfeeding. Sci. Rep. 7, 9762 (2017).
Silvers, K. M. et al. Breastfeeding protects against current asthma up to 6 years of age. J. Pediatr. 160, 991–996 (2012).
Fall, T. et al. Early exposure to dogs and farm animals and the risk of childhood asthma. JAMA Pediatr. 169, e153219 (2015).
Genuneit, J. Exposure to farming environments in childhood and asthma and wheeze in rural populations: a systematic review with meta-analysis. Pediatr. Allergy Immunol. 23, 509–518 (2012).
Gonzalez-Perez, G. et al. Maternal antibiotic treatment impacts development of the neonatal intestinal microbiome and antiviral immunity. J. Immunol. 196, 3768–3779 (2016).
Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).
Fujimura, K. E. et al. House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection. Proc. Natl Acad. Sci. USA 111, 805–810 (2014).
Arrieta, M.-C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl. Med. 7, 307ra152 (2015).
Fujimura, K. E. et al. Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation. Nat. Med. 22, 1187–1191 (2016).
Durack, J. et al. Delayed gut microbiota development in high-risk for asthma infants is temporarily modifiable by Lactobacillus supplementation. Nat. Commun. 9, 707 (2018).
Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat. Med. 20, 159–166 (2014).
Fonseca, W. et al. Lactobacillus johnsonii supplementation attenuates respiratory viral infection via metabolic reprogramming and immune cell modulation. Mucosal Immunol. 10, 1569–1580 (2017).
Hartl, D. et al. Quantitative and functional impairment of pulmonary CD4+ CD25hi regulatory T cells in pediatric asthma. J. Allergy Clin. Immunol. 119, 1258–1266 (2007).
Lundström, S. L. et al. Allergic asthmatics show divergent lipid mediator profiles from healthy controls both at baseline and following birch pollen provocation. PLoS ONE 7, e33780 (2012).
Lynes, M. D. et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat. Med. 37, 631–637 (2017).
Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120 (2018).
Zimmer, B. et al. The oxidized linoleic acid metabolite 12,13-DiHOME mediates thermal hyperalgesia during inflammatory pain. Biochim. Biophys. Acta 1863, 669–678 (2018).
Gouveia-Figueira, S., Späth, J., Zivkovic, A. M. & Nording, M. L. Profiling the oxylipin and endocannabinoid metabolome by UPLC-ESI-MS/MS in human plasma to monitor postprandial inflammation. PLoS ONE 10, e0132042 (2015).
Byndloss, M. X. et al. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357, 570–575 (2017).
Khare, A., Chakraborty, K., Raundhal, M., Ray, P. & Ray, A. Cutting edge: dual function of PPARγ in CD11c+ cells ensures immune tolerance in the airways. J. Immunol. 195, 431–435 (2015).
Wahli, W. & Michalik, L. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol. Metab. 23, 351–363 (2012).
Iyer, S. S. & Cheng, G. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit. Rev. Immunol. 32, 23–63 (2012).
Szatmari, I. et al. PPAR regulates the function of human dendritic cells primarily by altering lipid metabolism. Blood 110, 3271–3280 (2007).
Choo, J. et al. A novel peroxisome proliferator-activated receptor (PPAR)γ agonist 2-hydroxyethyl 5-chloro-4,5-didehydrojasmonate exerts anti-inflammatory effects in colitis. J. Biol. Chem. 290, 25609–25619 (2015).
Woerly, G. et al. Peroxisome proliferator-activated receptors α and γ down-regulate allergic inflammation and eosinophil activation. J. Exp. Med. 198, 411–421 (2003).
Nobs, S. P. et al. PPARγ in dendritic cells and T cells drives pathogenic type-2 effector responses in lung inflammation. J. Exp. Med. 8, 3015 (2017).
Green, D. et al. Central activation of TRPV1 and TRPA1 by novel endogenous agonists contributes to mechanical allodynia and thermal hyperalgesia after burn injury. Mol. Pain 12, 1–9 (2016).
Wang, Q. et al. [TRPV1 UTR-3 polymorphism and susceptibility of childhood asthma of the Han nationality in Beijing]. Wei Sheng Yan Jiu 38, 516–521 (2009).
Baker, K. et al. Role of the ion channel, transient receptor potential cation channel subfamily V member 1 (TRPV1), in allergic asthma. Respir. Res. 17, 67 (2016).
Ha, J., Dobretsov, M., Kurten, R. C., Grant, D. F. & Stimers, J. R. Effect of linoleic acid metabolites on Na+/K+ pump current in N20.1 oligodendrocytes: role of membrane fluidity. Toxicol. Appl. Pharmacol. 182, 76–83 (2002).
Morisseau, C. Role of epoxide hydrolases in lipid metabolism. Biochimie 95, 91–95 (2013).
Biswal, B. K. et al. The molecular structure of epoxide hydrolase B from Mycobacterium tuberculosis and its complex with a urea-based inhibitor. J. Mol. Biol. 381, 897–912 (2008).
Decker, M., Arand, M. & Cronin, A. Mammalian epoxide hydrolases in xenobiotic metabolism and signalling. Arch. Toxicol. 83, 297–318 (2009).
Kaminski, J. et al. High-specificity targeted functional profiling in microbial communities with ShortBRED. PLoS Comput. Biol. 11, e1004557 (2015).
Cedrone, F., Bhatnagar, T. & Baratti, J. C. Colorimetric assays for quantitative analysis and screening of epoxide hydrolase activity. Biotechnol. Lett. 27, 1921–1927 (2005).
Wegienka, G. et al. Combined effects of prenatal medication use and delivery type are associated with eczema at age 2 years. Clin. Exp. Allergy 45, 660–668 (2015).
Havstad, S. et al. Effect of prenatal indoor pet exposure on the trajectory of total IgE levels in early childhood. J. Allergy Clin. Immunol. 128, 880–885 (2011).
Burke, H. et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics 129, 735–744 (2012).
Bao, Y. et al. Risk factors in preschool children for predicting asthma during the preschool age and the early school age: a systematic review and meta-analysis. Curr. Allergy Asthma Rep. 17, 85 (2017).
Cabana, M. D. et al. Early probiotic supplementation for eczema and asthma prevention: a randomized controlled trial. Pediatrics 140, e20163000 (2017).
Gratton, J. et al. Optimized sample handling strategy for metabolic profiling of human feces. Anal. Chem. 88, 4661–4668 (2016).
Tedjo, D. I. et al. The effect of sampling and storage on the fecal microbiota composition in healthy and diseased subjects. PLoS ONE 10, e0126685 (2015).
Ye, F. et al. The dipeptide H-Trp-Glu-OH shows highly antagonistic activity against PPARγ: bioassay with molecular modeling simulation. Chembiochem 7, 74–82 (2005).
Laukens, D., Brinkman, B. M., Raes, J., De Vos, M. & Vandenabeele, P. Heterogeneity of the gut microbiome in mice: guidelines for optimizing experimental design. FEMS Microbiol. Rev. 40, 117–132 (2016).
Aichbhaumik, N. et al. Prenatal exposure to household pets influences fetal immunoglobulin E production. Clin. Exp. Allergy 38, 1787–1794 (2008).
Cabana, M. D., McKean, M., Wong, A. R., Chao, C. & Caughey, A. B. Examining the hygiene hypothesis: the Trial of Infant Probiotic Supplementation. Paediatr. Perinat. Epidemiol. 21, 23–28 (2007).
DeAngelis, K. M. et al. Selective progressive response of soil microbial community to wild oat roots. ISME J. 3, 168–178 (2009).
Han, M. et al. A novel affordable reagent for room temperature storage and transport of fecal samples for metagenomic analyses. Microbiome 6, 43 (2018).
Rounge, T. B. et al. Evaluating gut microbiota profiles from archived fecal samples. BMC Gastroenterol. 18, 171 (2018).
Li, D., Liu, C.-M., Luo, R., Sadakane, K. & Lam, T.-W. MEGAHIT: an ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph. Bioinformatics 31, 1674–1676 (2015).
Suzek, B. E. et al. UniRef clusters: a comprehensive and scalable alternative for improving sequence similarity searches. Bioinformatics 31, 926–932 (2015).
Tang, L. et al. A high‐throughput adrenaline test for the exploration of the catalytic potential of halohydrin dehalogenases in epoxide ring‐opening reactions. Biotechnol. Appl. Biochem. 62, 451–457 (2015).
Maldonado, G. & Greenland, S. Simulation study of confounder-selection strategies. Am. J. Epidemiol. 138, 923–936 (1993).
Henke, BradR. et al. N-(2-Benzoylphenyl)-l-tyrosine PPARγ agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J. Med. Chem. 41, 5020–5036 (1998).
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.
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.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.