Gut microbiome derived 12,13 dihome promotes antigen presenting cell dysfunction in vitro and airway allergic inflammation in vivo
Levan S, Lin DL, Stamnes KA, Panzer AR, Fujimura KE, Ownby DR, Lukacs NW, Zoratti EM, Boushey HA, Johnson CC, and Lynch SV. Gut microbiome derived 12,13 dihome promotes antigen presenting cell dysfunction in vitro and airway allergic inflammation in vivo. American Journal of Respiratory and Critical Care Medicine 2020; 201(1).
American Journal of Respiratory and Critical Care Medicine
Rationale: Multiple independent birth cohorts have identified structurally and metabolically distinct microbial communities in the gut of infants at heightened risk of developing childhood allergies and asthma. Despite this growing evidence for a relationship between early life gut microbiome perturbation and childhood allergic airway disease, mechanisms by which the neonatal gut microbiome may contribute to childhood disease remain unknown. We previously showed that the cell-free products of 1-month-old gut microbiomes shape human immune cell function, cell-free products from neonates at heightened risk of childhood allergy and asthma promote expansion of Th2 cells, increased IL4 production and decreased regulatory T cells in vitro. Moreover, 12,13 DiHOME concentrations are elevated in the feces of these high-risk neonates, and exposure to this lipid alone recapitulates the effect of fecal water on regulatory T cells in vitro. Using shotgun metagenomic analyses of their feces coupled with functional assays, we identified three bacterial epoxide hydrolase (EH) genes that specifically produce 12,13 DiHOME in the neonatal gut microbiome and showed that elevated fecal copy number of these EH genes is significantly related to risk of allergies and asthma in childhood. Thus, we sought to determine how this lipid may contribute to childhood allergic asthma development by examining its effect on antigen presenting cells (APC) in vitro and in a mouse model of airway allergic inflammation.
Methods: Human dendritic cell, macrophage, and T cell assays were used to assess the pro-inflammatory properties of 12,13 DiHOME. Mice were challenged with aeroallergens and treated with intra-peritoneal 12,13 DiHOME or orally supplemented with bacterial EH genes to examine the effect on airway allergic inflammation.
Results: Treatment of human APCs with 12,13 DiHOME consistently caused a pro-inflammatory shift in gene expression and cytokine production. This included polarization of macrophages towards an M1 phenotype (p=0.0002), a decrease in IL-10 secretion from DCs (p=0.0009), and a subsequent decrease in Tregs (p=0.0004). Adult mice treated either orally with EH-expressing bacteria or intra-peritoneally with 12,13 DiHOME exhibited increased 12,13 DiHOME in their circulation (p=0.038 and p=0.033, respectively), increased airway inflammation, and decreased lung Tregs (p=0.00007 and p=0.031, respectively).
Conclusions: Elevated concentrations of 12,13 DiHOME induce pro-inflammatory phenotypes in human APCs and exacerbate airway inflammation in mice. Bacteria expressing epoxide hydrolase genes in the neonatal gut microbiome may increase risk of childhood disease by increasing the concentration of 12,13 DiHOME in the circulation.