Neonatal gut-microbiome-derived 12,13 DiHOME suppresses immune tolerance via PPARg

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Conference Proceeding

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J Allergy Clin Immunol


RATIONALE: 12,13 DiHOME is enriched in the stool of neonates with a perturbed gut microbiota, who are at high risk of developing multisensitized atopy at age 2. This linoleic acid-derivative is structurally similar to known ligands of peroxisome proliferator-activated receptor gamma (PPARg), is generated by an epoxide hydrolase (EH) and can suppress regulatory T cells (Treg) ex vivo. Therefore, we hypothesize that gut microbiome-derived 12,13 DiHOME contributes to allergic sensitization in childhood via PPARg signaling on human dendritic cells (DCs), resulting in suppression of Tregs. METHODS: Human DC/T cell co-culture assays, qPCR, and a mouse model of cockroach antigen (CRA) allergic airway sensitization were used to evaluate the effects of 12,13 DiHOME. Metagenomics and LC-MS were used to quantify EH genes and 12,13 DiHOME in stool samples from the Wayne County Health, Environment, Allergy, and Asthma Longitudinal Study. RESULTS: Human DCs treated with 12,13 DiHOME exhibited significantly decreased IL-10 secretion (p=0.0009), altered expression of PPARg-regulated genes, CD36 (p=0.002) and CD1a (p=0.002), and decreased Treg frequency following co-culture (p=0.0004). CRA-sensitized mice, treated with peritoneal-delivered 12,13 DiHOME, exhibited an increase in circulating IgE (p=0.055) and a significant decrease in lung Tregs (p=0.019). Neonates who developed multi-sensitized atopy at age 2 years exhibited a significantly increased abundance of fecal bacterial EH genes (p=0.0017) and of 12,13 DiHOME (p=0.002). CONCLUSIONS: Early-life 12,13 DiHOME synthesis by the gut microbiome may contribute to loss of immune tolerance and the development of allergic disease in childhood.




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