Neonatal gut-microbiome-derived 12,13 DiHOME suppresses immune tolerance via PPARγ
Sunday, March 4, 2018: 4:30 PM
South Hall A2 (Convention Center)
Sophia R. Levan, Kei E. Fujimura, PhD, Din L. Lin, PhD, Kelsey A. Stamnes, Edward M. Zoratti, MD FAAAAI, Nicholas W. Lukacs, PhD, Dennis R. Ownby, MD FAAAAI, Homer A. Boushey, MD FAAAAI, Christine Cole Johnson, PhD MPH FAAAAI, Susan V Lynch, PhD

RATIONALE: 12,13 DiHOME is enriched in the stool of neonates with a perturbed gut microbiota, who are at high risk of developing multi-sensitized atopy at age 2. This linoleic acid-derivative is structurally similar to known ligands of peroxisome proliferator-activated receptor gamma (PPARγ), 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 PPARγ 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 PPARγ-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.