Lactobacilus johnsonii supplemented mice modulate RSV-induced disease and is associated with increased DHA metabolite that alters DC activation through PPAR- γ. (VIR9P.1148)

Abstract

Abstract The gut microbiome contributes to a variety of mammalian processes, including modulation of host immune responses. We have found that L. johnsonii-supplemented mice displayed altered gut microbiome profiles and reduced RSV-induced pulmonary immunopathology. Metabolomics analysis of plasma from L. johnsonii-supplemented mice identified docosahexaenoic acid (DHA) and 2-hydroxyisobutyrate (butyrate precursor) as increased metabolites. We hypothesized that DHA and butyrate played a role in the modulation of the immune response in lung. We found that bone marrow-derived dendritic cells (BMDC) treated with DHA or butyrate expressed and produced reduced levels of IL-12, IL-6, IL-1β, IFN-β and TNF-α when stimulated with LPS, CpG or RSV compared to untreated cells. DHA treatment of RSV-infected BMDC prior to their co-culture with T cells isolated from RSV-infected mice significantly reduced their production of Th2 cytokines and IFNΥ. Then, we determined whether DHA was activating the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) in BMDC, which has been described as an inflammatory response inhibitor. We observed that BMDC treated with DHA and PPAR- γ antagonist (GW9662), had altered expression of mRNA and production of cytokines compared to DHA treated cells. These results suggest that DHA is modulating the immune response through PPAR-γ in dendritic cells and may be one mechanism of attenuating RSV immunopathology in mice supplemented with L. johnsonii.