Elucidation of Essential Fatty Acid Metabolite Functions in the Immune System and the Involvement of Gut Microbiota

Abstract

The immune system exhibits individual variations which are involved in the development of allergic inflammatory diseases and infectious diseases. Accumulating evidence suggests that the immune system is not only regulated by the genetic background, but also by gut environmental factors, including dietary nutrition and intestinal microbes. This article reviews our new findings that essential fatty acid metabolites regulate the immune system. α-Linolenic acid and linoleic acid are representative essential fatty acids in dietary oils, and they are classified as ω3 and ω6 fatty acids, respectively. In mice, we found that a diet containing linseed oil, which is high in α-linolenic acid, led to the suppression of the development of food allergy when compared with mice fed a conventional diet containing soybean oil. Lipidomic analysis revealed that the amount of 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) was markedly increased in the gut of mice fed with linseed oil. We also found that 17,18-EpETE exerts anti-allergic activity in food allergy. We then extended our analysis by investigating the role of 17,18-EpETE in skin inflammation, and found that 17,18-EpETE was effective at ameliorating contact hypersensitivity in mice and cynomolgus macaques. Mechanistically, 17,18-EpETE inhibited neutrophil infiltration of the skin by suppressing chemoattractant-induced Rac activation and pseudopod formation in a GPR40-dependent manner. Moreover, we established a bacterial production system by introducing bacterial CYP BM3 to E. coli for stereospecific production of 17(S),18(R)-EpETE which exerts a potent anti-inflammatory activity. Regarding the metabolites of ω6 fatty acid, we found that a high affinity receptor for leukotriene B4 (BLT1) was expressed on IgA+ B cells and plasma cells in the gut. We further found that a BLT1-mediated pathway played an essential role in oral vaccines by enhancing the production of antigen-specific secretory IgA in the feces through the promotion of plasma cell proliferation. Indeed, we found that the BLT1-mediated pathway elevated the gene expression level of MyD88 which transmits innate immune signals from commensal bacteria for plasma cell proliferation. These findings suggest that nutrition and intestinal microbes in vaccine recipients are key factors for the success of oral vaccines. This evidence will lead to the development of personalized/stratified medicine and nutrition, tailored to individual dietary habits, metabolism and intestinal microbiota.