Intestinal microbe-dependent omega 3 lipid metabolite alpha KetoA prevents inflammatory diseases in mice and cynomolgus macaques

Dietary omega 3 fatty acids have important health benefits and exert their potent bioactivity through conversion to lipid mediators. Here, we demonstrate that microbiota play an essential role in the body's use of dietary lipids for the control of inflammatory diseases. We found that amounts of 10-hydroxy-cis-12-cis-15-octadecadienoic acid (alpha HYA) and 10-oxo-cis-12-cis-15-octadecadienoic acid (alpha KetoA) increased in the feces and serum of specific-pathogen-free, but not germ-free, mice when they were maintained on a linseed oil diet, which is high in alpha-linolenic acid. Intake of alpha KetoA, but not alpha HYA, exerted anti-inflammatory properties through a peroxisome proliferator-activated receptor (PPAR)gamma-dependent pathway and ameliorated hapten-induced contact hypersensitivity by inhibiting the development of inducible skin-associated lymphoid tissue through suppression of chemokine secretion from macrophages and inhibition of NF-kappa B activation in mice and cynomolgus macaques. Administering alpha KetoA also improved diabetic glucose intolerance by inhibiting adipose tissue inflammation and fibrosis through decreased macrophage infiltration in adipose tissues and altering macrophage M1/M2 polarization in mice fed a high-fat diet. These results collectively indicate that alpha KetoA is a novel postbiotic derived from alpha-linolenic acid, which controls macrophage-associated inflammatory diseases and may have potential for developing therapeutic drugs as well as probiotic food products.

Automated summary

Microbiota plays an essential role in utilizing dietary lipids for controlling inflammatory diseases. A novel postbiotic, alpha KetoA, derived from alpha-linolenic acid, exerts anti-inflammatory effects and improves glucose intolerance through immune modulation.