Identification of a probiotic bacteria‐derived activator of the aryl hydrocarbon receptor that inhibits colitis

Abstract

The aryl hydrocarbon receptor (AhR) recognizes environmental xenobiotics and is originally thought to be involved in the metabolism (detoxification) of the substances. Recently, AhR is highlighted as an important regulator of inflammation. Notably, accumulating evidence suggests that activation of the AhR suppresses inflammatory bowel diseases (IBDs). Therefore, non-toxic AhR activators become attractive drug candidates for IBD. This study identified 1,4-dihydroxy-2-naphthoic acid (DHNA), a precursor of menaquinone (vitamin K2) abundantly produced by Propionibacterium freudenreichii ET-3 isolated from Swiss-type cheese, as an AhR activator. DHNA activated the AhR pathway in human intestinal epithelial cell line Caco2 cells and in the mouse intestine. Oral treatment of mice with DHNA induced anti-microbial proteins RegIIIβ and γ in the intestine, altered intestinal microbial flora and inhibited dextran sodium sulfate (DSS)-induced colitis, which recapitulated the phenotypes of AhR activation in the gut. As DHNA is commercially available in Japan as a prebiotic supplement without severe adverse effects, DHNA or its derivatives might become a promising drug candidate for IBD via AhR activation. The results also implicate that intestinal AhR might act not only as a sensor for xenobiotics in diet and water but also for commensal bacterial activity because DHNA is a precursor of vitamin K2 produced by vitamin K2-synthesizing commensal bacteria as well as propionic bacteria. Hence, DHNA might be a key bacterial metabolite in the host-microbe interaction to maintain intestinal microbial ecosystem.