title: 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.
authors: Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors: Suguru
authors: S
authors: Fukumoto
authors: Food Science Research Labs, Division of Research and Development, Meiji Co. Ltd, Kanagawa, Japan.
authors: Takayuki
authors: T
authors: Toshimitsu
authors: Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors: Shuji
authors: S
authors: Matsuoka
authors: Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors: Atsushi
authors: A
authors: Maruyama
authors: Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors: Kyoko
authors: K
authors: Oh-Oka
authors: Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors: Takeyuki
authors: T
authors: Takamura
authors: Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors: Yuki
authors: Y
authors: Nakamura
authors: Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
authors: Kayoko
authors: K
authors: Ishimaru
authors: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors: Yoshiaki
authors: Y
authors: Fujii-Kuriyama
authors: Food Science Research Labs, Division of Research and Development, Meiji Co. Ltd, Kanagawa, Japan.
authors: Shuji
authors: S
authors: Ikegami
authors: Food Science Research Labs, Division of Research and Development, Meiji Co. Ltd, Kanagawa, Japan.
authors: Hiroyuki
authors: H
authors: Itou
authors: 1] Department of Immunology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan [2] Atopy Research Center, Juntendo University School of Medicine, Tokyo, Japan.
authors: Atsuhito
authors: A
authors: Nakao
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000382:microbiology* / Q000401:mortality; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D009284:Naphthols / Q000494:pharmacology; D019936:Probiotics / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D009284:Naphthols; D018336:Receptors, Aryl Hydrocarbon; C024023:1,4-dihydroxy-2-naphthoic acid; D016264:Dextran Sulfate