title: A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, ameliorates intestinal epithelial barrier impairment partially via GPR40-MEK-ERK pathway.
abstract: Gut microbial metabolites of polyunsaturated fatty acids have attracted much attention because of their various physiological properties. Dysfunction of tight junction (TJ) in the intestine contributes to the pathogenesis of many disorders such as inflammatory bowel disease. We evaluated the effects of five novel gut microbial metabolites on tumor necrosis factor (TNF)-α-induced barrier impairment in Caco-2 cells and dextran sulfate sodium-induced colitis in mice. 10-Hydroxy-cis-12-octadecenoic acid (HYA), a gut microbial metabolite of linoleic acid, suppressed TNF-α and dextran sulfate sodium-induced changes in the expression of TJ-related molecules, occludin, zonula occludens-1, and myosin light chain kinase. HYA also suppressed the expression of TNF receptor 2 (TNFR2) mRNA and protein expression in Caco-2 cells and colonic tissue. In addition, HYA suppressed the protein expression of TNFR2 in murine intestinal epithelial cells. Furthermore, HYA significantly up-regulated G protein-coupled receptor (GPR) 40 expression in Caco-2 cells. It also induced [Ca(2+)]i responses in HEK293 cells expressing human GPR40 with higher sensitivity than linoleic acid, its metabolic precursor. The barrier-recovering effects of HYA were abrogated by a GPR40 antagonist and MEK inhibitor in Caco-2 cells. Conversely, 10-hydroxyoctadacanoic acid, which is a gut microbial metabolite of oleic acid and lacks a carbon-carbon double bond at Δ12 position, did not show these TJ-restoring activities and down-regulated GPR40 expression. Therefore, HYA modulates TNFR2 expression, at least partially, via the GPR40-MEK-ERK pathway and may be useful in the treatment of TJ-related disorders such as inflammatory bowel disease.
authors.affiliation: From the Graduate School of Biosphere Science, Hiroshima University, 1-4-4 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8528, Japan.
authors.forename: Junki
authors.initials: J
authors.lastname: Miyamoto
authors.affiliation: From the Graduate School of Biosphere Science, Hiroshima University, 1-4-4 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8528, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Mizukure
authors.affiliation: the Graduate School of Agriculture, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Si-Bum
authors.initials: SB
authors.lastname: Park
authors.affiliation: the Graduate School of Agriculture, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Kishino
authors.affiliation: the Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachicho, Sakyo-ku, Kyoto 606-8501, Japan, the Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kimura
authors.affiliation: the Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachicho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Hirano
authors.affiliation: the Institute of Food Sciences, National Research Council, via Roma 64, Avellino 83100, Italy, and.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bergamo
authors.affiliation: the Institute of Food Sciences, National Research Council, via Roma 64, Avellino 83100, Italy, and.
authors.forename: Mauro
authors.initials: M
authors.lastname: Rossi
authors.affiliation: From the Graduate School of Biosphere Science, Hiroshima University, 1-4-4 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8528, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: the Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.affiliation: the Graduate School of Agriculture, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto 606-8502, Japan, ogawa@kais.kyoto-u.ac.jp.
authors.forename: Jun
authors.initials: J
authors.lastname: Ogawa
authors.affiliation: From the Graduate School of Biosphere Science, Hiroshima University, 1-4-4 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8528, Japan, stanabe@hiroshima-u.ac.jp.
authors.forename: Soichi
authors.initials: S
authors.lastname: Tanabe
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D003092:Colitis / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007422:Intestines / Q000166:cytology*; D019787:Linoleic Acid / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009829:Oleic Acids / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: C473034:FFAR1 protein, human; C473036:Ffar1 protein, mouse; D009829:Oleic Acids; D043562:Receptors, G-Protein-Coupled; C040430:10-hydroxy-12-octadecenoic acid; D019787:Linoleic Acid
keywords: Caco-2; Colitis; Epithelial Cell; G Protein-coupled Receptor; Linoleic Acid; Metabolite; Microbiome; Tight Junction; Tumor Necrosis Factor (TNF)