A Gut Microbial Metabolite of Linoleic Acid, 10-Hydroxy-cis-12-octadecenoic Acid, Ameliorates Intestinal Epithelial Barrier Impairment Partially via GPR40-MEK-ERK Pathway
Open accessAbstract
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. Background: The physiological activity of gut microbial metabolites has recently attracted much attention. Results: A gut microbial metabolite of linoleic acid, 10-hydroxy- cis -12-octadecenoic acid (HYA), ameliorates intestinal epithelial barrier impairments by regulating TNFR2 expression via the GPR40-MEK-ERK pathway. Conclusion: HYA-induced GPR40 signaling contributes to the intestinal homeostasis. Significance: Our findings indicate a novel function of GPR40 in the inflamed intestine.
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10-hydroxy-cis-12-octadecenoic acid enhances intestinal barrier function and suppresses the development of colitis in mice in a free fatty acids 1 (FFR1/GPR40)-dependent manner.
“10-hydroxy-cis-12-octadecenoic acid (HYA) enhances intestinal barrier function and suppresses the development of colitis in mice in a free fatty acids 1 (FFR1/GPR40)-dependent manner [27].”
From Dietary lipids, gut microbiota and lipid metabolism (2019) · cites this paper as [27]
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- Authors
- Miyamoto, J., Mizukure, T., Park, S.-B., Kishino, S., Kimura, I., Hirano, K., Bergamo, P., Rossi, M., Suzuki, T., Arita, M., Ogawa, J., & Tanabe, S.
- Affiliations
- Hiroshima University (JP)
- Kyoto University (JP)
- Institute of Food Science (IT)
- RIKEN Center for Integrative Medical Sciences (JP)
- Corresponding author
- Ogawa, Jun
- Tanabe, Soichi
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 290
- Issue
- 5
- Pages
- 2902-2918
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4317025
- OpenAlex
- W2055291719
- Cited by
- 272
- References
- 6
- Citations by year
- 2026: 21 · 2025: 34 · 2024: 27 · 2023: 18 · 2022: 37 · 2021: 26 · 2020: 20 · 2019: 31 · 2018: 16 · 2017: 17 · 2016: 17 · 2015: 6 · 2012: 1
- FWCI
- 5.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (22380076, 25292074, 14J06559)
- Bio-oriented Technology Research Advancement Institution
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- gut microbiota metabolites, linoleic acid, intestinal epithelial barrier, tight junctions, TNF receptor 2, GPR40, MEK/ERK signaling, DSS-induced colitis, inflammatory bowel disease
- MeSH terms
- Animals, Colitis, Epithelial Cells, Female, Flow Cytometry, Humans, Immunohistochemistry, Intestines, Mice, Inbred BALB C, Oleic Acids, Caco-2 Cells, Linoleic Acid, MAP Kinase Signaling System, Receptors, G-Protein-Coupled, Mice
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