The omega-3 postbiotic trans-10- cis-15-octadecadienoic acid attenuates contact hypersensitivity in mice through downregulation of vascular endothelial growth factor A

Front Cell Infect Microbiol. 2024 May 22:14:1355679. doi: 10.3389/fcimb.2024.1355679. eCollection 2024.

Abstract

Intestinal bacteria metabolize dietary substances to produce bioactive postbiotics, among which some are recognized for their role in promoting host health. We here explored the postbiotic potential of two omega-3 α-linolenic acid-derived metabolites: trans-10-cis-15-octadecadienoic acid (t10,c15-18:2) and cis-9-cis-15-octadecadienoic acid (c9,c15-18:2). Dietary intake of lipids rich in omega-3 α-linolenic acid elevated levels of t10,c15-18:2 and c9,c15-18:2 in the serum and feces of mice, an effect dependent on the presence of intestinal bacteria. Notably, t10,c15-18:2 mitigated skin inflammation in mice that became hypersensitive after exposure to 2,4-dinitrofluorobenzene, an experimental model for allergic contact dermatitis. In particular, t10,c15-18:2-but not c9,c15-18:2-attenuated ear swelling and edema, characteristic symptoms of contact hypersensitivity. The anti-inflammatory effects of t10,c15-18:2 were due to its ability to suppress the release of vascular endothelial growth factor A from keratinocytes, thereby mitigating the enhanced vascular permeability induced by hapten stimulation. Our study identified retinoid X receptor as a functional receptor that mediates the downregulation of skin inflammation upon treatment with t10,c15-18:2. Our results suggest that t10,c15-18:2 holds promise as an omega-3 fatty acid-derived postbiotic with potential therapeutic implications for alleviating the skin edema seen in allergic contact dermatitis-induced inflammation.

Keywords: contact hypersensitivity; intestinal bacteria; omega-3 fatty acid; postbiotics; vascular endothelial growth factor.

MeSH terms

  • Animals
  • Dermatitis, Allergic Contact / metabolism
  • Dermatitis, Contact / metabolism
  • Dinitrofluorobenzene
  • Disease Models, Animal*
  • Down-Regulation*
  • Fatty Acids, Omega-3* / metabolism
  • Fatty Acids, Omega-3* / pharmacology
  • Feces / chemistry
  • Feces / microbiology
  • Female
  • Gastrointestinal Microbiome / drug effects
  • Humans
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Mice
  • Skin / metabolism
  • Skin / pathology
  • Vascular Endothelial Growth Factor A* / metabolism

Substances

  • Vascular Endothelial Growth Factor A
  • Fatty Acids, Omega-3
  • Dinitrofluorobenzene
  • vascular endothelial growth factor A, mouse

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)/Japan Society for the Promotion of Science KAKENHI (grant numbers 21K20769 to AS; 19K07617 to TN; 22K15004 to KH; and 21H02757 to JK); the Japan Agency for Medical Research and Development (AMED; grant numbers 22ae0121035s012 to KH; and 22fk0108145h0003, 22ae0121042h0002 and 223fa727001h0001 to JK); the Ministry of Health and Welfare of Japan and Public/Private R&D Investment Strategic Expansion Program: PRISM (grant number 20AC5004 to JK); the Cross-ministerial Strategic Innovation Promotion Program (SIP) (grant number 18087292 to JK); the Grant for the Joint Research Project of the Institute of Medical Science, the University of Tokyo (to JK); the Ono Medical Research Foundation (to JK); and the Canon Foundation (to JK); Programs for Bridging the Gap between R&D and the Ideal Society (Society 5.0) and Generating Economic and Social Value (BRIDGE to JK).