Omega-3 fatty acids protect from colitis via an Alox15-derived eicosanoid.

Area of Science:

• Lipid mediator synthesis
• Inflammation and immunology
• Gastroenterology

Background:

• Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert anti-inflammatory effects.
• Arachidonic acid lipoxygenases (ALOX) play roles in inflammatory bowel disease (IBD) pathogenesis.
• Fat1 transgenic mice exhibit elevated endogenous n-3 PUFA levels and protection from colitis.

Purpose of the Study:

• To investigate the role of Arachidonic acid 15-lipoxygenase (Alox15) in the n-3 PUFA-mediated protection against colitis.
• To elucidate the molecular mechanisms underlying the anti-inflammatory effects of n-3 PUFAs in a colitis model.

Main Methods:

• Fat1 transgenic mice were crossed with Alox15-deficient mice.
• Mice were challenged with dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulphonic acid (TNBS) to induce colitis.
• Analysis of Alox15 lipid metabolites, specifically 15-hydroxy eicosapentaenoic acid (15-HEPE).
• Administration of 15S-HEPE to wild-type mice to assess its protective effects.

Main Results:

• Fat1 transgenic mice were protected from DSS- and TNBS-induced colitis.
• Alox15 deficiency abrogated the protective effect of endogenous n-3 PUFAs in fat1 mice.
• Alox15 deficiency suppressed the formation of 15-HEPE.
• Exogenous administration of 15S-HEPE conferred protection against colitis in wild-type mice.

Conclusions:

• The anti-colitis effect observed in fat1 transgenic mice is partly mediated by Alox15-dependent production of 15-HEPE.
• Alox15 and its metabolite 15-HEPE are key players in the resolution of intestinal inflammation driven by n-3 PUFAs.