Dietary EPA-Enriched Phospholipids Alleviate Chronic Stress and LPS-Induced Depression- and Anxiety-Like Behavior by Regulating Immunity and Neuroinflammation

Mol Nutr Food Res. 2021 Sep;65(17):e2100009. doi: 10.1002/mnfr.202100009. Epub 2021 Jul 22.


Scope: A growing number of studies have reported the effects of eicosapentaenoic acid (EPA) and terrestrial phospholipids on ameliorating mood disorders. Marine-derived EPA-enriched phospholipids (EPA-PL) exhibit the structural characteristics of EPA and phospholipids. However, the effect of dietary EPA-PL, and the differences between amphiphilic EPA-PL and lyophobic EPA on mood disorders had not been studied.

Methods and results: A comparative investigation to determine the effects of dietary EPA-enriched ethyl ester (EPA-EE) and EPA-PL on improving depression- and anxiety-like behavior in a mouse model is performed, induced by 4 week chronic unpredictable mild stress (CUMS) coupled with lipopolysaccharide (LPS) challenge. It is found that dietary 4 week 0.6% (w/w) EPA-PL rescued depression- and anxiety-like behavior to a greater extent than did EPA-EE. Moreover, dietary EPA-PL significantly reduced the immobility time by 56.6%, close to the normal level, in forced swimming test, which revealed a reversal of depression-like behavior. Further studies revealed that dietary EPA-PL regulated immunity, monoamine systems, and the hypothalamic-pituitary-adrenal (HPA) axis by multi-target interactions, including inhibition of neuroinflammation and apoptosis.

Conclusion: EPA-PL exerted superior effects to EPA-EE in alleviating depression- and anxiety-like behavior. The data suggest potential novel candidate or targeted dietary patterns to prevent and treat mood disorder.

Keywords: HPA axis; NLRP3; T cell subpopulations; apoptosis; glial activation; monoamine systems; mood disorder.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / chemically induced
  • Anxiety / diet therapy
  • Behavior, Animal / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Corticosterone / blood
  • Depression / chemically induced
  • Depression / diet therapy*
  • Disease Models, Animal
  • Eicosapentaenoic Acid / analogs & derivatives
  • Eicosapentaenoic Acid / chemistry
  • Eicosapentaenoic Acid / pharmacology*
  • Kynurenine / metabolism
  • Lipopolysaccharides / toxicity
  • Male
  • Mice, Inbred ICR
  • Neuroinflammatory Diseases / diet therapy*
  • Neuroinflammatory Diseases / immunology
  • Neuroinflammatory Diseases / physiopathology
  • Neurotransmitter Agents / metabolism
  • Phospholipids / chemistry
  • Phospholipids / pharmacology*
  • Spleen / drug effects
  • Spleen / pathology
  • Stress, Psychological / diet therapy*
  • Stress, Psychological / immunology


  • Lipopolysaccharides
  • Neurotransmitter Agents
  • Phospholipids
  • Kynurenine
  • eicosapentaenoic acid ethyl ester
  • Eicosapentaenoic Acid
  • Corticosterone