Differential interactions of dietary EPA and DHA with the gut microbiota dictate distinct metabolic outcomes in the host

Background: Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are known to modulate host physiology, but their differential interactions with the gut microbiota and consequent host metabolic effects remain poorly understood.
Methods: We employed shotgun metagenomics, untargeted metabolomics, and lipidomics to assess microbial composition and host metabolism. Antibiotic-treated (Abx) mice were used to validate microbiota-dependent effects. Altered gut microbial community structures induced by specific antibiotics and subsequent correlation analyses were applied to identify key bacteria involved. Behavioral tests and molecular assays were conducted in a depression model to evaluate neuroimmune mechanisms.
Results: DHA and EPA induced divergent structural shifts in the gut microbiota. Specifically, DHA supplementation significantly enriched Bifidobacterium pseudolongum, whereas both fatty acids modulated lipid metabolism in a manner dependent on the gut microbiota. Importantly, varying microbial community structures were shown to influence DHA metabolism. Metronidazole-induced microbial remodeling markedly elevated serum levels of 14-HDHA, which exhibited a strong positive correlation with the abundance of Akkermansia muciniphila and B. pseudolongum. Subsequent validation confirmed that A. muciniphila facilitates the bioconversion of DHA into 14-HDHA. Furthermore, 14-HDHA ameliorated depressive-like behaviors through regulation of inflammatory cytokines (IL-6, TNF-α, IL-10), suppression of NF-κB activation, and enhancement of hippocampal neurogenesis. Collectively, these results indicate that both DHA and A. muciniphila can alleviate depression via 14-HDHA.
Conclusion: Our findings demonstrate that DHA and EPA differentially reshape the gut microbiota, which in turn directs distinct metabolic outcomes. Specifically, DHA promotes A. muciniphila-dependent production of 14-HDHA, which confers resilience to depression through immunomodulatory and neurogenic mechanisms.