It remains unclear whether folic acid (FA) and docosahexaenoic acid (DHA) could improve cognitive performance by regulating microglia-mediated neuroimmune mechanisms. This study aimed to reveal the underlying mechanisms of FA and DHA supplementation in improving the cognitive performance. A randomized controlled trial was conducted in elderly patients with mild cognitive impairment (MCI) to examine the impact of FA (800 μg/day) and DHA (1.2 g/day) on cognitive functions and neuroimmune-related inflammatory cytokines, such as interleukin (IL)-18, IL-1β, IL-17, IL-21, IL-2, and IL-15. Besides, it was further explored whether FA and DHA may enhance cognitive performance by modifying neuroimmune and microglia in Alzheimer’s disease (AD) inflammation mice. Our results found that FA and/or DHA improved cognitive performance and decreased the level of inflammatory cytokines in MCI patients and AD inflammation mice. The combined intervention was more effective than the FA or DHA intervention alone. Meanwhile, FA and/or DHA inhibited the microglia activation and modulated the microglia phenotype, manifested as an increased level of the M2 phenotype and a decreased level of the M1 phenotype. Additionally, the combined intervention with FA and DHA reduced the concentration of C-C motif chemokine ligand 2, C-C motif chemokine receptor 2, and CD8⁺ T cells in brain, but increased the coverage of neurons. More importantly, after microglial depletion using PLX5622, the combined intervention with FA and DHA further improved cognitive performance and reduced the level of inflammatory cytokines. These findings provide compelling evidence that FA and DHA are expected to constitute a promising nutritional intervention strategy for preventing the development of AD by restoring neuroimmune homeostasis through microglial modulation.

It remains unclear whether probiotics could alleviate depression by regulating the tryptophan (Trp) metabolism and secretion of its metabolites via affecting indoleamine 2,3-dioxygenase (IDO-1). Therefore, this study was conducted to explore the underlying mechanism of Lacticaseibacillus paracasei LPB27 in resisting depression. The results demonstrated that LPB27 intervention improved the depressive-like behavior in rats with depression and reversed the altered microbiota and decreased inflammatory factors. LPB27 intervention down-regulated the expression of HMGB1, RAGE, and IDO-1, and regulated Trp metabolism in depression rats, manifested as elevated concentrations of 5-HT and 5-hydroxy-L-tryptophan (5-HTP) and decreased levels of L-kynurenine, kynurenate, picolinic acid, and cinnavalininate. Moreover, LPB27 also significantly increased the levels of dopamine (DA), norepinephrine (NE), glutamate (GLU), and gamma-aminobutyric acid (GABA). These results corroborated that LPB27 intervention could restore the disrupted homeostasis of certain gut microbiota, decrease the level of inflammation, HMGB1, RAGE and IDO-1, and regulate Trp metabolism, which collectively contributed to the improvement of depressive-like behavior.