Tryptophan-rich diet improves high-fat diet-induced cognitive dysfunction and blood-brain barrier disruption through FFAR3 activation

Increasing evidence indicates that high-fat diets (HFDs) are strongly associated with cognitive deficits. Tryptophan (Trp), an essential amino acid, has been implicated in regulating metabolic and neurological pathways, but its direct role in mitigating HFD-induced cognitive dysfunction has been insufficiently explored. We hypothesized that enhancing Trp availability could protect the brain from HFD-induced impairments by preserving blood-brain barrier (BBB) integrity and neuronal function. Mice fed HFD alone exhibited deficits in Morris Water Maze, Fear Conditioning, and Novel Object Recognition tests, accompanied by decreased expression of tight junction proteins claudin-1 and occludin. Trp supplementation restored these behavioral and molecular indices to levels comparable to the normal diet mice. Notably, we identified indole-3-propionic acid (IPA), a metabolite of Trp, as a key mediator underlying these protective effects. Administration of IPA replicated the cognitive improvements and BBB preservation seen with Trp supplementation. Transcriptomic analyses further revealed that both IPA and Trp supplementation converge on pathways regulating neuronal health and BBB function, including PPAR signaling, extracellular matrix organization, and adherens junction regulation. Mechanistically, IPA activates free fatty acid receptor 3 (FFAR3) in brain microvascular endothelial cells, thereby reducing paracellular permeability and restoring tight junction protein expression. Collectively, these results highlight the therapeutic promise of a Trp-rich diet in countering HFD-induced cognitive decline, with IPA-mediated FFAR3 activation as a pivotal mechanism underlying BBB preservation and neuronal protection. Our findings pave the way for novel, diet-based strategies to mitigate the growing burden of obesity-related neurocognitive disorders.