Tryptophan-Rich Diet Improves High-Fat Diet-Induced Cognitive Dysfunction and Blood–Brain Barrier Disruption in C57BL/6 Mice 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 role in mitigating HFD-induced cognitive dysfunction remains insufficiently explored. We hypothesized that enhancing Trp availability (0.1 or 0.5%) could protect the brain from HFD-induced impairments by preserving blood-brain barrier (BBB) integrity and neuronal function. HFD-fed mice exhibited deficits in Morris water maze, fear conditioning, and novel object recognition tests, accompanied by decreased tight junction proteins claudin-1 and occludin. Trp supplementation restored these indices to levels comparable to normal diet mice. Indole-3-propionic acid (IPA), a Trp metabolite, was identified as a mediator underlying these protective effects. IPA administration replicated cognitive improvements and BBB preservation. Transcriptomic analyses revealed both IPA and Trp converge on pathways regulating neuronal health and BBB function, including PPAR signaling, extracellular matrix organization, and adherens junction regulation. Mechanistically, IPA activated free fatty acid receptor 3 (FFAR3) in brain endothelial cells, reducing paracellular permeability and restoring tight junction protein expression. These results highlight a Trp-rich diet as a therapeutic strategy to mitigate HFD-induced cognitive decline through IPA-mediated FFAR3 activation.