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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE288055 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Carotenoids are naturally occurring pigments in plants responsible for the orange, yellow, and red color of fruits and vegetables. Carrots are one of the primary dietary sources of carotenoids. The biological activities of carotenoids in higher organisms are well documented in most tissues but not the large intestine. The gastrointestinal barrier acts as a line of defense against the systemic invasion of pathogenic bacteria, especially at the colonic level. Proteins involved in tight junction assembly between epithelial cells and mucus secretion from goblet cells are essential for maintaining intestinal barrier homeostasis. A high-fat diet can cause gut impairment by inducing barrier permeability, leading to low-grade chronic inflammation via metabolic endotoxemia. Our hypothesis for this study is that the dietary intake of carotenoid-rich foods can alleviate obesity-associated gut inflammation and strengthen the intestinal barrier function. Male C57BL/6J mice were randomized to one of four experimental diets for 20 weeks (n = 20 animals/group): Low-fat diet (LFD, 10% calories from fat), high-fat diet (HFD, 45% calories from fat), HFD with white carrot powder (HFD + WC), or HFD with orange carrot powder (HFD + OC). Colon tissues were harvested to analyze the biochemical effects of carotenoids in carrots. The distal sections were subjected to isobaric labeling-based quantitative proteomics in which tryptic peptides were labeled with tandem mass tags, followed by fractionation and LC-MS/MS analysis in an Orbitrap Eclipse Tribrid instrument. High-performance liquid chromatography results depicted that the HFD+WC pellets were carotenoid-deficient, and the HFD+OC pellets contained high concentrations of provitamin A carotenoids, specifically α-carotene and β-carotene. As a result of the quantitative proteomics, a total of 4410 differentially expressed proteins were identified. Intestinal barrier-associated proteins were highly upregulated in the HFD+OC group, particularly mucin-2 (MUC-2). Upon closer investigation into mucosal activity, other proteins related to MUC-2 functionality and tight junction management were upregulated by the HFD+OC dietary intervention. Carotenoid-rich foods may prevent high-fat diet-induced intestinal barrier disruption by promoting colonic mucus synthesis and secretion in mammalian organisms.

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

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