α-Methyltryptophan mitigates cognitive impairment in db/db mice: involvement of gut-brain metabolic remodeling.

BACKGROUND: Cognitive dysfunction in diabetes significantly impairs quality of life, yet effective therapies remain limited. Our previous work showed that α-methyltryptophan (α-MT), an inhibitor of the amino acid transporter SLC6A14 and indoleamine 2,3-dioxygenase 1 (IDO1), ameliorates diabetic nephropathy by modulating renal metabolism. Given its role in metabolic regulation, we hypothesized that α-MT may also protect against cognitive decline in diabetes by influencing gut-brain metabolic crosstalk. METHODS: Db/db mice were used as an in vivo model of type 2 diabetes, complemented by high-glucose-treated Caco-2 cells in vitro. Cognitive function was assessed using the Morris water maze. Gene expression related to synaptic plasticity (c-FOS, ARC, BDNF, EGR1) was measured by RT-qPCR. Colon morphology and SLC6A14 expression were evaluated by H&E, AB-PAS, immunohistochemistry, and Western blotting. ¹H NMR-based metabolomics was applied to profile metabolic changes in the colon and hippocampus. RESULTS: α-MT treatment significantly reduced hyperglycemia, restored intestinal barrier integrity, and improved cognitive performance in db/db mice. It also downregulated SLC6A14 overexpression under hyperglycemic conditions in both models. Metabolomic analysis revealed that α-MT induced significant metabolic reprogramming in the colon, with amino acid metabolism as the most affected pathway. Notably, metabolite alterations in the colon were positively correlated with those in the hippocampus, and both were negatively associated with increased expression of c-FOS, ARC, BDNF, and EGR1, suggesting coordinated gut-brain metabolic responses. CONCLUSIONS: These findings indicate that α-MT alleviates diabetes-associated cognitive impairment by promoting gut-brain metabolic remodeling. Targeting intestinal amino acid transport may represent a promising nutritional and therapeutic strategy for neuroprotection in diabetic encephalopathy (DE).