Synergistic Enhancement: Whole Wheat Substrate Improves Memory in Mice by Optimizing Folate Metabolism and Systemic Antioxidant Capacity

ABSTRACT This study rigorously assessed the impact of folic acid‐fortified whole wheat products on mitigating mild liver injury caused by prolonged excessive folic acid consumption, improving folic acid bioavailability, and enhancing spatial cognitive functions in mice over a 48‐day intervention period. In the water maze evaluation of the medium‐dose folic acid‐fortified group (M‐B + FA), this group demonstrated the smallest escape latency (5.20 ± 1.49 s) and the longest length in the novel object recognition test (24.37 ± 17.21 s), signifying enhanced spatial memory and recognition capabilities. The whole wheat matrix markedly elevated folic acid concentrations in plasma (75.25 vs. 57.09 μg/mL) and cerebral tissue. The findings on serum antioxidant capacity indicated that folate‐fortified whole wheat products markedly elevated superoxide dismutase (SOD) levels and decreased malondialdehyde (MDA). The liver function indicators indicated that the Folic acid group (FA) reduced aspartate aminotransferase (AST) and aminotransferase (ALT) levels, with minor vacuolation noted in the liver, which was mitigated by the consumption of whole wheat products. Histological evaluation revealed that folate supplementation resulted in a heightened quantity of Nissl bodies in the CA3 area of the hippocampus. Furthermore, metabolomic analysis demonstrated that constituents in whole grains, via synergistic interactions, stimulated pathways associated with vitamin digestion and absorption, cofactor biosynthesis, and neuroactive ligand‐receptor interactions, consequently elevating the levels of neuroprotective metabolites such as tryptophan and bile acids. The whole grain diet actively enhances cognitive performance through synergistic interaction with folic acid by boosting its absorption, elevating systemic antioxidant levels and metabolic health, and regulating essential metabolic pathways associated with cognition.