Heat-Inactivated Bifidobacterium longum Z1 Improves Recognition Memory in Mice in Association with Enhanced Trk-CREB Signaling and Reduced Methylglyoxal Levels

Probiotics can modulate brain function via the microbiota–gut–brain axis; however, their cognitive effects in healthy hosts and the underlying pathways remain unclear. We previously reported that Bifidobacterium longum Z1 protects neuronal cells against methylglyoxal (MGO)-induced glycotoxicity. Here, we investigated whether oral heat-inactivated B. longum Z1 enhances memory in normal mice and examined associated molecular changes. Male C57BL/6 mice received heat-inactivated B. longum Z1 (5 or 20 mg/kg/day) or piracetam (400 mg/kg/day) for seven days before behavioral testing. High-dose B. longum Z1 (High-Z1) significantly increased the recognition index in the novel object recognition test. In exploratory brain analyses of mice selected by recognition index, High-Z1 increased the level of a nerve growth factor-immunoreactive band and the phosphorylation of tropomyosin receptor kinase B (TrkB) and cAMP response element-binding protein (CREB), whereas TrkA phosphorylation was not significantly changed. High-Z1 reduced MGO levels in the liver, brain, and serum, and in a separate exploratory cohort, a higher dose (100 mg/kg) upregulated hepatic glyoxalase-I and II and increased nuclear levels of nuclear factor erythroid 2-related factor-2 (Nrf-2). These molecular changes are associative and do not establish that neurotrophin-Trk-CREB signaling, the glyoxalase pathway, or MGO reduction mediates the behavioral effect. These findings support further investigation of this heat-inactivated B. longum Z1 preparation as a postbiotic for cognitive health.