Abstract
Methylglyoxal (MGO), a reactive byproduct of microbial metabolism, contributes to neurodegeneration and may be further exacerbated by gut dysbiosis. Probiotic strategies that restore microbial balance and barrier integrity thus represent a promising therapeutic approach. In this study, we explored the neuroprotective potential of the probiotic strain Bifidobacterium longum Z1 (B. longum Z1) in MGO-challenged mouse neuronal cells (N2a). B. longum Z1 treatment effectively reduced apoptosis and reactive oxygen species (ROS) production, indicating its substantial neuroprotective activity. Mechanistically, B. longum Z1 treatment downregulated apoptotic signaling pathways involving mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Furthermore, B. longum Z1 enhanced cellular detoxification through activation of the glyoxalase system and bolstered antioxidant defenses via induction of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Metabolite analysis identified bioactive compounds within B. longum Z1, notably tryptophan, which exhibited a high affinity for MGO and modulated the expression of apoptosis-related proteins. Our findings indicate that B. longum Z1 and its microbial bioactive metabolites, including tryptophan, may serve as potential nutraceutical candidates for neuroprotection against glycotoxins such as MGO.