The ameliorative effects and underlying mechanisms of Lactobacillus plantarum on glyoxal-induced cytotoxicity

Glyoxal (GO) is known to induce oxidative stress, trigger inflammation, and cause cytotoxicity. Current inhibitors of GO toxicity often result in significant side effects, necessitating the exploration of new, safe inhibitors devoid of adverse effects. Lactic acid bacteria (LAB), recognized for their natural non-toxicity and dietary benefits, exhibit potential as inhibitors of GO toxicity. This study aimed to identify LAB capable of mitigating GOinduced cytotoxicity and to elucidate the underlying mechanisms. Lactobacillus plantarum YT3-3 treatment significantly reduced GO-induced cytotoxicity and enhanced cell viability. Compared to the GO-treated group, YT3-3 treatment markedly inhibited apoptosis in Caco-2 cells, reduced the production of reactive oxygen species (ROS) and oxidized glutathione (GSSG), and increased the activities of superoxide dismutase (SOD) and catalase (CAT). Additionally, transcriptomic and metabolomic analyses showed that the expression of three genes (FGA, FGB and AKR1C3) and five metabolites (uracil, cytosine, adenine, methylmalonic acid and cytidine-5 '-monophosphate) were significantly upregulated after YT3-3 treatment. Co-occurrence network analysis suggested that the cell apoptosis was significantly correlated with differential genes and metabolites, antioxidant indexes, and the NF-kappa B and Bcl-2 signaling pathways. Therefore, YT3-3 could enhance the metabolism of indolyl lactate, pyrimidine and nucleotide in the mixed system, increase the activity of antioxidant enzymes and mitigate the oxidative stress damage. Meanwhile, these metabolites inhibited the excessive activation of NF-kappa B and Bcl-2 signaling pathways induced by GO, moderated the cellular inflammatory and mitochondrial apoptosis, resulting in the enhancement of cellular viability and alleviation of GO-induced cellular toxicity. These findings provide a theoretical basis for the development of inhibitors against GO toxicity and offer new directions for the functional development of LAB.