神经毒性
促炎细胞因子
肠道菌群
肠-脑轴
生物
免疫学
医学
内科学
炎症
毒性
作者
Jiajia Duan,Jiaxing Sun,Tao Jiang,Xiao Ma,Xuejiao Li,Yuming Wang,Fangfang Zhang,Chuanxin Liu
标识
DOI:10.1016/j.scitotenv.2023.168106
摘要
Podophyllotoxin (PPT) is a naturally occurring aryltetralin lignan. However, its clinical application has been limited due to its neurotoxicity, the mechanism of which remains unclear. This study aimed to investigate the potential involvement of the microbiota-gut-brain (MGB) axis in PPT-induced neurotoxicity using the toxicological evidence chain concept. Our approach included behavioral testing in rats, evaluation of colon and hippocampal pathological changes, examination of proinflammatory factors, brain-gut peptides, and an in-depth analysis of gut microbiome and metabolic profiles. Our results demonstrated that PPT exposure compromised cognitive functions, induced damage to the colon and hippocampus, and increased intestinal permeability in rats. Furthermore, it elevated proinflammatory factors, particularly TNF-α and IL-6, while causing disruptions in the gut microbiota, favoring Escherichia-Shigella over Lactobacillus. Significant alterations in metabolic profiles in feces, serum, and hippocampus, particularly in tryptophan metabolism with a correlation to inflammatory factors and Escherichia-Shigella, were also observed. Our findings suggest that PPT promotes the enrichment of Escherichia-Shigella leading to inflammatory factor production and alterations in kynurenine metabolism in the hippocampus, potentially contributing to neurotoxicity. The study provides novel insights into the mechanistic pathways of PPT-induced neurotoxicity, emphasizing the role of the MGB axis and offering avenues for therapeutic interventions.
科研通智能强力驱动
Strongly Powered by AbleSci AI