Podophyllotoxin-mediated neurotoxicity via the microbiota-gut-brain axis in SD rats based on the toxicological evidence chain (TEC) concept

被引:42
作者
Duan, Jiajia [1 ,2 ]
Sun, Jiaxing [1 ,2 ]
Jiang, Tao [1 ,2 ]
Ma, Xiao [1 ,2 ]
Li, Xuejiao [1 ,2 ]
Wang, Yuming [4 ]
Zhang, Fangfang [4 ]
Liu, Chuanxin [3 ]
机构
[1] Henan Univ Sci & Technol, Affiliated Hosp 1, Dept Clin Lab, Luoyang 471003, Peoples R China
[2] Henan Univ Sci & Technol, Coll Clin Med, Luoyang 471003, Peoples R China
[3] Henan Univ Sci & Technol, Affiliated Hosp 1, Endocrinol & Metab Ctr, Henan Key Lab Rare Dis, Luoyang 471003, Peoples R China
[4] Tianjin Univ Tradit Chinese Med, Sch Chinese Mat Med, Tianjin 301617, Peoples R China
关键词
Podophyllotoxin; Neurotoxicity; Gut microbiota; Metabolome; Microbiota-gut-brain axis; VASOACTIVE-INTESTINAL-PEPTIDE; INFLAMMATION; RESPONSES; TOXICITY; BEHAVIOR; FEATURES; STRESS; MICE; LPS;
D O I
10.1016/j.scitotenv.2023.168106
中图分类号
X [环境科学、安全科学];
学科分类号
08 ; 0830 ;
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 toxico-logical evidence chain concept. Our approach included behavioral testing in rats, evaluation of colon and hip-pocampal 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-alpha 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 Escher-ichia-Shigella leading to inflammatory factor production and alterations in kynurenine metabolism in the hip-pocampus, 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 thera-peutic interventions.
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页数:12
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