肠道菌群在帕金森病(PD)的发病机制中起重要作用。然而,关于特定微生物物种的相互矛盾的发现已经被报道,可能是由于人群中的混杂因素。在这里,我们目前的研究使用多组学方法和自我控制设计,调查了1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的非人灵长类动物(NHP)PD模型中肠道微生物群与宿主之间的相互作用.我们对外周血白细胞(PBL)的转录组测序确定了参与促炎细胞因子失调的关键基因,线粒体功能调节,神经保护激活,和与PD相关的神经发生,如IL1B,ATP1A3和SLC5A3。血清和粪便中的代谢组学谱始终表现出显著的变化,特别是那些与炎症密切相关的,PD中的线粒体功能障碍和神经变性,例如TUDCA,乙基丙二酸,和L-高苯丙氨酸。此外,粪便宏基因组分析显示与PD相关的肠道菌群失调,以alpha多样性和共生区变化显著减少为特征,特别是链球菌等物种,Butyrivibrio,和梭菌。此外,PD相关微生物和代谢物之间存在显著相关性,如鞘磷脂和磷脂。重要的是,PD猴粪便和血清中的PDPC显着降低,与PD相关基因和微生物表现出很强的相关性,如SLC5A3和Butyrivibrio物种。此外,此类多组差异生物标志物与PD猴的临床评定量表相关.我们的发现提供了新的见解,以了解关键代谢物在PD发病机理中涉及的宿主-微生物群相互作用中的潜在作用。
The gut microbiota has been demonstrated to play a significant role in the pathogenesis of Parkinson\'s disease (PD). However, conflicting findings regarding specific microbial species have been reported, possibly due to confounding factors within human populations. Herein, our current study investigated the interaction between the gut microbiota and host in a non-human primate (NHP) PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a multi-omic approach and a self-controlled design. Our transcriptomic sequencing of peripheral blood leukocytes (PBL) identified key genes involved in pro-inflammatory cytokine dysregulation, mitochondrial function regulation, neuroprotection activation, and neurogenesis associated with PD, such as IL1B, ATP1A3, and SLC5A3. The metabolomic profiles in serum and feces consistently exhibited significant alterations, particularly those closely associated with inflammation, mitochondrial dysfunctions and neurodegeneration in PD, such as TUDCA, ethylmalonic acid, and L-homophenylalanine. Furthermore, fecal metagenome analysis revealed gut dysbiosis associated with PD, characterized by a significant decrease in alpha diversity and altered commensals, particularly species such as Streptococcus, Butyrivibrio, and Clostridium. Additionally, significant correlations were observed between PD-associated microbes and metabolites, such as sphingomyelin and phospholipids. Importantly, PDPC significantly reduced in both PD monkey feces and serum, exhibiting strong correlation with PD-associated genes and microbes, such as SLC5A3 and Butyrivibrio species. Moreover, such multi-omic differential biomarkers were linked to the clinical rating scales of PD monkeys. Our findings provided novel insights into understanding the potential role of key metabolites in the host-microbiota interaction involved in PD pathogenesis.