中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2024, Vol. 19 ›› Issue (on line): 1-8.

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Gut microbiota dysbiosis contributes to the α-synuclein pathology, associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson’s disease

  

  • 出版日期:2024-01-01 发布日期:2023-11-04

Xiaoli Fang1, 2, #, Sha Liu2, #, Bilal Muhammad2, Mingxuan Zheng3, Xing Ge3, Yan Xu2, Shu Kan2, Yang Zhang4, Yinghua Yu3, #br# Kuiyang Zheng3, Deqin Geng2, *, Chun-Feng Liu1, 5, *#br#   

  1. 1Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China; 2Department of Neurology, Affiliated Hospital of XuZhou Medical University, Jiangsu, Jiangsu Province, China; 3Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu Province, China; 4Department of Neurology, Xuzhou Central Hospital, Xuzhou, Jiangsu Province, China; 5Jiangsu Key Laboratory of Neuropsychiatric Disease and Institute of Neuroscience, Soochow University, Suzhou, Jiangsu Province, China
  • Online:2024-01-01 Published:2023-11-04
  • Contact: Chun-Feng Liu, PhD, liuchunfeng@suda.edu.cn; Deqin Geng, PhD, gengdeqin@hotmail.com.
  • Supported by:
    This work was supported by Jiangsu Provincial Medical Key Discipline No. ZDXK202217 (to CFL), and Jiangsu Planned Projects For Postdoctoral Research Funds No. 1601056C (to SL).

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摘要： https://orcid.org/0000-0002-8364-0219 (Chun-Feng Liu); https://orcid.org/0000-0002-5308-7213 (Deqin Geng)

Abstract: Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction. Gastrointestinal dysfunction can precede the onset of motor symptoms by several years. Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease, but its causal role and mechanism in motor dysfunction remains fully unknown. CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling, activated by bacterial endotoxin, can promote the transcription of α-synuclein to contribute to Parkinson’s disease pathologies. In this study, we aimed to investigate the role of gut microbiota in C/EBPβ/AEP signaling, α-synuclein pathology and motor symptoms using a mouse model of Parkinson’s disease induced by rotenone, combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation. We found that rotenone administration resulted in the gut microbiota dysbiosis, perturbed intestinal barrier, as well as the activation of C/EBP/AEP pathway, α-synuclein aggregation and tyrosine hydroxylase-neuron loss in the substantia nigra in mice with motor deficits. However, rotenone did not have these adverse effects in gut microbiota-depleted mice with antibiotics pretreatment. Importantly, we found that rotenone-derived gut microbiota induced motor deficits, intestinal inflammation and endotoxemia. The transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits, intestinal inflammation, endotoxemia and intestinal barrier impairment. These results highlight the vital role of gut microbiota dysbiosis in motor deficits, C/EBPβ/AEP signaling activation and the α-synuclein pathology in Parkinson’s disease mouse model induced by rotenone. Additionally, supplementing with healthy microbiota may provide safe and effective treatments to ameliorate the progression of motor deficits in Parkinson’s disease.

Key words: C/EBP/AEP signaling pathway, endotoxemia, fecal microbiota transplantation, intestinal barrier, intestinal inflammation, microbiota-gut-brain axis, Parkinson’s disease