Early Dysbiosis and Dampened Gut Microbe Oscillation Precede Motor Dysfunction and Neuropathology in Animal Models of Parkinson’s Disease

Article type: Research Article

Authors: Liang, Feng^a | Chen, Cheng-Yu^{a; b} | Li, Yun-Pu^a | Ke, Yi-Ci^c | Ho, En-Pong^c | Jeng, Chih-Fan^a | Lin, Chin-Hsien^{c; *} | Chen, Shih-Kuo^{a; d; *}

Affiliations: [a] Department of Life Science, National Taiwan University, Taipei, Taiwan | [b] Biodiversity Research Center, Academia Sinica, Taipei, Taiwan | [c] Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan | [d] Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan

Correspondence: [*] Correspondence to: Dr. Shih-Kuo Chen, Department of Life Science, National Taiwan University, Taipei 100, Taiwan. E-mail: [email protected]. and Dr. Chin-Hsien Lin, Department of Neurology, National Taiwan University Hospital, Taipei 100, Taiwan. E-mail: [email protected].

Abstract: Background:Studies have shown different gut microbiomes in patients with Parkinson’s disease (PD) compared to unaffected controls. However, when the gut microbiota shift toward dysbiosis in the PD process remains unclear. Objective:We aim to investigate the changes in gut microbiota, locomotor function, and neuropathology longitudinally in PD rodent models. Methods:Fecal microbiota were longitudinally assessed by sequencing the V4–V5 region of the 16S ribosomal RNA gene in a human mutant α-synuclein over-expressing mouse model of PD, SNCA p.A53T mice, and the non-transgenic littermate controls. The locomotor function, neuronal integrity, and α-synuclein expression in the different brain regions were compared between groups. Human fecal microbiota communities from 58 patients with PD and 46 unaffected controls were also analyzed using metagenomic sequencing for comparison. Results:Compared to non-transgenic littermate controls, the altered gut microbiota of the SNCA p.A53T mice can be detected as early as 2 months old, and the diurnal oscillation of the gut microbiome was dampened throughout PD progression starting from 4 months old. However, neuropathology changes and motor deficits were observed starting at 6 months old. Similar changes in altered gut microbiota were also observed in another PD genetic mouse model carrying the LRRK2 p.G2019S mutation at 2 months old. Among the commonly enriched gut microbiota in both PD genetic mouse models, the abundance of Parabateroides Merdae and Ruminococcus torques were also increased in human PD patients compared to controls. Conclusion:These findings revealed the altered gut microbiota communities and oscillations preceding the occurrence of neuropathy and motor dysfunction in the PD process.

Keywords: Parkinson’s disease, gut microbiota, dysbiosis, circadian, daily oscillation, SNCA

DOI: 10.3233/JPD-223431

Journal: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2423-2440, 2022