The Association Between the Gut Microbiota and Parkinson's Disease, a Meta-Analysis

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The Association Between the Gut Microbiota and Parkinson's Disease, a Meta-Analysis

Ting Shen^1,2*, Yumei Yue³, Tingting He^1,2, Cong Huang⁴, Boyi Qu², Wen Lv³ and Hsin-Yi Lai^1,2,3*

• ¹Department of Neurology of the Second Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
• ²Key Laboratory for Biomedical Engineering of Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, China
• ³Department of Neurology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
• ⁴Department of Sports and Exercise Science, Zhejiang University, Hangzhou, China

Patients with Parkinson's disease (PD) were often observed with gastrointestinal symptoms, which preceded the onset of motor symptoms. Neuropathology of PD has also been found in the enteric nervous system (ENS). Many studies have reported significant PD-related alterations of gut microbiota. This meta-analysis was performed to evaluate the differences of gut microbiota between patients with PD and healthy controls (HCs) across different geographical regions. We conducted a systematic online search for case-control studies detecting gut microbiota in patients with PD and HCs. Mean difference (MD) and 95% confidence interval (CI) were calculated to access alterations in the abundance of certain microbiota families in PD. Fifteen case-control studies were included in this meta-analysis study. Our results showed significant lower abundance levels of Prevotellaceae (MD = −0.37, 95% CI = −0.62 to −0.11), Faecalibacterium (MD = −0.41, 95% CI: −0.57 to −0.24), and Lachnospiraceae (MD = −0.34, 95% CI = −0.59 to −0.09) in patients with PD compared to HCs. Significant higher abundance level of Bifidobacteriaceae (MD = 0.38, 95%; CI = 0.12 to 0.63), Ruminococcaceae (MD = 0.58, 95% CI = 0.07 to 1.10), Verrucomicrobiaceae (MD = 0.45, 95% CI = 0.21 to 0.69), and Christensenellaceae (MD = 0.20, 95% CI = 0.07 to 0.34) was also found in patients with PD. Thus, shared alterations of certain gut microbiota were detected in patients with PD across different geographical regions. These PD-related gut microbiota dysbiosis might lead to the impairment of short-chain fatty acids (SCFAs) producing process, lipid metabolism, immunoregulatory function, and intestinal permeability, which contribute to the pathogenesis of PD.

Introduction

Parkinson's disease (PD) is a chronic, progressive, multisystem neurodegenerative movement disorder (Poewe et al., 2017). Patients with PD suffer from characteristic motor symptoms including resting tremor, bradykinesia, rigidity, and gait abnormalities, as well as non-motor symptoms such as hyposmia, sleep disorders, depression, and gastrointestinal (GI) symptoms (Kalia and Lang, 2015). Up to 80% of patients with PD are observed with constipation, the most common GI symptom in PD and are often preceded by the onset of motor symptoms by years (Su et al., 2017). Thus, the constipation symptom is regarded as a clinical biomarker for diagnosing prodromal PD (Berg et al., 2015). The main neuropathological characteristics of PD are loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies (LBs) or Lewy neurites, which consist of the abnormal α-synuclein aggregates (Abeliovich and Gitler, 2016). Braak staging traced the course of pathology, stating that PD started when a pathogen enters the body via the nose or the GI system (Braak et al., 2003), leading to the formation of LBs and spreading from the enteric nervous system (ENS) to the central nervous system (CNS) through the vagus nerve (Rietdijk et al., 2017). Therefore, the role of the “gut-brain axis” started drawing more attention in investigating the pathogenic mechanism of PD.

Higher susceptibility to PD was observed when intestinal infection existed (Huang et al., 2018; Brudek, 2019), which might trigger PD-like symptoms (Matheoud et al., 2019). PD-derived gut microbiota could enhance α-synuclein-mediated motor deficits and brain pathology in a mouse model, while germ-free mouse PD model showed milder α-synuclein pathology (Sampson et al., 2016). Thus, intestinal microbiota disturbance could be considered as a potential risk factor for PD. Gut microbiota is a complex system, producing all sorts of protective compounds and acting as a barrier against pathogens (Nair et al., 2018). Growing evidence has indicated that the abnormality of gut microbiota and its metabolic products may be triggers for the formation of LBs in the ENS. The Hepatitis C virus infection was thought to be dopaminergic toxic, which was similar to the effect of 1-methyl-4-phenylpyridinium (MPP+; Wu et al., 2015). The helicobacter pylori infection was observed to be associated with an increased risk of PD and worse PD motor severity (Shen et al., 2017). However, although fungal DNA and proteins were detected in post-mortem PD brains, there was no compelling evidence of gut microbiome contribution to PD pathophysiology (Cirstea et al., 2020), which still needs further investigation.

Recently, studies mainly focused on the bacterial component of microbiota in fecal samples. And PD-related alterations of abundance and equilibrium of gut microbiota were reported (Keshavarzian et al., 2015; Hill-Burns et al., 2017; Mertsalmi et al., 2017; Heintz-Buschart et al., 2018; Tetz et al., 2018; Aho et al., 2019; Barichella et al., 2019; Li C. et al., 2019; Li F. et al., 2019; Ren et al., 2020). Significant reduction of several gut microbiota's metabolic products were found in patients with PD, which may contribute to constipation in patients with PD (Unger et al., 2016). Functional differences in β-glucuronate and tryptophan degrading pathways were revealed in patients with PD compared to healthy controls (HCs) (Bedarf et al., 2017). Putative neuroprotective bioactive molecules such as short-chain fatty acids (SCFAs), ubiquinones, and salicylate, as well as neurodegeneration related compounds such as ceramides, sphingosine, and trimethylamine N-oxide, were altered in PD (Tan et al., 2020). Several gut microbiota were also found to be correlated with the clinical characteristics of PD, including disease duration, motor symptom severity, and non-motor symptoms (Qian et al., 2018). In addition, metabolome compositional differences such as the lower SCFAs were associated with poorer cognition, and lower butyrate levels were correlated with worse postural instability gait disorder scores in PD (Tan et al., 2020). A 2-year follow-up study indicated that the total counts of gut microbiota decreased during the course of PD progression and differed between deteriorating and stable PD groups, which may be used as a diagnostic tool for monitoring the progression of PD (Minato et al., 2017). An index was calculated based on 25 gene markers from the gut microbiota that were significantly changed in PD, and this potential diagnostic biomarker had the power to distinguish patients with PD from multiple system atrophy patients (Qian et al., 2020). Furthermore, alterations in the gut microbial activities could possibly lead to heterogeneous responses to levodopa observed among patients with PD, including decreased efficacy and harmful side effects (Maini Rekdal et al., 2019). Therefore, the pathogenesis and clinical manifestations of PD may be related to the dysfunction of the “gut microbiota-gut-brain axis.”

However, the gut microbiota structure varied across different geographical regions, which might lead to inconsistent results. Therefore, in order to verify the shared variations of certain gut microbiota, which presented relatively stable in patients with PD, we performed a meta-analysis to review the alterations of gut microbiota in patients with PD compared to HCs around the world and discussed its possible role in PD.

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