Gut Microbiota Across Early Stages of Synucleinopathy: From High-risk Relatives, REM Sleep Behavior Disorder to Early Parkinson's Disease

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With the global ageing population, neurodegenerative disorders including synucleinopathy are major burdens to patients, carers and society. Synucleinopathy refers to a group of neurodegenerative diseases characterized by abnormal aggregation of alpha-synuclein protein in the central nervous system (CNS). Common examples of synucleinopathy are Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Among all the premotor clinical markers that have been identified, a sleep disorder known as REM sleep behavior disorder (RBD) is associated with the highest likelihood ratio of developing PD. In addition, it has been shown that almost all RBD patients (over 80%) eventually developed neurodegenerative diseases after 14 years follow-up. Gut microbiota and synucleinopathy In recent years, several key studies have advanced our understanding regarding the roles that brain-gut-microbiota axis plays in the pathogenesis of brain diseases, including PD. It has been shown that gut microbiota is implicated in a series of pathophysiological changes in PD, including motor deficits, microglia activation, and αSyn pathology in mice model with overexpression of αSyn. Furthermore, some microbiotas, such as enterobacteriaceae, have been shown to be positively associated with the severity of PD symptoms, including postural instability and gait difficulty. Limitations in previous studies and knowledge gaps Nonetheless, the answers for several key questions regarding the roles of gut microbiota in the progression of synucleinopathy are still unclear. First, whether these microbiotas found in previous studies are the causes or the effects of PD. For example, medications treating PD may also affect the gut microbiome. Moreover, the microbiota may be affected by a number of factors commonly found in PD, such as constipation per se and diet. In this regard, an influential hypothesis of synucleinopahy was proposed by Braak et al at which the early premotor features including gastro-enterology symptoms, such as constipation and RBD would predate the onset of PD by some years. Thus, it is crucial to compare the microbiota among individuals at different stages of synucleinopathy. In view of slow progression of synucleinopathy and a relatively low prevalence of synucleinopathy in the general population, it is impractical to run a prospective study to examine this research question. Finally, gut microbiota is determined by both genetic and environmental factors. A family cohort design will help to understand the genetic and environmental influences on the association between microbiota and synucleinopathy.

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