REVIEW Implications of the Gut Microbiome in Parkinson’s Disease Mohamed Elfil, MD, 1 * Serageldin Kamel, MD, 1 Mohamed Kandil, MD, 1 Brian B. Koo, MD, 1,2,3 and Sara M. Schaefer, MD, MHS-Med Ed 1 1 Department of Neurology, Yale University, New Haven, Connecticut, USA 2 Center for Neuroepidemiology and Clinical Neurologic Research, Yale, New Haven, Connecticut, USA 3 Department of Neurology, Connecticut Veterans Affairs Healthcare System, West Haven, Connecticut, USA ABSTRACT: Parkinson’s disease is a common neuro- degenerative disorder that presents with nonmotor and motor symptoms. The nonmotor manifestations of Parkinson’s disease often begin years before the motor symptoms. Autopsy studies, including both Parkinson’s disease patients and matched controls, demonstrated that α-synuclein aggregates in Parkinson’s disease patients can be found in both the substantia nigra and the enteric nervous system. Therefore, it has been hypothesized that the pathological process that leads eventually to Parkinson’s disease might initially take place in the enteric nervous system years before the appearance of motor features. The gut microbiome plays essential roles in the development and maintenance of different body systems. Dysbiosis of the normal gut microbiome is thought to be associated with pathophysiologic changes not only in the gastrointestinal system itself but also in the enteric and central nervous systems. These changes are thought to ultimately cause loss of dopaminergic neurons via various mechanisms including the release of neurotoxins into the systemic cir- culation, decreased production of neuroprotective fac- tors, and triggering inflammatory and autoimmune responses. In this review, we review the gut microbiome changes in Parkinson’s disease and discuss the mecha- nisms by which gut microbiome dysbiosis may be a con- tributing factor to the pathophysiology of Parkinson’s disease. © 2020 International Parkinson and Movement Disorder Society Key Words: GM; gut microbiome; neuroinflammation; Parkinson’s disease; PD; α-synuclein; α-synucleinopathy The adult human gut contains more than 1 kilogram of bacteria, with 10 to 100 trillion microorganisms occupying the gut and exhibiting a large diversity in genomic and biochemical properties. 1 This human gut microbiome (GM) varies significantly even among healthy individuals, and the exact explanation of this variability is still unclear despite the possible implica- tion of dietary habits, environmental circumstances, and host genetics. 2 The GM plays an essential role in the digestive process, especially of human milk oligo- saccharides during infancy 3 and of dietary fibers. 4 It also has an important role in immune homeostasis. 5 The concept of the microbiome-gut-brain axis refers to a 2-way communication system in which the micro- biome in the gut can modulate brain functionality and activity via its metabolic products and ability to stimu- late the enteric nervous system (ENS) and by sending neuronal signals directly to the brain via the vagus nerve. 6,7 Thus, the vagus nerve plays a vital role in the neural pathway involved in the microbiome-gut-brain axis by influencing gut permeability and also mediating changes in central nervous system (CNS) signaling according to GM changes as suggested by both animal and clinical studies. 1,8,9 In turn, the brain can affect gut functions through the stress response, which is reflected in the association of psychiatric conditions known for stress, such as anxiety, with gastrointestinal disorders such as irritable bowel syndrome and inflammatory bowel disease (IBD). 10,11 Also, the CNS can alter gut motility, secretions, permeability, and immune response via its autonomic communication with the ENS, intestinal muscle layers, and mucosa. 12 The essential components of this communication system include interconnecting --------------------------------------------------------- *Correspondence to: Dr. Mohamed Elfil, 15 York Street, Clinic Building, New Haven, CT 06510; E-mail: mohamed.elfil@yale.edu, m_elfil13@alexmed.edu.eg Relevant conflicts of interests/financial disclosures: Nothing to report. Received: 13 September 2019; Revised: 6 January 2020; Accepted: 4 February 2020 Published online 00 Month 2020 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.28004 Movement Disorders, 2020 1