key: cord-0801466-8nibgv06 authors: Follmer, Cristian title: Gut Microbiome Imbalance and Neuroinflammation: Impact of COVID ‐19 on Parkinson's Disease date: 2020-08-21 journal: Mov Disord DOI: 10.1002/mds.28231 sha: 5c8260c68d66c06829d2eb0e0d307e730dfc21bc doc_id: 801466 cord_uid: 8nibgv06 nan obvious from a neurologic perspective is the impact of the gastrointestinal (GI) abnormalities caused by SARS-CoV-2 infection-notably an imbalance of the gut microbiome (dysbiosis) and intestinal inflammation-on gut-brain axis homeostasis and central nervous system (CNS) disorders. Dysbiosis, impaired intestinal barrier integrity and colon inflammation are important factors that have been associated with the pathogenesis of Parkinson's disease (PD) and other neurological disorders. Indeed, several evidences support the hypothesis that PD first begins in the gut and then spreads to the CNS, which is corroborated by GI manifestations commonly preceding the onset of movement-related symptoms. In this context, an important question arising is whether COVID-19 might represent a risk factor for PD. Some patients with COVID-19 exhibit significantly lower microbial diversity, with increased abundance of opportunistic pathogens and a decreased population of protective bacteria, 1 which could explain the occurrence of diarrhea and colon inflammation. The entry receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE-2), is highly expressed in small intestinal enterocytes, in which it plays a crucial role in the composition of the gut microbiome. 2 ACE-2 is responsible for the renin-angiotensin system (RAS) balance, and its dysfunction has been associated with PD pathogenesis. For instance, hyperactivation of RAS was reported to exacerbate microglia-mediated inflammation and oxidative stress, which may contribute to degeneration of dopamine neurons in PD. 3 In a scenario of hyperinflammation ("cytokine storm"), as reported in critically ill COVID-19 patients, increased proinflammatory cytokines and gut dysbiosis may compromise intestinal barrier integrity, causing elevation of circulating lipopolysaccharides (LPS), which eventually might trigger microglial activation and neuroinflammation (Fig. 1) . The loss of dopaminergic neurons in the substantia nigra pars compacta and the intraneuronal accumulation of aggregates of the protein α-synuclein (aSyn), called Lewy bodies, are the main histopathological hallmarks of PD. In this respect, LPS can stimulate the formation of deposits of aSyn in enteric nerves, 4 and, importantly, aSyn pathology in colon tissue of PD patients seems to occur prior to the onset of motor symptoms. 5 Interestingly, treatment with a specific gut bacterium that is markedly increased in PD mouse models was sufficient to provoke selective death of dopamine neurons and motor deficits in mice, accompanied by neuroinflammation and accumulation of aggregates of aSyn in both colon and brain. 6 Additionally, aSyn seems to play an important role in immune cell activation in the GI system (likely via a chemoattractant activity and stimulation of dendritic cell maturation), in which the expression of the protein can be induced following viral infection, 7 potentially contributing to the formation of aSyn aggregates in enteric nervous system. Although COVID-19 infection has not been linked so far to any specific long-term neurological disorder, the data outlined-above argue in favor of further investigations of the impact of SARS-CoV-2 infection on the incidence of PD and other neurological disorders. Alterations of the Gut Microbiota in Patients with COVID-19 or H1N1 Influenza ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation Dopamine-angiotensin interactions in the basal ganglia and their relevance for Parkinson's disease Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease Is alpha-synuclein in the colon a biomarker for premotor Parkinson's disease? Evidence from 3 cases Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice A role for neuronal alphasynuclein in gastrointestinal immunity Acknowledgments: The author is grateful to the Carlos Chagas Foundation for Research Support of the State of Rio de Janeiro (FAPERJ) and the Brazilian National Council for Scientific and Technological Development (CNPq).