Microbiome–gut–brain dysfunction in prodromal and symptomatic Lewy body diseases

Abstract

Lewy body diseases, such as Parkinson’s disease and dementia with Lewy bodies, vary in their clinical phenotype but exhibit the same defining pathological feature, α-synuclein aggregation. Microbiome–gut–brain dysfunction may play a role in the initiation or progression of disease processes, though there are multiple potential mechanisms. We discuss the need to evaluate gastrointestinal mechanisms of pathogenesis across Lewy body diseases, as disease mechanisms likely span across diagnostic categories and a ‘body first’ clinical syndrome may better account for the heterogeneity of clinical presentations across the disorders. We discuss two primary hypotheses that suggest that either α-synuclein aggregation occurs in the gut and spreads in a prion-like fashion to the brain or systemic inflammatory processes driven by gastrointestinal dysfunction contribute to the pathophysiology of Lewy body diseases. Both of these hypotheses posit that dysbiosis and intestinal permeability are key mechanisms and potential treatment targets. Ultimately, this work can identify early interventions targeting initial disease pathogenic processes before the development of overt motor and cognitive symptoms.

Alpha Synuclein: Neurodegeneration and Inflammation

“…PD can be considered a multi-system disorder with neuroinflammation and immune dysfunction implicated in the development of various non-motor symptoms, such as sleep and gastrointestinal dysfunction, which can precede the disease diagnosis by decades [ 142 , 143 , 144 ]. Disturbances in the gut–brain axis have been found to be associated with PD; neuropathological changes in the enteric nervous system (ENS) and significant alterations of the gut microbiota suggest an important role of these systems [ 145 , 146 ]. Alpha-Syn appears to have a fundamental role in the deleterious crosstalk between neuronal and immune system dysfunction in the early stages of PD pathology involving proinflammatory factors and the gut microbiota.…”

Gut-brain pathogenesis of post-acute COVID-19 neurocognitive symptoms

“…Similar models along the gut-brain axis have been described previously (Vakili et al, 2022;Gareau and Barrett, 2023), and while our narrative for the initiation and maintenance of neurocognitive symptomology reflects these existing models, we also elaborate on the specific metrics that can be quantified experimentally to assess each component of the model. The described mechanism of gut-brain pathology has been described extensively in other disorders, such as depression (Valles-Colomer et al, 2019), anxiety (Kim and Shin, 2018), neurodegenerative conditions (Ryman et al, 2023), and other chronic multi-symptom illnesses such as Gulf War illness (Alhasson al., 2017;Bajaj et al, 2019;Keating et al, 2019). Systemic inflammation due to increased permeability in the gut has been implicated in conditions such as irritable bowel syndrome (Camilleri et al, 2012;Fukui, 2016;Moser et al, 2018), and these pathways are highly relevant to COVID-19 due to its well-established cytokine storms that can result in fatal hyperinflammation (Cron et al, 2021).…”

Gut-Modulating Agents and Amyotrophic Lateral Sclerosis: Current Evidence and Future Perspectives

“…Factors contributing to overall gut health, such as intestinal inflammation and barrier permeability, can have profound effects on brain function and well-being [ 3 , 4 ]. Symptoms of GI upset or dysfunction (e.g., pain, dysphagia, reflux, and constipation) have also been noted in ALS, further suggesting a link between gut and brain pathology [ 5 , 6 , 7 ].…”