The Gut-Brain Axis – Part 5, Parkinson’s Diseaseby Sara Adaes, PhD | January 15, 2016
The view that Parkinson’s disease (PD) may be a neurodegenerative disorder of both the brain and the gut is on the rise. PD is primarily recognized for its motor symptoms. Slow movements (bradykinesia), rigidity, tremor and postural instability, collectively known as Parkinsonism, are the most obvious traits of the disease. But patients with PD also experience nonmotor symptoms, namely olfactory disturbances, sleep disorders, depression, and, importantly, constipation.
In fact, gastrointestinal (GI) impairments are very commonly observed in Parkinson’s disease, with around 30% of patients reporting such symptoms. These GI changes used to be regarded as nonmotor symptoms of advanced PD, but it is now known that the GI tract can be affected before motor signs are evident, despite becoming more prominent in advanced PD.
Constipation is a highly common complaint among PD patients. Studies have suggested that constipation may be an early clinical manifestation of PD as it can sometimes precede the onset of motor symptoms by over a decade. The prominence of GI symptoms and the rise in awareness of the role of the gut-brain axis in a number of pathologies has steered PD research towards the study of a possible contribution of the gut to the progression of the disease.
Recently, an increasing amount of evidence has been pointing to the possibility that PD may actually start in the gut. Besides the high prevalence of GI symptoms before and during PD development, other findings have supported this view. An important finding was that Lewy bodies – the deposits of alfa-synuclein observed in PD patients – can be found not only in the central nervous system (CNS), but also in the enteric nervous system (ENS) in the gut.
Studies focusing on Lewy body pathology have actually reported alpha-synuclein deposits in the ENS of nearly every patient with PD. Furthermore, a positive correlation between gut permeability and intestinal levels of alfa?synuclein has been observed in patients with early PD.
New evidence strongly suggests that the neuropathological changes in PD may follow a specific chronological and regional pattern. Several studies have shown that alpha-synuclein can be transported between neurons. Therefore, this supports the hypothesis that the neurodegenerative process in PD may start in the ENS and spread through cell-to-cell transmission via the vagus nerve to the substantia nigra and other areas of the CNS, before the manifestation of motor symptoms occurs.
These will only become apparent after loss of around 80% of dopaminergic neurons in the substantia nigra and dysfunction of the local dopaminergic pathway. Further neurodegeneration can then lead to dysfunction of higher cortical structures, which may manifest as cognitive decline.
The pathogenesis of PD could thus start years before the clinical onset of motor PD. The presence of nonmotor symptoms long before Parkinsonism is detectable supports this hypothesis. The possibility that PD pathogenesis may start in the GI system also agrees with the role that has been attributed to environmental factors in triggering and propagating PD pathology in the CNS. The ENS is exposed to ingested toxic substances from the environment, such as pesticides, herbicides and metals, which have all been linked to high levels of alpha-synuclein in the brain and to Parkinsonian symptoms.
In fact, a number of bacterial families have been shown to be significantly altered in PD patients. Significant associations have been found between the composition of the gut microbiota and the PD motor symptoms, with the magnitude of bacterial changes correlating with the severity of motor and postural difficulties. Recent data even suggests that the abundance of specific bacterial families, together with the severity of constipation, may be highly sensitive and specific diagnostic criteria for PD.
Nevertheless, whether changes in the gut microbiota are a risk factor or a consequence of PD is still in need of further clarification. No current therapeutic strategies directly target the gut–brain axis to prevent the initiation and progression of PD. But a better understanding of the exact mechanisms of PD onset will help develop new strategies and offer new paradigms for understanding and treating PD.
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