Microbiota-gut-brain signalling in Parkinson's disease: Implications for non-motor symptoms

Highlights

• Parkinsons disease patients suffer from imbalanced microbial colonisation of the gut.

• Some of the PD non motor symptoms are also associated with microbial imbalance.

• Gastrointestinal disturbances occur in PD and often precede motor symptoms.

• α-synuclein is present in the enteric nervous system prior to their appearance in the brain.

• Microbiota manipulation may relieve non motor symptoms and improve quality of life.

Abstract

Parkinson's disease is the second most common neurodegenerative disorder, affecting 1–2% of the population over 65 years of age. The primary neuropathology is the loss of midbrain dopaminergic neurons, resulting in characteristic motor deficits, upon which the clinical diagnosis is based. However, a number of significant non-motor symptoms (NMS) are also evident that appear to have a greater impact on the quality of life of these patients.

In recent years, it has become increasingly apparent that neurobiological processes can be modified by the bi-directional communication that occurs along the brain-gut axis. The microbiota plays a key role in this communication throughout different routes in both physiological and pathological conditions. Thus, there has been an increasing interest in investigating how microbiota changes within the gastrointestinal tract may be implicated in health and disease including PD.

Interestingly α-synuclein-aggregates, the cardinal neuropathological feature in PD, are present in both the submucosal and myenteric plexuses of the enteric nervous system, prior to their appearance in the brain, indicating a possible gut to brain route of “prion-like” spread. In this review we highlight the potential importance of gut to brain signalling in PD with particular focus on the role of the microbiota as major player in this communication.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 1–2% of people over 65 years [1], [2]. Even though the cardinal symptoms of PD include tremor, bradykinesia and rigidity [3], a number of non-motor symptoms (NMS) are also apparent, affecting the quality of life for PD patients more negatively than the motor symptoms [8]. These NMS include neuropsychiatric disorders (depression, anxiety, apathy, psychosis and dementia), problems arising from dysfunction of the ANS and ENS (constipation, orthostatic hypotension, urinary changes, thermoregulation), sleep disturbances and sensory alterations (pain, olfactory dysfunction) [9].

In recent years, it has become apparent that neurobiological processes can be modified by the bi-directional communications that occur along the brain-gut axis [14]. Brain-gut interactions or linkages could develop in a number of ways; including, firstly, through the impact of central input on gut functions (e.g. the stress response), secondly, through the impact of incoming activity from the gut on CNS function (e.g. cognitive and mood changes associated with gastro-intestinal disorders), or, thirdly through the parallel involvement of the brain and the gut by the same disease process (e.g. neuronal degeneration). While, traditionally, communications and interactions along the gut-brain axis have been viewed primarily as mediated by neuro-hormonal factors or inflammatory mediators, recent research has identified another gastrointestinal factor that could influence both gut and bran function: the gut microbiota. The gut microbiota is increasingly recognised as playing a central role, not just in gastrointestinal homeostasis but in regulating several essential physiological processes in the body. Of relevance to our topic, there is a growing acceptance that the gut can influence CNS function and vice versa giving rise to the communication pathway – the microbiota-gut-brain axis [15]. NMS symptoms in PD are evident before the classical motor symptoms and may be related to a dysfunction in the communication between gut and brain [16]. Here we extend that concept by reviewing the evidence that suggests that modulation of the microbiota-gut-brain axis through pharmabiotic intervention may represent a new therapeutic approach in the clinical management of some of the NMS in PD. (see Fig. 1).