by Richard Day Medical Director / ADM Protexin
Today, a simple PubMed search for “gut-brain axis” will return over 1,800 different peer-reviewed scientific papers. The gut-brain axis – this is the bi-directional communication system that links these two organs, via a number of neuronal, hormonal and immune pathways – is particularly interesting as it holds the prospect for potential dietary and therapeutic interventions for many of the world’s most disabling diagnoses and for overall mental health. While in previous years much of the work on gut-brain communication concentrated on digestive function and satiety(1), recent research has taken a look at cognitive, psychological and neurological effects of gut-to-brain / brain-to-gut communication.(2, 3) Growing evidence shows the pivotal role of the microbiota in the gut-brain axis – demonstrating the role microbiome in influencing brain function across a range of pathologies. An increasing array of psychiatric diagnoses are being linked to the gut microbiome, including depression, anxiety, autism and bi-polar affective disorder.(4) Interestingly a number of neurological diagnoses are also being linked to the gut microbiome, including Alzheimer’s disease, epilepsy and – the focus of this article – Parkinson’s disease.(5, 6, 7)
Parkinson’s disease is a neurodegenerative disorder, characterised by a clinical triad of tremor, rigidity, and bradykinesia. It is also commonly associated with other symptoms such as gait abnormalities and postural instability. The pathophysiology of Parkinson’s disease includes aggregation of the protein α-synuclein and the progressive loss of dopamine producing neurones in a region of the basal ganglia called the substantia nigra.(8) There are approximately 10 million people worldwide living with Parkinson’s disease and the impact of this diagnosis can be enormous for individuals and their families. Currently, the mainstay of treatment for Parkinson’s disease is symptom management. Most pharmaceutical treatments seek to increase the availability of dopamine in order to reduce the severity of symptoms. Interestingly, current Parkinson’s treatments do not seek to address the underlying pathology – α-synuclein aggregation and Lewy body formation.
The Braak hypothesis for the development of Parkinson’s disease has gained attention in recent years. It proposes that an unknown stimulus (a virus or bacteria) in the gut and the nasal cavity is responsible for the initiation of the disease cascade that ultimately leads to Parkinson’s disease.(9) It is proposed that α-synuclein spreads from the enteric nervous system to the central nervous system, via the vagus nerve (which anatomically links the two).
Interestingly, GI microbiome analysis shows that healthy control subjects have different GI microbiomes compared to patients with Parkinson’s – with a higher relative abundance of Prevotellaceae bacteria noted. Of particular interest is the finding that between Parkinson’s patients, a higher relative abundance of Enterobacteriaceae is associated with more postural and gait symptoms and less tremor: put simply, different clinical symptoms correlate with different patterns of the GI microbiome.(10) These and other observations document an association, not a causality. Such observations can be theoretically explained by the cumulation of multiple factors (e.g. diet, metabolic, gut motility, and so on.) and do not indicate whether the microbiota is the cause of the Parkinson’s or if Parkinson’s is the cause of the microbiota dysbiosis.
There is criticism of the Braak hypothesis, namely that the current evidence does not fit for all Parkinson’s patients or all subtypes of the disorder. But perhaps the exact disease aetiology is not needed in the search for treatments? A number of research teams around the world have begun to look at how the GI microbiome might impact Parkinson’s disease. One such team – El Aidy et al. at the University of Groningen – demonstrated that certain microbes in the jejunum (the proximal small intestine) produce an enzyme called tyrosine decarboxylase (TDC) that converts the Parkinson’s drug levodopa into dopamine.(6) People with Parkinson’s disease will often be prescribed levodopa with the aim of increasing dopamine levels in the brain; the inappropriate conversion of levodopa into dopamine in the small intestine reduces the bioavailability of the drug, reducing the amount that reaches the brain – and makes the treatment significantly less effective. In fact, the authors suggest that levodopa conversion by bacterial TDC in the small intestine should be considered as a significant explanatory factor for the increased levodopa/carbidopa dosage regimen required in a subset of Parkinson’s patients. These TDC producing bacteria may potentially serve as a predictive biomarker to stratify PD patients for efficacy of conventional pharmacological treatment.
Another fascinating aspect of the interaction between the GI microbiome and Parkinson’s involves the protein α-synuclein. In a ground-breaking piece of research at the University of Edinburgh, researchers have shown that certain probiotic strains of the Bacillus subtilis species can prevent the accumulation of new α-synuclein in an established model of Parkinson’s pathophysiology, using the nematode Caenorhabditis elegans.(11) Perhaps even more interesting is that the B. subtilis reduced established aggregates of α-synuclein. While research in C. elegans is still some years away from positive results in human clinical trials, it certainly paves the way for future research and the team at Edinburgh University are now planning further pre-clinical and clinical research to understand how and if this strain of B. subtilis might be used for Parkinson’s disease in humans.
Overall, research in the gut-brain axis – and in the microbiota-gut-brain axis – is still in its relative infancy and relies heavily on preclinical evidence. But given the breadth and depth of research currently ongoing in this field, the pace of progress has been rapid. Currently there are multiple lines of evidence linking the microbiome and the gut-brain axis to Parkinson’s disease and – excitingly – this is translating into research that has the potential to have a hugely positive impact for people diagnosed with Parkinson’s disease: either through increasing the effectiveness of current pharmaceutical therapies, or by modifying the underlying disease process and reducing the accumulation of α-synuclein. This constantly evolving field also holds promise for addressing broader mental health issues for the general population such as reduction of stress and anxiety.
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11. Goya ME, Xue F, Sampedro-Torres-Quevedo C, Arnaouteli S, Riquelme-Dominguez L, Romanowski A, et al. Probiotic Bacillus subtilis Protects against α-Synuclein Aggregation in C. elegans. Cell Rep. 2020 Jan;30(2):367-380.e7.