'Feeling the Guts': Controversies About the Role of the Gastrointestinal System in the Development of Parkinson’s Disease

Date: February 2018
Authors: Filip Scheperjans, MD, Glenda Halliday, MD, Álvaro Sánchez-Ferro, MD
Blog Editor: Stella Papa, MD
 

Gastrointestinal systemIn recent years, the importance of non-motor features in Parkinson’s disease (PD) has become increasingly recognized, and one of them that may have a pathophysiologic role is the gastrointestinal dysfunction. Different studies have documented the relevance of the enteric system in PD. Go to Discussion

 

Discussion

In recent years, the importance of non-motor features in Parkinson’s disease (PD) has become increasingly recognized, and one of them that may have a pathophysiologic role is the gastrointestinal dysfunction. Different studies have documented the relevance of the enteric system in PD. For example, alpha-synuclein, one of the most reliable markers of the disease, can be found in gastrointestinal biopsies of patients with PD. Further, recently described changes in the gut microbiota of people with PD are currently under study as an associated mechanism in the enteric pathology.  Other significant evidence for a role of the so-called gut-brain axis in PD comes from large epidemiological studies that linked abnormalities in the enteric nervous system and the brain of patients with PD through the vagus nerve connection to the gut. These findings led some investigators to put forward the hypothesis that PD might start in the gut. We have invited two experts in the field, Dr. Scheperjens and Dr. Halliday, to discuss the role of the gastrointestinal system in the origin of the disease.

Based on the available data, do you think that Parkinson’s disease could start in the gut?


Dr. Scheperjans

Gastrointestinal (GI) symptoms are very prevalent in PD patients. Even before motor symptoms appear, colonic dysfunction, and constipation, had been recognized as a risk-factor for PD. Clearly, biological mechanisms enable spread of a neuropathological process initiated in the GI-tract to the central nervous system (CNS). For example, in rodents GI alpha-synuclein pathology can be introduced by intragastric infusion of rotenone and spreads via the vagus nerve to the CNS.1 Similar results have been seen after injection of PD brain lysate into the intestinal wall.2 Moreover, epidemiologic studies found a protective effect of truncal vagotomy against PD, and thus findings suggest the contribution of the vagal nerve to PD pathogenesis in human subjects.3,4 Recently, a correlation of alpha-synuclein expression in the enteric nervous system (ENS) with acute and chronic intestinal inflammation was demonstrated in pediatric patients with persistence of alpha-synuclein in the tissue up to 6 months.5 These intriguing findings support a role of GI inflammation in the initiation and of the vagal nerve in the gut-to-brain spread of alpha-synuclein pathology and strongly warrant further studies in this direction.

However, one should not forget that also brain-to-gut directed mechanisms may be involved. Namely a primary central nigrostriatal lesion can cause alterations of the ENS and GI motility.6 Also alpha-synuclein can spread from the CNS to the periphery.7 Currently, clinical and epidemiological studies favor a primary involvement of the GI tract, and experimental data show that such gut-to-brain alpha-synuclein spreading is possible. However, GI disturbance is not found in all PD patients, and there is a scarcity of neuropathologically confirmed cases with isolated GI alpha-synuclein pathology.8 Also, it remains an open question how an initiation exclusively in the gut would be compatible with early olfactory dysfunction, one of the most frequent symptoms at early stages of the disease.

Eventually, we likely deal with a multifactorial disease, and therefore, different mechanisms may be at play in different patients.

Dr. Halliday

The motor symptoms of PD are well known to be caused by the degeneration of substantial numbers of dopamine neurons in the midbrain. Gut problems are not directly responsible for these. The question of whether there could be alpha-synuclein pathology in the gut caused by something that would eventually indirectly lead to degeneration of substantial numbers of dopamine neurons in the midbrain and produce PD is a different question. The impact of chronic physiological changes in any peripheral organ is likely to have significant impact on the nervous system, and it will be important to determine how these may predispose to any permanent damage.

What will convince you that the gut plays or does not play an important role in the origin of Parkinson’s disease?


Dr. Scheperjans

I guess to satisfy a devil’s advocate in this case we would need:

  • A biomarker to select patients with an increased PD risk from a population suffering from unexplained gastrointestinal dysfunction (biopsy, microbiome, donepezil-PET…?)
  • A biomarker to exclude patients with early, asymptomatic CNS pathology (neuroimaging, nuclear imaging of alpha-synuclein or microglia?)
  • A randomized controlled trial of an intervention targeting exclusively the GI pathology or its spreading to the CNS (dietary, probiotic, vagotomy…?)
  • A sufficiently long follow-up period to assess efficacy of the intervention in terms of progression to clinical PD or through a surrogate biomarker.
     

For starters, GI related interventions in subjects with established PD or idiopathic REM sleep behavior disorder may be more feasible. Even though in these patients the neuropathological process is already established in the CNS, manipulations of neuroinflammatory or metabolic processes through the gut-brain axis may have symptomatic or even disease modifying effects. Any of the abovementioned biomarkers would improve our understanding of the gut-brain relations and their pathogenetic relevance in PD.

Dr. Halliday

As the motor symptoms of PD are caused by the degeneration of substantial numbers of dopamine neurons in the midbrain, the key evidence that PD is initiated in the gut would be experiments showing a more direct effect on killing dopamine neurons.

And finally, how changes in gut microbiota could lead to PD pathology?


Dr. Scheperjans

There are several ways by which gut microbiota could be involved. For example, a shift of the microbiota balance could be related to disturbance of the gut barrier. This barrier, consisting of a mucous layer and the epithelial cells beneath it, prevents the access of hazardous molecules to the tissue and bloodstream. It has been demonstrated that in PD, this barrier is malfunctioning leading to a “leaky gut”.9 Thus, potentially toxic or pro-inflammatory molecules, or even bacteria itself, could penetrate from the gut lumen into the gut tissue and bloodstream. Indeed, there is evidence of a low grade inflammation in the colonic mucosa of PD patients and signs of increased exposure to proinflammatory bacteria-derived molecules such as lipopolysaccharide.9 Local alpha-synuclein expression seems to be increased in response to local gut inflammation.5 Furthermore, enteric neurons show activity-dependent alpha-synuclein excretion and their activity can be influenced by gut microbiota.10,11  When pathological forms of alpha-synuclein have accumulated locally in the gut, this pathology could spread in a prion-like fashion e.g. via the vagal nerve to the brain. Another proposed mechanism could be so called cross-seeding, where bacterial amyloid proteins could interact with human alpha-synuclein leading to formation and spreading of pathological protein-aggregates.12 Bacteria-derived molecules such as short-chain fatty acids could also play a role, although it is currently not clear whether they have beneficial or deleterious effects.13,14 Finally, also the immune system is in an intense interaction with gut microbiota, and the activity of microglia in the CNS can be modulated by gut microbiota.15 Therefore, there is a multitude of pathways that could be relevant.

Dr. Halliday

My concepts on this are purely speculative in the absence of any human data in this area. There is solid evidence that the gut microbiome expresses small chain fatty acids that are active mediators in the maintenance of a variety of cells (mature microglia and peripheral immune cells) and also produce epigenetic changes.16 Microglia are thought to play a role in the early, selective death of dopamine neurons in the substantia nigra, but other factors would have to play a role to explain the selectivity.17

Dr. Sánchez-Ferro

Based on the opinion of two experts, a common saying in science, and our “gut feeling”, we finalize this post by stating that further research is needed to solve this important aspect of PD.

References

1.        Pan-Montojo, F. et al. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci. Rep. 2, 898 (2012).
2.        Holmqvist, S. et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 128, 805–820 (2014).

3.        Svensson, E. et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–9 (2015).
4.        Liu, B. et al. Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study. Neurology 88, 1996–2002 (2017).
5.        Stolzenberg, E. et al. A Role for Neuronal Alpha-Synuclein in Gastrointestinal Immunity. J. Innate Immun. 9, 456–463 (2017).
6.        Blandini, F. et al. Functional and neurochemical changes of the gastrointestinal tract in a rodent model of Parkinson’s disease. Neurosci. Lett. 467, 203–207 (2009).
7.        Ulusoy, A. et al. Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections. Acta Neuropathol. 133, 381–393 (2017).
8.        Borghammer, P. How does parkinson’s disease begin? Perspectives on neuroanatomical pathways, prions, and histology. Mov. Disord. 33, 48–57 (2018).
9.        Forsyth, C. B. et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One 6, e28032 (2011).
10.      Paillusson, S., Clairembault, T., Biraud, M., Neunlist, M. & Derkinderen, P. Activity-dependent secretion of alpha-synuclein by enteric neurons. J. Neurochem. 125, 512–7 (2013).
11.      Kunze, W. A. et al. Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calcium-dependent potassium channel opening. J. Cell. Mol. Med. 13, 2261–70 (2009).
12.      Chen, S. G. et al. Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans. Sci. Rep. 6, 34477 (2016).
13.      Sampson, T. R. et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell 167, 1469–1480.e12 (2016).
14.      Liu, J. et al. Sodium butyrate exerts protective effect against Parkinson’s disease in mice via stimulation of glucagon like peptide-1. J. Neurol. Sci. 381, 176–181 (2017).
15.      Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–77 (2015).
16.      Sharon, G., Sampson, T. R., Geschwind, D. H. & Mazmanian, S. K. The Central Nervous System and the Gut Microbiome. Cell 167, 915–932 (2016).
17.      Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18, 101–113 (2017).

 

Comments on this Blog Post

Title:
6th Annual Digestive Diseases: New Advances Conference | eMedEvents
By:
Robert
Date:
February-11-2019  12:43:51 AM
Comment:

Hi,

Thank you for sharing this information.There are some conferences happening in which medical specialty would be Gastroenterology and here is one of those conferences the conference details are given below.

6th Annual Digestive Diseases: New Advances Conference is organized by Global Academy for Medical Education and will be held from Mar 15 - 16, 2019 at Philadelphia, Pennsylvania, USA. The target audience for this medical event is gastroenterologists, hepatologists, primary care physicians, internists, advanced practice nurses, nurses, pharmacists, and physician assistants.

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Title:
Minimally Invasive Surgery Symposium 2019 | MISS conference 2019 Nevada |Minimally Invasive Surgery Symposium (MISS) | Surgery Conferences 2019 Las Vegas | Bariatric Surgery Conferences Las Vegas 2019 | eMedEvents
By:
Robert
Date:
December-05-2018  12:15:54 AM
Comment:

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19th Annual Minimally Invasive Surgery Symposium (MISS) is organized by Global Academy for Medical Education and will be held from Feb 25 - 28, 2019 at Encore Las Vegas, Las Vegas, Nevada, United States of America.

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Title:
Cedars-Sinai International Endoscopy Symposium 2019 | Cedars-Sinai International Endoscopy Symposium in California | Gastrointestinal Endoscopy Conferences in Los Angeles | Gastrointestinal Endoscopy Conferences in California | eMedEvents
By:
Robert
Date:
October-23-2018  4:46:25 AM
Comment:

Hi,

Thanks for sharing this information.There are some conferences happening in which medical specialty would be Gastroenterology and here is one of those conferences.the conference details are given below.

Cedars-Sinai International Endoscopy Symposium 2019 is organized by Cedars-Sinai Medical Center and will be held from Jan 24 - 27, 2019 at Cedars Sinai Medical Center Harvey Morse Conference Center South Tower, Los Angeles, California, United States of America.

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Title:
Medicinal Cannabis GI and Hepatic Disorders | eMedEvents
By:
Robert
Date:
September-15-2018  6:45:33 AM
Comment:

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Medicinal Cannabis: GI and Hepatic Disorders is organized by Thomas Jefferson University (TJU) and will be held from May 31, 2018 - May 31, 2020. This CME Conference has been approved for a maximum of 1.0 AMA PRA Category 1 Credits.

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Thank You,

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About the Authors

Filip Scheperjans, MD
Department of Neurology, Helsinki University Hospital,
and Clinical Neurosciences, Neurology
University of Helsinki
Helsinki, Finland

Glenda Halliday, MD
NHMRC Senior Principal Research Fellow
University of Sydney
Sydney, Australia

Álvaro Sánchez-Ferro, 
MDM+Vision Cofund Fellow
(Marie Sklodowska-Curie Actions) at HM CINAC
Móstoles. Spain  

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