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Published in final edited form as: Gastroenterology. 2022 Feb 8;162(6):1574–1582. doi: 10.1053/j.gastro.2022.02.004

2021 Workshop: Neurodegenerative Diseases in the Gut-Brain Axis - Parkinson’s Disease

Gary M Mawe 1, Kirsteen N Browning 2, Fredric P Manfredsson 3, Michael Camilleri 4, Frank A Hamilton 5, Jonathan A Hollander 6, Beth-Anne Sieber 7, Patricia Greenwel 5, Terez Shea-Donohue 5, John W Wiley 8
PMCID: PMC9038653  NIHMSID: NIHMS1778888  PMID: 35149029

Meeting Summary Overview

Parkinson's disease (PD) is the second most common neurodegenerative disease, after Alzheimer’s disease, with an estimated annual cost in the United States of 52 billion dollars 1. It is also the fastest growing neurological disease estimated to reach 13,000,000 patients by 2040.

For many decades, PD research focused on the brain; however, PD symptoms are not limited to motor dysfunction and patients frequently exhibit non-motor problems that have a significant impact on their quality of life. Notably, patients who develop PD often have a history of bowel issues, predominantly constipation and gastroparesis (slow gastric emptying). In fact, gastrointestinal (GI) symptoms may be present decades before the appearance of motor symptoms1-3 suggesting that GI dysfunction is an early manifestation of the disease. This has provided support for the novel concept proposed by Braak in 2003 2 that PD may originate in the gut rather than the brain and the more recent theory that the GI tract is be a major source of inflammation contributing to neurodegeneration in PD 3. Thus, a better understanding of the role of the GI tract in the initiation and propagation of PD pathology could lead to the identification of GI-based targets for all stages of the disease.

From September 30-October 1, 2021, a public workshop was convened by the NIDDK, in collaboration with the NINDS and NIEHS, to identify and discuss issues related to the involvement of the GI tract in PD, including its role in the etiology and manifestation of symptoms associated with the disease. The workshop objectives included following topics: (1) coordinating care of motor symptoms and non-motor GI dysfunction in patients with PD; (2) evaluating gut brain communication in neurodegenerative disorders; (3) addressing the gaps in knowledge regarding changes in enteric sensory processes and the structure and function of the enteric nervous system in PD; (4) assessing the potential of the GI tract as a source of biomarkers and novel therapeutic targets for early PD; (5) facilitating cross-talk among brain-gut investigators to identify collaborative opportunities and (6) define areas of common interests in brain-gut research among NIDDK, NINDS and NIEHS.

This workshop summary includes an overview of the sessions that were in the workshop, a table (Table 1) summarizing identified gaps and potential future directions, and a figure (Fig. 1) summarizing the key elements in the involvement of the gut-brain axis in PD.

Table 1.

Summary of break out group discussions identifying gaps, opportunities, and resources needed to advance the field.

Group Members Key Discussion Points Gaps /Opportunities Resources Required
Group 1:
Michael Camilleri
Frank Hamilton
Laren Becker
Ali Keshavarzian Anthony Lang Meenakshi Rao Thyagarajan Subramanian		 The burden of GI dysfunction in Parkinson’s disease

  1. What is the role of GI symptoms in PD pathology?

  2. Can the nonmotor symptoms (prodromal phase) be leveraged for PD detection?

  3. What is needed to increase the opportunities for data/resource sharing across foundations, international/national institutes?
  1. GI dysfunction in PD
    1. Gender/sex differences in gut symptoms
    2. Onset of symptoms in PD patients, covert GI dysfunction
    3. Differences in prodromal (non-motor) phase in early vs late onset of disease
    4. More GI testing (e.g. barrier function, histopathology)
    5. Biomarkers for prodromal GI dysfunction/disease progression/disease severity/ UPSIT (University of Pennsylvania Smell Identification Test)
    6. Relationship of α-SYN to disease burden
    7. IBD and PD risk
    8. Co-morbidity with mental health
    9. Gut inflammation and PD symptoms

  2. Establish additional and leverage existing cohorts with early-stage patients, including collaborations with international institutes

  3. Include consideration of health disparities and environmental impact

  1. Partner with pharma to advance promising therapeutic approaches

  2. Add relevant GI measures to and collect biospecimens from existing and novel PD cohorts

  3. Establish and leverage PD registries

  4. Collect longitudinal GI samples from patient cohorts
Group 2:
Fredric Manfredsson Kirsteen Browning
Jon Hollander
James Galligan
Tim Greenamyre Jeffrey Kordower
Kara Margolis
Shanthi Srinivasan		 Parkinson’s disease initiation: Top down or bottom up

  1. Is pathology in the ENS related to the cause or the result of CNS pathology (directionality)?

  2. Are GI symptoms due to early brain or early gut effects?
  1. Hyper focus on α-SYN, why does it aggregate in specific cells
    1. Microbiome as cause or effect in PD GI dysfunction
    2. L-dopa/diet/genetic effects

  2. Microbial products

  3. Autonomic dysfunction - directionality
    1. Same or different pathways for direction of transmission
    2. Sympathetic NS – sacral spinal cord
    3. Nigral/GI dysfunction vs motor dysfunction
    4. Affected areas outside GI tract – bladder, pancreas

  4. Lymphatics/Liver – role in route of transmission of α-SYN

  5. Visceral pain

  6. Animal Models
    1. Emergence of non-motor symptoms
    2. Validity and applicability to humans

  1. NHP availability

  2. Validity of animal models

  3. Improved communication across siloed research fields
Group 3:
Gary Mawe,
Terez Shea-Donohue
Art Beyder
Issac Chiu
Brain Gulbransen
Bryan Killinger
Malu Tansey
Laura Volpicelli-Daley		 Mechanisms of gut dysfunction related to the ENS

  1. How does gut dysfunction in PD inform us of possible changes in ENS and ENS circuitry?

  2. What are the potential mechanisms of these changes?

  3. Does PD affect gut sensation?

  4. What other cell types could be involved (e.g glia, immune cells, ICC)?
  1. α-SYN in the ENS
    1. Physiological function
    2. Cell types (neurons, glia, epithelial cells, EEC, SIP)
      1. Markers for glial subtypes
      2. specific changes in subtypes,
      3. communication with CNS
    3. Processes in folding, misfolding and aggregation and effects on cell function
    4. Aging
  2. ENS and ENS circuitry dysfunction
    1. Determine whether and where ENS cell loss (neurodegeneration) occurs in PD
    2. Dopaminergic neuron function – physiology
    3. Nitrergic/cholinergic (other) susceptibility in PD
    4. Sensation
    5. Neuroimmune interactions
    6. Cell types involved (immune and other epithelial cells that have immune function)
    7. Neurogenic inflammation - calprotectin

  1. More translational animal models

  2. Validated biomarkers

  3. Links between animal and human pathology
Group 4:
John Wiley,
Patricia Greenwel
Faranak Fattahi
Madhu Grover
Purna Kashyap
Roger Liddle
Eamonn Quigley
Lorenz Studer		 Diagnostic and therapeutic potential of the gut in Parkinson’s Disease

  1. What data bases, biospecimens or other are needed to be in place to allow patient screening/diagnosis/phenotyping or to validate future cellular biomarkers?

  2. What would be needed for cellular and clinical phenotypes that would facilitate early diagnosis and/or stratification of PD subpopulations?

  3. What’s the future for GI-focused interventions?

  4. Are there potential initial GI relevant targets?
  1. Improved Databases
    1. Longitudinal samples relevant to both neurology and GI,
    2. Improved coordination of care of motor and non-motor manifestations, particularly recognition of prodromal GI symptoms
    3. Standardizations of protocols for sample collection/development of patient questionnaires
    4. Comparison of PD patients with and without GI symptoms

  2. Multidisciplinary approach (multiomics) - consortia

  3. Use of AI approaches

  4. PD therapy effects on gut function/microbiome/ inflammation

  5. Identified therapeutic targets
    1. Barrier function
    2. Microbiome
  6. Potential gut related therapeutics
    1. Vagal nerve stimulation
    2. Probiotics
    3. Immunomodulation (TNF)
    4. Enteric α-SYN
    5. Prokinetics

  1. Improved animal and cell-based models

  2. Access to PD patients with well characterized GI symptoms

  3. Foster team-based approaches using expertise at PD centers and through global collaboration
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Bolded names indicate break out group leaders and facilitators

Abbreviations: AI, artificial intelligence; IBD, inflammatory bowel disease; ICC, interstitial cells of Cajal.; NHP, Non-human primate; SIP, smooth muscle–ICC–PDGFRα+ cells; TNF, tumor necrosis factor.

Figure 1.

Figure 1.

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Schematic diagram summarizing potential mechanisms contributing that underlie gastrointestinal dyfunctions associated with Parkinson’s Disease and related links between the gut and the brain. The integrity of the mucosal barrier is maintained by specific contribution from the lining epithelial cells including enteroendocrine cells (EEC), the enteric nervous system (ENS), and immune cells. Epithelial cells undergo constant renewal and are replenished by a stable population of stem cells at the base of the crypts. Aging and exposure to environmental toxins are risk factors for Parkinson’s disease and are associated with impaired mucosal barrier function. A "leaky" gut (1) facilitates entry of luminal microbes and their products as well as ingested toxins into the systemic circulation (2). This triggers activation of resident immune cells and inflammation (3) that disrupt enteric neuronal and glial function (4) that can lead to induction of α-SYN misfolding within enteric neurons and neurodegeneration (5). Misfolded α-SYN may be transferred to the CNS via retrograde transport through the efferent vagus nerve resulting in aggregated α-SYN within brainstem vagal motoneurons (6). Misfolded α-SYN may also spread centrally in a prion like manner, including to the SNpc via the monosynaptic nigro-vagal pathway, causing reactive astrogliosis and loss of dopaminergic neurons resulting in the classic motor symptoms of PD (7). In this manner, age, environment, diet, and toxins may affect the induction, pathogenesis, and rate of disease progression at multiple peripheral and central sites of action. Abbreviations: α-SYN , alpha-synuclein; AP, area postrema; NTS, nucleus tractus solitarius; DMV, dorsal motor nucleus of the vagus; SNpc, substantial nigra pars compacta

Session 1: Epidemiology of Parkinson's disease and gastrointestinal manifestations, environmental factors and the enteric nervous system

Rationale-

The objective of this session was to review epidemiology and risk factors of PD and its GI manifestations, and the involvement of the enteric nervous system (ENS) in PD.

Although the underlying cause for a vast majority of cases is unknown, several environmental (such as pesticide exposure and rural living) and genetic factors can contribute to the development of PD. Epidemiological studies have found an association of PD in humans with pesticide exposure, including the neurotoxins paraquat and rotenone4, both of which are absorbed by the gut, and involve the dopamine transporter and the organic cation transporter-35 on nerves and immune cells. Evident also is the socio-economic impact of GI manifestations of PD, including social embarrassment, emotional distress, decreased quality of life of both patients and their caregivers, and significant economic burden in the form of direct medical costs and indirect and non-medical costs.

Gastrointestinal manifestations constitute important non-motor, autonomic or sensory symptoms that may also be prodromal, and may facilitate early diagnosis. Retrospective studies have documented the occurrence of GI manifestations before motor symptoms, as summarized in Table 2. Prodromal GI symptoms may reflect important non-motor, autonomic or sensory changes and could facilitate early diagnosis. Dysfunctions of autonomic nerves, including the ENS, are key in the control of GI manifestations, and toxicant-mediated deficits in enteric neurons are reported in animal models of PD 6. An extensive review documenting diverse, though not always replicated, abnormalities in human ENS in PD has also been published recently 7.

Table 2.

Comparison of prevalence (shown as %) of gastrointestinal symptoms in patients with Parkinson’s disease in different series (NMS Quest is a 30-item screening questionnaire for Parkinson's disease)

Site Single center
U.S.A.		 Multicenter international Multicenter in
Italy		 Single center in
Argentina
Ref # 23 24 25 26 27
Reference Mov Disord 1991;6:151-156 Mov Disord 2006;21:916-923. Mov Disord 2007;22:1623-1629. Mov Disord 2009;24:1641-1649 J Neurol 2013;260:1332-1338.
PMID: 2057006 16547944 17546669 19514014 23263478
Patients/controls 94/50 123/96 545/No controls 1072/No controls 129/120
Evaluation tool Survey of GIS NMS QUEST NMS QUEST Semi structured interview on NMS Structured questionnaire of GI Symptoms
Taste/smell Not assessed 26 28.95 Not assessed Not assessed
Dry mouth Not assessed Not assessed Not assessed Not assessed 57.4
Drooling, dribbling 70.2 35 41.52 31.1 49.6
Dysphagia, swallow problems 52.1 23.6 28.38 16.1 20.2
Nausea, vomiting 24.4 8.1 14.31 9.7 9.3
Heartburn NS vs. controls Not assessed Not assessed Not assessed 34.1
Bloating NS vs. controls Not assessed Not assessed Not assessed 35.1
Constipation 28.7 46.7 52.48 24.6 53.6
Defecatory dysfunction 65.9 27.6 NS 29.9 11.4 61.2
Fecal incontinence Not assessed 4.9 NS 8.21 0.8 Not assessed
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NOTE. Non-motor symptoms (NMS) QUEST is a 30-item screening questionnaire for Parkinson disease. Abbreviations: GIS, Gastrointestinal symptoms; NS, not significant.

Prospective follow-up studies illustrate that severity of dysphagia, salivary drooling and defecatory disorders parallel the progression of motor symptoms in PD (based on Hoehn and Yahr stage). Indeed, severity of dysphagia is associated with hospitalizations and mortality in PD. Among the GI symptoms in PD, constipation has the most rapidly progressive severity and frequency over 18 months. Diagnostic tests are available to diagnose motor dysfunction of the esophagus, stomach, colon and defecatory mechanisms. Treatments for the GI complications, which may be aggravated by anti-PD therapy, are generally suboptimal and the GI dysfunction may impact the response to PD treatment because of altered pharmacokinetics of orally administered medications.

These keynote presentations underscored the concept that several converging factors likely contribute to the development of PD and provided the background and framework for the subsequent scientific sessions.

Session 2: Gut-brain communication in Parkinson’s disease

Rationale-

One of the most active research areas in PD focuses on the mechanisms of communication between brain and gut. These investigations involve this inter-relationship as it relates to CNS pathology and neurodegeneration, as well as defining the role of peripheral versus central pathology in GI dysfunction.

There is now strong support for a functional neural circuitry link between the GI tract and areas of the CNS that are typically associated with PD. For example, a direct connection between substantia nigra pars compacta (SNc) dopaminergic neurons, the dorsal motor nucleus of the vagus (DMV), and vagal enteric innervation has been demonstrated using tracing studies. Importantly, acute modulation of SNc neurons confers an immediate effect on GI function supporting the idea that the SN (via the vagus nerve) provides an ongoing tonic drive to enhance the tone throughout the GI tract. However, it is also important to consider the bidirectionality of the gut brain axis in the pathogenesis of PD and consideration of other neural as well as non-neural pathways.

There is considerable interest in the potential spread of α-SYN pathology between the ENS to the CNS where the GI system and olfactory tracts may serve as important conduits for the transfer of injurious substances, specifically α-SYN, the chief component of Lewy pathology in the CNS and ENS. Indeed, an intriguing epidemiological observation is that truncal vagotomy is associated with lower population evidence of PD 8. Similarly, in the systemic paraquat/lectin model, SNc degeneration, as a result from ENS α-SYN pathology, was dependent on intact vagal connectivity. Such results are consistent with the Braak hypothesis of the etiology of PD. Interestingly, in the latter example, functional inhibition of nigral projections to the ENS prevented the spread of pathology, suggesting that the mechanism(s) underlying this spread is more complex than mere anatomical connectivity. Although the role of α-SYN in neurodegeneration is unknown, alteration to α-SYN homeostasis is considered a key event in disease etiology. It is important to note, however, that α-SYN is also expressed in myenteric neurons in healthy individuals, begging the question as to what precipitates pathological changes.

Nonetheless, it was emphasized that the literature presents divergent results as it relates to the relationship between ENS and CNS pathology, where recent papers have shown very robust pathology following peripheral inoculations of pathogenic α-SYN in a mouse model 9 while other published and unpublished studies have failed to confirm these findings 10, 11. For example, a recent study from the Bezard group demonstrated putamenal α-SYN pathology following administration of α-SYN to the gut in a non-human primate model; however, with no detectable α-SYN pathology in the DMV, suggesting an alternate route of pathological spread 10.

One such alternative to the “vagal highway” of disease propagation is the idea that intestinal inflammation may drive PD pathogenesis and progression via a humoral process. There is evidence for both central and peripheral inflammation in various stages of PD, with markers of inflammation (e.g. tumor necrosis factor) being present in cerebral spinal fluid and blood. This concept is supported by reports that pro-inflammatory cytokines are detected in stool from PD patients; however, their presence in stool is not correlated with plasma makers. Thus, the overarching hypothesis describes some form of gut-environment-aging interplay that may be triggered by dysbiosis, irritable bowel syndrome, infection, or inflammation, 3 in which the immune system is the arbiter. With aging, the capacity of the immune system to “protect” dissipates and in turn leads to a chronic inflammatory state and innate immune dysfunction that may drive PD pathogenesis.

Despite the traction of the Braak hypothesis12, the brain-gut axis is a route of bidirectional communication and there is evidence in support of both gut-brain and brain-gut etiologies for PD. This has led to potentially defining subsets of PD based on progression (e.g. brain first versus periphery first). Moreover, one must also consider the alternative threshold theory which posits that concurrent pathologies of α-SYN in the brain and the gut, due to differing abilities of generating compensatory mechanism, can lead to varying symptomatic onsets and thus provide the impression of temporal progression of disease 13.

Sessions 3 and 4: The enteric nervous system and sensory function in Parkinson’s disease

Rationale -

There is considerable interest in the role of the ENS in the pathogenesis of PD as well as the impact of PD on the ability of the ENS to coordinate secretomotor function. In addition, there are sensory disturbances in PD, but little is known of changes in the cells and mechanisms involved in enteric sensation, which are critical to the control of gut function.

Enteric neurons are chronically exposed to mechanical and chemical stressors throughout life which may increase susceptibility to stress and damage. While there are inconsistent findings about which enteric neurons are affected by PD, and whether there is de facto ENS neurodegeneration in PD, many GI motility disorders (gastroparesis, aging, diabetes) are associated with loss of enteric nitrergic neurons as well as aberrations in mitochondrial structure/mitophagy and/or pyroptosis 14. The ENS develops as neural crest cells migrate and colonize the developing gut tube. Modeling/studying enteric neural crest migration may be a suitable means by which human physiology/pathophysiology can be studied and/or therapeutic targets identified for disorders involving the ENS such as PD. Because of its ability to recapitulate many developmental aspects in culture and its amenability to high-throughput drug discovery, leveraging human pluripotent stem cell differentiation may be an efficient means by which human ENS development can be studied 15.

In the past decade it has become abundantly clear that enteric glia are actively involved in the control of regulated functions of the GI tract, including motility and secretion, and they are also playing a role in pathological conditions 16. In the intestines, brain-gut crosstalk produces inflammation that may drive microglial activation and, while little is known about enteric glial involvement in PD, valuable clues could be derived from the CNS literature. The substantia nigra (SN), for example, has a lower abundance of astrocytes and higher abundance of microglia compared to other brain regions. In the early stages of PD, microglia are mixed population of pro and anti-inflammatory phenotypes, which allows sampling of environment and homeostatic regulation. Astrocytes are mobilized/activated to help clear α-SYN and upregulate neuroprotective pathways to preserve neurons/neuronal function. As the disease progresses, however, microglia lose their capacity for tissue defense and repair, and shift to a proinflammatory neurotoxic state. As a result, astrocytes lose support and dopaminergic neurons become more vulnerable as a form of maladaptive plasticity. Aging has also been shown to enrich PD related genes in microglia and astrocytes, as well as alter lipid handling and lysosome function, mitochondrial health and inflammatory responses.

The GI mucosal barrier is lined by epithelial barrier composed of highly organized, multiple diverse cell types that arise from the self-sustaining stem cell poolPD patients display disruptions in epithelial barrier function, more gut inflammation, and have increased levels of pro-inflammatory cytokines 17. Similarly, dysbiosis and a leaky gut lead to inflammation and changes in glial fibrillary acidic protein (with a potential role for glial PD genes) causing a change in enteric glia function leading enteric neurodegeneration/neuroplasticity/immune modulation. As described above, disruptions in the glial cell population are observed in the CNS, and if this is also occurring in the gut it could contribute to the disruptions in barrier function.

The peripheral trigger of ENS PD pathology may originate via entry of a pathogen that crosses the GI mucosal barrier inducing α-SYN misfolding and aggregation. Enteroendocrine cells (EECs) could play an important role in the response to environmental toxins, and thus act as a first “falling domino” in the pathogenesis of PD. EECs, which have been likened to taste buds of the GI tract, comprise about 1% of the epithelial cell population, and they can be further subdivided by their signaling type/hormone content. They are electrically excitable, which makes them energy demanding and sensitive to environmental toxins present in the lumen and can be activated selectively by luminal contents via mechanical stimulation, and express chemoreceptors, including those that detect nutrients and bacterial products. Notably, EECs are high expressers of α-SYN, and communicate with a variety of cell types, including glial cells, other epithelial cells, immune cells, and both intrinsic and extrinsic primary afferent neurons.

Viviane Labrie and her colleagues investigated the vermiform appendix as possible player in the development of gut-derived PD 18. The appendix is a unique immune-enriched appendage that has been hypothesized to serve as an incubator of sorts for the microbiome that can recolonize the gut microbiota after major disruptions that occur in conditions such as secretory diarrhea. The appendix may be involved in disease spread through both indirect (e.g. immune surveillance leading to community based toxicity) and direct mechanisms, including the seeding and promotion of α-SYN aggregation in response to environmental insults, which then spreads to the CNS. In support of this scenario, α-SYN pathology has been identified within mucosal macrophages of the appendix, possibly indicating accumulation of pathological aggregates while global inactivation or suppression of autophagy/lysosomal function within human PD appendix may enhance α-SYN pathology.

Given the multiple potential etiologies of PD, the extensive bilateral connections between the gut and the brain, and the continued exposure of the GI tract to mechanical, chemical, and environmental stressors throughout life, it seems likely that the ENS plays a significant role in both gut-brain and brain-gut etiologies of PD.

Session 5: Emerging targets and therapies-

Rationale-

This section highlights potential emerging targets and treatments for PD beyond α-SYN as a biomarker and therapeutic target and historic approaches to enhance CNS dopamine levels.

There is broad interest in characterizing the role of the microbiome (bacteria, fungi, protozoans, viruses and, possibly, prions) and intestinal barrier dysfunction mentioned previously in the early pathophysiology of PD. Enthusiasm for this approach is based on the temporal relationship between GI and somatic symptoms.

Specific areas of interest include assessment of whether dysbiosis is present in newly diagnosed patients with PD and identifying individuals who are at increased risk of developing PD based on multi-omics assessment of genetic, epigenetic and metabolomic profiling. Key questions to be answered include: i) determine whether PD is associated with an overall reduction in microbial diversity favoring an increase in abundance of microbial species associated with intestinal barrier dysfunction, ii) assess whether activation of the gut immune system, i.e. increase in pro-inflammatory cytokines and/or decrease in anti-inflammatory cytokines is present in individuals who develop PD, and iii) examine whether microbial dysbiosis is a consequence or driver of intestinal barrier dysfunction and activation of the gut immune system. Thus, does activation of the gut immune system precede development of epithelial barrier dysfunction or does dysbiosis precede development of barrier dysfunction and activation of the gut immune system 19, 20?

Potential interventions could include use of targeted probiotics, prebiotics and, possibly, fecal microbial transplantation which could have potentially protective and/or restorative effects that promote a healthy intestinal barrier. Alternatively, supplementing the diet with specific amino acids such as L-glutamine may have beneficial anti-inflammatory and/or trophic effects on the integrity of the gut barrier. If specific pro-inflammatory pathways such as TNF-α are activated in PD, targeted interventions, including current anti-inflammatory therapies, may be useful.

While there is emerging interest in applications of cell-based and neuroprotective interventions to mitigate the effects of PD in the ENS, most novel therapies have focused on slowing progression or reversing CNS motor symptoms. CNS cell and gene therapy approaches aimed at protecting dopamine neurons or enhancing dopamine tone have been extensively evaluated in clinical trials. For example, fetal mesencephalic or autologous stem cell grafts or virally mediated gene therapy have been utilized to improve dopaminergic tone in the striatum. Conversely, gene therapy with neuroprotective compounds such as GDNF and neurturin have also been tested in patients. Although the outcomes of such clinical trials have been mixed, they provide a backdrop for analogous approaches aimed at protecting ENS neurons and restoring their function in disease. The use of fetal tissue in the treatment of PD has well-described obstacles and concerns, including the ethical concern related to acquisition of fetal tissue, the limited availability of such tissue and the observation that grafted tissue from one individual demonstrates variable rejection when implanted in the brain of another subject. These obstacles motivated interest in developing alternate approaches to generate stem cells via somatic nuclear transfer or by using transcription factors to reprogram cells to “induced” pluripotent stem cells (iPSCs)21 . It appears that somatic cells taken from a patient and implanted later as induced dopamine neurons (immune-matched) may fare better than non-matched or partially matched cells. Harnessing the therapeutic potential of transplantation of neurons or programmed iPSCs to treat neuropathology is a shared interest among CNS and ENS neuroscientists. Neurotrophins such as GDNF and brain-derived neurotrophic factor (BDNF) exert similar effects in the ENS. Challenges remain including validating selectivity and durability of the intervention for DA neurons, particularly when translating promising animal studies to clinical trials in humans. 22

In summary, while there continues to be keen interest in development of new symptomatic treatments, disease-modifying drugs, strategies to replace or protect CNS dopamine neurons, innovative drug delivery systems and novel surgical interventions for patients with PD, much of the discussion at this NIH workshop was devoted to the gut-brain axis and PD focused on the potential role of microbial dysbiosis in the early pathophysiology of PD, including activation of gut mucosal pro-inflammatory cascades and relationship to intestinal barrier dysfunction. Improved understanding of the role of the gut-brain axis in PD may lead to gut-focused therapeutic strategies to slow progression or, possibly, reverse PD in the future.

Acknowledgments

The following individuals, in addition to the co-authors, served as speakers, moderators, and/or breakout session participants: Anthony Lang, Timothy Greenamyre, James Galligan, Laura Volpicelli-Daley, Jeffrey Kordower, Malú Tansey, Faranak Fattahi, Meenakshi Rao, Bryan Killinger, Rodger Liddle, Arthur Beyder, Brian Gulbransen, Shanthi Srinivasan, Eamonn Quigley, Ali Keshavarzian, Purna Kashyap, Lorenz Studer. Invited discussants: Laren Becker, Issac Chiu, Madhu Grover, Kara Margolis, and Tyagajaran Subramanian. BioRender was used to produce the summary figure.

Funding:

Funding for this meeting was provided by NIDDK. Preparation of this manuscript was supported by the following NIH grants: AT011203 (GMM), DK55530 (KNB), DK124098 (KNB), DK108798 (FPM), DK115950 (MC) DK122280 (MC), R21AT009253 (JWW), NS113127 (JWW), and DK098205 (JWW).

Abbreviations:

PD

Parkinson’s disease

GI

gastrointestinal

ENS

enteric nervous system

CNS

central nervous system

α-SYN

α-synuclein

SNc

substantia nigra pars compacta

DMV

dorsal motor nucleus of the vagus

EECs

enteroendocrine cells

GAD

glutamic acid decarboxylase

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclosures: Dr M Camilleri reports having of stock options (current worth <$1) for serving as an advisor to ENTERIN INC. Dr. F Manfredsson Founder and co-owner of nVector and Neuralina Therapeutics. He has received funds from Alector, RegenXbio and Aspen Neuroscience. The other authors have no conflicts to disclose. This report does not represent the official view of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Environmental Health Sciences (NIEHS), the National Institutes of Health (NIH), the Department of Health and Human Services (HHS), or any part of the US Federal Government. No official support or endorsement of this article by the NIDDK, NINDS, NIEHS or NIH is intended or should be inferred.

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