The Gut–Brain Axis in Parkinson's Disease

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Keyword:</label> <input value="" title="Search Cold Spring Harbor Perspectives in Medicine" type="text" name="fulltext" id="header-qs-input" /><input type="hidden" name="submit" value="yes" /><label for="header-qs-search" id="header-qs-search-label">GO</label><input value="GO" alt="Link: Go" type="image" id="header-qs-search-go" src="/shared/img/standard-design/design2/go.gif" /> </div> <div class="adv-search-link"><a href="/search">Advanced Search</a></div> </form> </div> <div class="header-ac-elements"> <div class="inst-branding"> </div> <div id="authstring" class="suppress-header-login"> </div> <div id="hdr-login" class="suppress-header-login"></div> </div> <div class="bar"> <div class="bar-inner"></div> </div> </div> <div id="content-block"> <div class="article fulltext-view " itemprop="articleBody"><h1 id="article-title-1" itemprop="headline">The Gut–Brain Axis in Parkinson's Disease</h1> <div class="contributors"> <ol class="contributor-list" id="contrib-group-1"> <li class="contributor" id="contrib-1" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><a class="name-search" href="/search?author1=Virginia+Gao&sortspec=date&submit=Submit">Virginia Gao</a><a id="xref-aff-1-1" class="xref-aff" href="#aff-1">1</a>,<a id="xref-aff-2-1" class="xref-aff" href="#aff-2">2</a>,<a id="xref-aff-3-1" class="xref-aff" href="#aff-3">3</a>, </li> <li class="contributor" id="contrib-2" itemprop="author" itemscope="itemscope" itemtype="http://schema.org/Person"><a class="name-search" href="/search?author1=Carl+V.+Crawford&sortspec=date&submit=Submit">Carl V. Crawford</a><a id="xref-aff-4-1" class="xref-aff" href="#aff-4">4</a> and </li> <li class="last" id="contrib-3"><a class="name-search" href="/search?author1=Jacqueline+Burr%C3%A9&sortspec=date&submit=Submit">Jacqueline Burré</a><a id="xref-aff-1-2" class="xref-aff" href="#aff-1">1</a></li> </ol> <ol class="affiliation-list"> <li class="aff"><a id="aff-1" name="aff-1"></a><address>1Appel Institute for Alzheimer's Disease Research and Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10021, USA </address> </li> <li class="aff"><a id="aff-2" name="aff-2"></a><address>2Parkinson's Disease and Movement Disorders Institute, Department of Neurology, Weill Cornell Medicine, New York, New York 10065, USA </address> </li> <li class="aff"><a id="aff-3" name="aff-3"></a><address>3Division of Movement Disorders, The Neurological Institute of New York, Columbia University Irving Medical Center, New York, New York 10033, USA </address> </li> <li class="aff"><a id="aff-4" name="aff-4"></a><address>4Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York 10065, USA </address> </li> </ol> <ol class="corresp-list"> <li class="corresp" id="corresp-1">Correspondence: vig9070{at}med.cornell.edu</li> </ol> </div> <div class="section abstract" id="abstract-1" itemprop="description"> <div class="section-nav"> <div class="nav-placeholder"> </div><a href="#sec-1" title="Next Section" class="next-section-link">Next Section</a></div> <h2>Abstract</h2> Parkinson's disease (PD) involves both the central nervous system (CNS) and enteric nervous system (ENS), and their interaction is important for understanding both the clinical manifestations of the disease and the underlying disease pathophysiology. Although the neuroanatomical distribution of pathology strongly suggests that the ENS is involved in disease pathophysiology, there are significant gaps in knowledge about the underlying mechanisms. In this article, we review the clinical presentation and management of gastrointestinal dysfunction in PD. In addition, we discuss the current understanding of disease pathophysiology in the gut, including controversies about early involvement of the gut in disease pathogenesis. We also review current knowledge about gut α-synuclein and the microbiome, discuss experimental models of PD-linked gastrointestinal pathophysiology, and highlight areas for further research. Finally, we discuss opportunities to use the gut–brain axis for the development of biomarkers and disease-modifying treatments. </div> <div class="section" id="sec-1"> <div class="section-nav"><a href="#abstract-1" title="Abstract" class="prev-section-link">Previous Section</a><a href="#sec-2" title="GASTROINTESTINAL DYSFUNCTION IN PARKINSON'S DISEASE" class="next-section-link">Next Section</a></div> Parkinson's disease (PD) is the fastest-growing neurological disorder worldwide (<a id="xref-ref-45-1" class="xref-bibr" href="#ref-45">Dorsey et al. 2018</a>), and this growth is driven both by an increase in population age and longevity and by environmental factors. Although the disease is classically defined by its motor manifestations (bradykinesia, rigidity, rest tremor, and postural instability) due to degeneration of substantia nigra dopamine neurons, PD is now understood to involve both the central nervous system (CNS) and peripheral nervous system, including the enteric nervous system (ENS) (<a id="xref-ref-51-1" class="xref-bibr" href="#ref-51">Fasano et al. 2015</a>). The ENS controls the function of the gastrointestinal tract and is a main division of the peripheral nervous system. It is likely involved early in the disease course, before motor symptoms manifest, as gastrointestinal dysfunction can precede motor dysfunction in PD by decades (<a id="xref-ref-88-1" class="xref-bibr" href="#ref-88">Kalia and Lang 2015</a>). The gut provides a route for environmental exposure and can serve as a conduit for pathogenesis to the CNS, given the lack of a blood–ganglia barrier. This idea is further supported by the epidemiological link between PD and environmental factors, especially those related to industrialization, including pesticides, industrial solvents, and heavy metals (<a id="xref-ref-67-1" class="xref-bibr" href="#ref-67">Goldman 2014</a>). James Parkinson's first formal description of the disease in 1817 occurred during the Industrial Revolution. He highlighted early gastrointestinal symptoms—“The bowels, which had been all along torpid, now, in most cases, demand stimulating medicines of very considerable power”—and postulated that pathology in the bowels could induce pathology in the CNS—“Although unable to trace the connection by which a disordered state of the stomach and bowels may induce a morbid action in a part of the medulla spinalis … little hesitation need be employed before we determine on the probability of such occurrence” (<a id="xref-ref-123-1" class="xref-bibr" href="#ref-123">Parkinson 2002</a>). Despite this early recognition of the involvement of the ENS in PD, significant gaps remain in our understanding about the underlying mechanisms. Here, we discuss clinical manifestations, evaluation, and treatment of gastrointestinal dysfunction in PD, and review our understanding to date of the gastrointestinal pathophysiology underlying the disease, highlighting current gaps in knowledge and areas for further investigation. </div> <div class="section" id="sec-2"> <div class="section-nav"><a href="#sec-1" title="Previous Section" class="prev-section-link">Previous Section</a><a href="#sec-3" title="NEUROANATOMY OF THE ENS" class="next-section-link">Next Section</a></div> <h2 class="">GASTROINTESTINAL DYSFUNCTION IN PARKINSON'S DISEASE</h2> Gastrointestinal symptoms are among the earliest manifestations of PD and precede the onset of motor symptoms (<a id="xref-fig-1-1" class="xref-fig" href="#F1">Fig. 1</a>). Gastrointestinal motor impairments and dysautonomia are intrinsic to the underlying disease process in PD (<a id="xref-ref-51-2" class="xref-bibr" href="#ref-51">Fasano et al. 2015</a>; <a id="xref-ref-172-1" class="xref-bibr" href="#ref-172">Warnecke et al. 2022</a>). This pathophysiology also underlies treatment-related motor fluctuations (wearing off and dyskinesia) due to altered absorption of medication. We begin by reviewing the neuroanatomy of the ENS (<a id="xref-fig-2-1" class="xref-fig" href="#F2">Fig. 2</a>) to lay the foundation for understanding its interaction with the CNS and how it may be involved in disease pathogenesis. We then discuss the symptomatic manifestations of PD throughout the gastrointestinal tract and the evaluation and management of these symptoms. <div id="F1" class="fig pos-float odd"> <div class="fig-inline"><a href="a041618/F1.expansion.html"><img alt="Figure 1." src="a041618/F1.small.gif" /></a><div class="callout">View larger version:<ul class="callout-links"> <li><a href="a041618/F1.expansion.html">In this window</a></li> <li><a class="in-nw" href="a041618/F1.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/1/a041618/F1">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption">Figure 1. Systemic manifestations of prodromal, early, and established Parkinson's disease (PD). Time line and severity of nonmotor and motor manifestations of PD, and typical timing of diagnosis during the course of the disease are shown. <div class="sb-div caption-clear"></div> </div> </div> <div id="F2" class="fig pos-float odd"> <div class="fig-inline"><a href="a041618/F2.expansion.html"><img alt="Figure 2." src="a041618/F2.small.gif" /></a><div class="callout">View larger version:<ul class="callout-links"> <li><a href="a041618/F2.expansion.html">In this window</a></li> <li><a class="in-nw" href="a041618/F2.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/1/a041618/F2">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption">Figure 2. Enteric nervous system (ENS) neuroanatomy. (A) Electron micrograph of an enteric axon (Ax) varicosity containing transmitter vesicles on a myenteric nerve (N) cell with pre- and postsynaptic densities at the synapse (arrows). (B) Electron micrograph of an enteric Ax at the surface of a nerve fiber bundle facing muscle (m), juxtaposed to the processes of glial (G) cells. (C) The processes arising from a single motor neuron axon innervating the longitudinal muscle of guinea pig ileum. The neuron was filled with marker dye through an intracellular electrode placed on the cell soma. The ganglia and connected strands of the myenteric plexus are shown in gray. (D) Types of neurons in the ENS defined by their function, key transmitters, and projections to targets. Excitatory motor neurons are marked + and inhibitory motor neurons are marked −. (ACh) Acetylcholine, (IPANs) intrinsic primary afferent neurons. (E) Extrinsic fibers connecting the central nervous system (CNS) and ENS. (A–D adapted from <a id="xref-ref-58-1" class="xref-bibr" href="#ref-58">Furness 2007</a>; E is based on data from <a id="xref-ref-59-1" class="xref-bibr" href="#ref-59">Furness 2012</a>.) <div class="sb-div caption-clear"></div> </div> </div> </div> <div class="section" id="sec-3"> <div class="section-nav"><a href="#sec-2" title="GASTROINTESTINAL DYSFUNCTION IN PARKINSON'S DISEASE" class="prev-section-link">Previous Section</a><a href="#sec-9" title="GASTROINTESTINAL PATHOPHYSIOLOGY IN PARKINSON'S DISEASE" class="next-section-link">Next Section</a></div> <h2 class="">NEUROANATOMY OF THE ENS</h2> The gastrointestinal tract is innervated from the esophagus to the anus by the ENS, the largest part of the peripheral nervous system containing hundreds of millions of neurons and even more glia (<a id="xref-ref-58-2" class="xref-bibr" href="#ref-58">Furness 2007</a>). Its functions include controlling movement in the gastrointestinal tract, regulating the shift of fluid across the epithelial lining, maintaining epithelial barrier integrity, regulating local blood flow and nutrient handling, and interacting with the immune and endocrine systems. The gastrointestinal tract is a unique peripheral organ in that its extensive intrinsic nervous system can function autonomously without extrinsic input (<a id="xref-ref-11-1" class="xref-bibr" href="#ref-11">Bayliss and Starling 1899</a>), although in practice, neuronal control of gastrointestinal function is modulated by both intrinsic and extrinsic fibers. Extrinsic or CNS fibers include the vagus nerve, sympathetic fibers from the prevertebral ganglia of the thoracic spinal cord, and the lumbosacral pathways (<a id="xref-fig-2-2" class="xref-fig" href="#F2">Fig. 2</a>E; <a id="xref-ref-59-2" class="xref-bibr" href="#ref-59">Furness 2012</a>). The vagus nerve contains 50,000 fibers, the majority of which are afferent fibers. The efferent vagal fibers from the dorsal motor nucleus of the vagus (DMV) and the nucleus ambiguus provide parasympathetic motor stimuli that regulate motility. Extrinsic modulation of gastrointestinal motility is more prominent in the esophagus and stomach (<a id="xref-ref-156-1" class="xref-bibr" href="#ref-156">Travagli and Anselmi 2016</a>), whereas intrinsic circuits are dominant in the small and large intestines and consist of autonomous reflex circuits (<a id="xref-ref-61-1" class="xref-bibr" href="#ref-61">Furness et al. 2014</a>). The intrinsic enteric neurons and glia cluster into interconnected ganglia (<a id="xref-fig-2-3" class="xref-fig" href="#F2">Fig. 2</a>C) in two autonomically distinct regions, the myenteric (Auerbach's) plexus, which resides between the outer longitudinal and circular muscle layers, and the submucosal (Meissner's) plexus (<a id="xref-fig-2-4" class="xref-fig" href="#F2">Fig. 2</a>D). The enteric ganglia are tightly packed, and ultrastructural imaging has shown that neurons within the myenteric and submucosal plexuses receive synaptic inputs showing typical presynaptic vesicles and postsynaptic densities (<a id="xref-fig-2-5" class="xref-fig" href="#F2">Fig. 2</a>A,B; <a id="xref-ref-35-1" class="xref-bibr" href="#ref-35">Cook and Burnstock 1976</a>). Enteric neurons have been classified by their morphology and physiological properties, their innervation, the transmitters they use, and, more recently, by transcriptomic profiling. Types of neurons include (1) motor neurons, including secretomotor and vasomotor neurons, (2) intrinsic primary afferent neurons (IPANs), also referred to as intrinsic sensory neurons, (3) interneurons, and (4) intestinofugal neurons (<a id="xref-fig-3-1" class="xref-fig" href="#F3">Fig. 3</a>D; <a id="xref-ref-58-3" class="xref-bibr" href="#ref-58">Furness 2007</a>). The primary transmitters for excitatory motor neurons, which innervate the muscular layers, are acetylcholine and tachykinins, whereas inhibitory motor neurons release multiple transmitters including nitric oxide (NO), vasoactive intestinal polypeptide (VIP), ATP, and pituitary adenylate-cyclase-activating polypeptide (PACAP). Secretomotor and vasomotor neurons control fluid exchange. Types of secretomotor and vasomotor neurons include VIP-ergic neurons, calretinin-containing cholinergic neurons, and neuropeptide Y (NPY)-containing cholinergic neurons (<a id="xref-ref-60-1" class="xref-bibr" href="#ref-60">Furness et al. 2003</a>). There are also motor neurons that innervate enteric endocrine cells and immune tissue, including lymphoid tissue, such as Peyer's patches, lymphocytes, and mast cells (<a id="xref-ref-58-4" class="xref-bibr" href="#ref-58">Furness 2007</a>). The IPANs respond to distension and mechanical stimulation from luminal contents to control movement, blood flow, and secretion. They contain the neurotransmitters acetylcholine, calcitonin gene-related peptide (CGRP), and tachykinin (<a id="xref-ref-140-1" class="xref-bibr" href="#ref-140">Schneider et al. 2022</a>). Interneurons include cholinergic interneurons containing NO synthase (NOS) and serotonin (5-HT) that mediate local motility reflexes, and cholinergic interneurons containing somatostatin that mediate migrating motor complexes, recurring cyclical patterns of motility that occur during fasting, a key feature of intrinsic ENS neural activity. There are also small populations of VIP and NOS-containing interneurons (<a id="xref-ref-58-5" class="xref-bibr" href="#ref-58">Furness 2007</a>). Finally, there is a small population of intestinofugal afferent fibers to the sympathetic ganglia that contain acetylcholine and VIP. <div id="F3" class="fig pos-float odd"> <div class="fig-inline"><a href="a041618/F3.expansion.html"><img alt="Figure 3." src="a041618/F3.small.gif" /></a><div class="callout">View larger version:<ul class="callout-links"> <li><a href="a041618/F3.expansion.html">In this window</a></li> <li><a class="in-nw" href="a041618/F3.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/1/a041618/F3">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption">Figure 3. Nonmotor symptoms and management of gastrointestinal symptoms. Depiction of organ systems involved in nonmotor manifestations and current management strategy for gastrointestinal symptoms. <div class="sb-div caption-clear"></div> </div> </div> In summary, the ENS contains hundreds of millions of neurons comprised mostly of a unique intrinsic nervous system capable of autonomous function, in addition to a smaller number of extrinsic fibers that connect it to the CNS. Classes of enteric neurons are classically defined by their morphology, location, and neurotransmitters, and include motor neurons, IPANs, interneurons, and intestinofugal neurons. Although ultrastructural imaging has suggested that enteric neurons form synapses similar to those seen in the brain, synaptic morphology and function in the ENS have not been systematically investigated. More recent technical advances have suggested a greater neuronal diversity than currently described. Transcriptomic profiling of enteric neurons at the single-cell level has revealed dozens of types of neurons, with numbers differing between regions (<a id="xref-ref-46-1" class="xref-bibr" href="#ref-46">Drokhlyansky et al. 2020</a>), allowing for further future functional dissection of ENS physiology. A better understanding of ENS physiology is critical for dissecting the pathophysiology of PD given its early role in the disease process. <div id="sec-4" class="subsection"> <h3>Dysphagia</h3> Swallowing involves the neuromuscular coordination of oral, pharyngeal, and esophageal phases. The causes of dysphagia, or difficulty swallowing, are multifactorial in PD. The common complaint of sialorrhea is due to both swallowing difficulties and difficulties maintaining saliva in the oral cavity. The excess saliva and associated drooling are not due to increased secretion, but the inability to handle normal secretory volumes in the mouth (<a id="xref-ref-135-1" class="xref-bibr" href="#ref-135">Proulx et al. 2005</a>). This is affected by characteristic slowed facial movements and reduction of facial expression, or hypomimia, unintentional mouth opening, and disease-related changes in head and neck posture. Sialorrhea is associated with an increased risk of aspiration (<a id="xref-ref-119-1" class="xref-bibr" href="#ref-119">Nóbrega et al. 2008b</a>) and respiratory infections (<a id="xref-ref-118-1" class="xref-bibr" href="#ref-118">Nóbrega et al. 2008a</a>), which are further associated with significantly increased mortality (<a id="xref-ref-175-1" class="xref-bibr" href="#ref-175">Won et al. 2021</a>). Objective testing of swallowing demonstrates dysphagia in >80% of patients (<a id="xref-ref-87-1" class="xref-bibr" href="#ref-87">Kalf et al. 2012</a>), occurring early in the course of the disease (<a id="xref-ref-130-1" class="xref-bibr" href="#ref-130">Pflug et al. 2018</a>). The sensory innervation of the pharynx includes sensory branches of the glossopharyngeal nerve (cranial nerve IX) and vagus nerve (cranial nerve X). These sensory branches are crucial for triggering swallowing and upper airway protective reflexes, and they demonstrate Lewy pathology postmortem (<a id="xref-ref-112-1" class="xref-bibr" href="#ref-112">Mu et al. 2013</a>). Many patients may be unaware of symptoms, possibly because of local somatosensory deficits, as there are higher sensory detection thresholds and increased oropharyngeal residue on endoscopic evaluation without a difference in self-reported swallow function in PD compared to control (<a id="xref-ref-74-1" class="xref-bibr" href="#ref-74">Hammer et al. 2013</a>). Peripheral mechanisms involving the pharyngeal nerves (<a id="xref-ref-111-1" class="xref-bibr" href="#ref-111">Mu et al. 2012</a>), including reduction of the neuropeptide substance P (<a id="xref-ref-141-1" class="xref-bibr" href="#ref-141">Shröder et al. 2019</a>), may also contribute. As the disease progresses, swallowing is also affected by higher cortical areas through the involvement of the supplementary motor areas and anterior cingulate cortex (<a id="xref-ref-91-1" class="xref-bibr" href="#ref-91">Kikuchi et al. 2013</a>). The gold standard for workup of dysphagia is videofluoroscopy or flexible endoscopic evaluation of swallowing (FEES) (<a id="xref-ref-100-1" class="xref-bibr" href="#ref-100">Langmore 2003</a>). Esophageal manometry and barium swallow are also used (<a id="xref-fig-3-2" class="xref-fig" href="#F3">Fig. 3</a>). Treatment of sialorrhea includes behavioral and pharmacologic interventions. Targeted local treatments include botulinum toxin, which decreases saliva production when injected into the parotid or submandibular glands (<a id="xref-ref-85-1" class="xref-bibr" href="#ref-85">Jost et al. 2019</a>), and local anticholinergics, such as sublingual atropine (<a id="xref-ref-82-1" class="xref-bibr" href="#ref-82">Hyson et al. 2002</a>) and ipratropium bromide (<a id="xref-ref-155-1" class="xref-bibr" href="#ref-155">Thomsen et al. 2007</a>). Systemic pharmacologic treatments include anticholinergics like glycopyrrolate (<a id="xref-ref-9-1" class="xref-bibr" href="#ref-9">Arbouw et al. 2010</a>) and the α-2 adrenergic agonist clonidine (<a id="xref-ref-142-1" class="xref-bibr" href="#ref-142">Serrano-Duenas 2003</a>). Levodopa and other dopaminergic medications also improve some aspects of swallowing (<a id="xref-ref-33-1" class="xref-bibr" href="#ref-33">Chang et al. 2021</a>). Behavioral interventions are commonly recommended, including head positioning and deliberate swallowing by use of gum or hard candies. Evidence-based behavioral management of swallowing includes expiratory muscle strength training and video-assisted swallowing therapy (<a id="xref-fig-3-3" class="xref-fig" href="#F3">Fig. 3</a>; <a id="xref-ref-158-1" class="xref-bibr" href="#ref-158">Troche et al. 2010</a>; <a id="xref-ref-106-1" class="xref-bibr" href="#ref-106">Manor et al. 2013</a>; <a id="xref-ref-10-1" class="xref-bibr" href="#ref-10">Athukorala et al. 2014</a>; <a id="xref-ref-34-1" class="xref-bibr" href="#ref-34">Claus et al. 2021</a>). </div> <div id="sec-5" class="subsection"> <h3>Gastroparesis</h3> The majority of patients with PD have impaired gastric emptying, which can be present at any point in the disease, although not all affected patients present with symptoms (<a id="xref-ref-107-1" class="xref-bibr" href="#ref-107">Marrinan et al. 2014</a>). Gastroparesis also affects treatment: It delays levodopa absorption in the small intestine, and, further, levodopa itself may delay gastric emptying (<a id="xref-ref-75-1" class="xref-bibr" href="#ref-75">Hardoff et al. 2001</a>; <a id="xref-ref-129-1" class="xref-bibr" href="#ref-129">Pfeiffer et al. 2020</a>). How levodopa plasma levels and efficacy are affected has not been studied in detail. Associated symptoms include nausea, vomiting, early satiety, and abdominal distention, and further workup should be considered in symptomatic patients and to rule out obstruction or gall bladder disease. Gastroparesis can contribute to malnutrition and weight loss seen frequently in PD. Diagnosis of gastroparesis is made using a quantitative technetium-99 labeled gastric emptying study (<a id="xref-ref-28-1" class="xref-bibr" href="#ref-28">Camilleri and Shin 2013</a>) or capsule endoscopy (<a id="xref-fig-3-4" class="xref-fig" href="#F3">Fig. 3</a>). Gastroparesis is classified according to gastric retention at 4 h, and includes mild (10%–15%), moderate (15%–35%), and severe (>35%), with severity guiding treatment. The first-line therapy for gastroparesis, metoclopramide, a dopamine antagonist, is contraindicated in PD because of its extrapyramidal side effects. However, imaging is useful to guide the use of another dopamine antagonist, domperidone, which does not cross the blood–brain barrier. Although domperidone is not readily available in the United States, it can be prescribed to patients through a Food and Drug Administration (FDA) Investigational New Drug application. Domperidone can also increase the risk of cardiac arrhythmias. Other treatment choices include macrolide antibiotics (<a id="xref-fig-3-5" class="xref-fig" href="#F3">Fig. 3</a>), including erythromycin, and motilin agonists, although their use is limited to 4 weeks at a time because of tachyphylaxis, reduced responsiveness with repeated use. Serotonin 5-HT4 receptor agonists can be used chronically, stimulate motility, and accelerate gastric emptying, although there are currently only investigational formulations available in the United States. Ghrelin agonists have shown promise in diabetic gastroparesis (<a id="xref-ref-146-1" class="xref-bibr" href="#ref-146">Shin and Wo 2015</a>). Botulinum toxin injection into the pyloric sphincter (<a id="xref-ref-66-1" class="xref-bibr" href="#ref-66">Gil et al. 2011</a>) and subthalamic nucleus deep brain stimulation (<a id="xref-ref-8-1" class="xref-bibr" href="#ref-8">Arai et al. 2012</a>) have also been proposed to provide benefits for gastroparesis. Other therapies for gastroparesis include surgical pyloroplasty, gastric peroral endoscopic myotomy (G-POEM), gastric drainage and jejunal feeding tube placement, or gastric electrical stimulation or gastric bypass or resection, but these have not been well-studied in PD. </div> <div id="sec-6" class="subsection"> <h3>Constipation</h3> Constipation is the most common gastrointestinal symptom in PD. It occurs in up to 80% of patients (<a id="xref-ref-93-1" class="xref-bibr" href="#ref-93">Knudsen et al. 2017</a>) and is part of the disease prodrome, emerging before the onset of motor symptoms. It is also one of the earliest autonomic features of the disease, developing up to 15 years before the onset of motor symptoms, and the risk of developing PD increases with constipation severity (<a id="xref-ref-103-1" class="xref-bibr" href="#ref-103">Lin et al. 2014</a>). Neurodegeneration may be involved, as reduced myenteric neuron numbers can be present in patients with severe, chronic constipation (<a id="xref-ref-173-1" class="xref-bibr" href="#ref-173">Wedel et al. 2002</a>), although neuron loss is not necessarily observed in PD (<a id="xref-ref-6-1" class="xref-bibr" href="#ref-6">Annerino et al. 2012</a>). Constipation can be further worsened by drugs used to treat motor symptoms, including anticholinergics and dopamine agonists. Workup should distinguish between disordered evacuation, or dyssynergic dysfunction, and a colonic transit abnormality. Although not validated in patients with PD specifically, this includes anorectal manometry, balloon expulsion test, and barium or magnetic resonance imaging (MRI) defecography for outlet dysfunction, and a radio-opaque markers study, scintigraphy, or capsule endoscopy for transit dysfunction (<a id="xref-fig-3-6" class="xref-fig" href="#F3">Fig. 3</a>; <a id="xref-ref-51-3" class="xref-bibr" href="#ref-51">Fasano et al. 2015</a>). Treatment for outlet dysfunction includes biofeedback and botulinum neurotoxin injection to the anal sphincter. Treatment for transit dysfunction includes an increase in dietary fiber, osmotic and stimulant laxatives, prokinetic drugs, and secretagogues (<a id="xref-fig-3-7" class="xref-fig" href="#F3">Fig. 3</a>; <a id="xref-ref-51-4" class="xref-bibr" href="#ref-51">Fasano et al. 2015</a>). </div> <div id="sec-7" class="subsection"> <h3>Systemic Manifestations and Treatment Considerations</h3> Malnutrition and weight loss occur in PD due to dysphagia, levodopa-induced nausea, and disruption of regular meals to limit interference with levodopa absorption. Endocrine mechanisms also contribute. Ghrelin, which is secreted in physiological conditions when the stomach is empty to increase motility in preparation for a meal, is reduced in PD (<a id="xref-ref-148-1" class="xref-bibr" href="#ref-148">Song et al. 2017</a>). Other nonmotor symptoms, including depression, apathy, and olfactory loss, can also contribute. On the other hand, weight gain can also occur and is associated with treatment with dopamine agonists (<a id="xref-ref-114-1" class="xref-bibr" href="#ref-114">Nirenberg and Waters 2006</a>) and deep brain stimulation in the subthalamic nucleus (<a id="xref-ref-139-1" class="xref-bibr" href="#ref-139">Sauleau et al. 2014</a>), both thought to be related to modulation of limbic mechanisms. Because of gastrointestinal dysfunction, treatment options that partially or wholly bypass the gastrointestinal tract have been explored. These include liquid levodopa or orally dissolving formulations, although these still require absorption in the proximal small intestine. Parenteral routes include dopamine agonist patch, apomorphine subcutaneous infusion, intranasal levodopa, and percutaneous endoscopic gastrostomy with a jejunal tube for intrajejunal levodopa infusion. Novel formulations include microspheres for drug delivery, microenemas, and esters or alkyl esters that can be administered by transdermal, intranasal, subcutaneous, and intramuscular routes (<a id="xref-ref-51-5" class="xref-bibr" href="#ref-51">Fasano et al. 2015</a>). </div> <div id="sec-8" class="subsection"> <h3>Summary</h3> In summary, symptoms of gastrointestinal dysfunction in PD can occur anywhere along the gastrointestinal tract, from mouth to anus. Symptoms are caused by dysfunctional motility due to both central and peripheral nervous system impairment, autonomic dysfunction, and endocrine dysfunction. Symptoms both affect and are affected by treatment. Constipation is the most common complaint and occurs early in the disease process. Although symptomatic treatment is available, there are no PD-specific treatments for gastrointestinal dysfunction. Development of disease-specific treatments requires a better understanding of the underlying disease pathophysiology within the gut. </div> </div> <div class="section" id="sec-9"> <div class="section-nav"><a href="#sec-3" title="NEUROANATOMY OF THE ENS" class="prev-section-link">Previous Section</a><a href="#sec-15" title="α-SYNUCLEIN IN THE ENTERIC NERVOUS SYSTEM" class="next-section-link">Next Section</a></div> <h2 class="">GASTROINTESTINAL PATHOPHYSIOLOGY IN PARKINSON'S DISEASE</h2> In addition to symptomatic manifestations throughout the gastrointestinal tract, typical neuropathological changes are also seen in the ENS, suggesting that pathophysiological changes in the gut are a critical part of the disease process. We first discuss hypotheses about where the initial pathophysiological changes leading to PD occur and conclude with a discussion on the potential role of ENS neurodegeneration. <div id="sec-10" class="subsection"> <h3>Braak Hypothesis</h3> <a id="xref-ref-20-1" class="xref-bibr" href="#ref-20">Braak et al. (2003b</a>) postulated that the disease mechanism underlying PD is the neuroinvasion of routes containing vulnerable neurons. This was in part based on the finding that pathology occurs in specific brain regions, notably the dopaminergic neurons of the substantia nigra (<a id="xref-ref-52-1" class="xref-bibr" href="#ref-52">Fearnley and Lees 1991</a>; <a id="xref-ref-73-1" class="xref-bibr" href="#ref-73">Halliday et al. 1996</a>) and the DMV (<a id="xref-fig-4-1" class="xref-fig" href="#F4">Fig. 4</a>). The vagus nerve connects the ENS and CNS, with initial pathology occurring in the brain in the DMV and then advancing upward to the medulla, pontine tegmentum, midbrain, basal forebrain, and cerebral cortex. “Incidental cases of idiopathic Parkinson's disease may show involvement of both the enteric nervous system and the dorsal motor nucleus of the vagus nerve,” and the hypothesis implies a gastrointestinal origin, prompting “the question whether the disorder might originate outside of the central nervous system … via postganglionic enteric neurons, entering the central nervous system along unmyelinated preganglionic fibers generated from the visceromotor projection cells of the vagus nerve” (<a id="xref-ref-20-2" class="xref-bibr" href="#ref-20">Braak et al. 2003b</a>). Indeed, Lewy bodies, the pathological hallmark of PD, composed primarily of α-synuclein (<a id="xref-ref-149-1" class="xref-bibr" href="#ref-149">Spillantini et al. 1997</a>), are found in both the brain and the ENS. <div id="F4" class="fig pos-float odd"> <div class="fig-inline"><a href="a041618/F4.expansion.html"><img alt="Figure 4." src="a041618/F4.small.gif" /></a><div class="callout">View larger version:<ul class="callout-links"> <li><a href="a041618/F4.expansion.html">In this window</a></li> <li><a class="in-nw" href="a041618/F4.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/1/a041618/F4">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption">Figure 4. Hypotheses concerning pathological origins and spread of Parkinson's disease (PD). Proposed pathological origins of PD in the olfactory and gastrointestinal system. Sites of hypothesized pathological initiation are in red. (SN) Substantia nigra, (LC) locus coeruleus, (DMV) dorsal motor nucleus of the vagus, (OB) olfactory bulb, (ENS) enteric nervous system. <div class="sb-div caption-clear"></div> </div> </div> Consistent with a gastrointestinal origin of pathology, gastrointestinal symptoms (especially constipation) are a prominent prodromal feature of PD (<a id="xref-fig-1-2" class="xref-fig" href="#F1">Fig. 1</a>; <a id="xref-ref-1-1" class="xref-bibr" href="#ref-1">Adams-Carr et al. 2016</a>). The vagal nuclei in the brainstem include the nucleus ambiguus, which innervates the palate, pharynx, larynx, and heart; the nucleus of the solitary tract, which contains afferent innervations from the viscera; and the dorsal motor nucleus, which innervates the postganglionic parasympathetic to the transverse colon. Of these, only the DMV is severely affected in early PD (<a id="xref-ref-42-1" class="xref-bibr" href="#ref-42">Del Tredici et al. 2002</a>). Lewy pathology in the ENS has been identified in both presymptomatic and clinically confirmed cases of PD (<a id="xref-ref-22-1" class="xref-bibr" href="#ref-22">Braak et al. 2006</a>), from where spread could occur to the preganglionic parasympathetic neurons of the DMV. Supporting the concept that α-synuclein pathology can spread from neuron to neuron, α-synuclein inclusions were seen in a small subset of striatal engrafted neurons in PD patients who had undergone a neuronal transplant a decade earlier (<a id="xref-ref-95-1" class="xref-bibr" href="#ref-95">Kordower et al. 2008</a>; <a id="xref-ref-102-1" class="xref-bibr" href="#ref-102">Li et al. 2008</a>). The pattern of progression of neuropathology and neurodegeneration in the brain led <a id="xref-ref-19-1" class="xref-bibr" href="#ref-19">Braak et al. (2003a</a>) to develop a neuropathological staging system for PD, with later stages corresponding to the clinical progression of the disease. </div> <div id="sec-11" class="subsection"> <h3>Dual-Hit Hypothesis</h3> To reconcile the presence of early pathology in both the olfactory bulb and the DMV, a dual-hit hypothesis was subsequently proposed, with pathology proposed to progress retrogradely from both the nasal and gastrointestinal epithelium to the brain (<a id="xref-ref-76-1" class="xref-bibr" href="#ref-76">Hawkes et al. 2007</a>). Olfactory dysfunction is an early feature of idiopathic PD (<a id="xref-fig-1-3" class="xref-fig" href="#F1">Fig. 1</a>) and can be used to distinguish between PD and other parkinsonism (<a id="xref-ref-57-1" class="xref-bibr" href="#ref-57">Fullard et al. 2017</a>). In olfactory areas, Lewy bodies are most numerous in the anterior olfactory nucleus and are also found in mitral cells, the first projection neurons to receive input from olfactory epithelial bipolar neurons (<a id="xref-ref-39-1" class="xref-bibr" href="#ref-39">Daniel and Hawkes 1992</a>; <a id="xref-ref-19-2" class="xref-bibr" href="#ref-19">Braak et al. 2003a</a>). Further, the extent of neuronal loss in the anterior olfactory nucleus correlated with disease duration (<a id="xref-ref-125-1" class="xref-bibr" href="#ref-125">Pearce et al. 1995</a>). From there, additional olfactory areas are affected, including the olfactory tubercle, the pyriform and periamygdalar cortex, and the entorhinal cortex (<a id="xref-ref-20-3" class="xref-bibr" href="#ref-20">Braak et al. 2003b</a>). </div> <div id="sec-12" class="subsection"> <h3>Body-First versus Brain-First Hypothesis</h3> A subsequent detailed pathological study suggested a revision to the dual-hit hypothesis and proposed that the pathological process starts in a single location. Across a number of neuropathological studies, the most frequent single-location-affected areas with incidental findings of Lewy bodies are the olfactory bulb, the DMV, and the sympathetics (<a id="xref-ref-14-1" class="xref-bibr" href="#ref-14">Borghammer 2021</a>). Triggered by environmental factors such as infection, inflammation, or toxic exposure to the nasal or enteric epithelium, pathology would most commonly initiate in the olfactory bulb or ENS, but rarely in both simultaneously (<a id="xref-ref-14-2" class="xref-bibr" href="#ref-14">Borghammer 2021</a>; <a id="xref-ref-16-1" class="xref-bibr" href="#ref-16">Borghammer et al. 2022</a>). Accordingly, a brain-first or body-first clinical phenotype corresponding to this pathology was proposed. In the brain-first subtype, pathology is postulated to spread from the olfactory bulb to the amygdala or vice versa, and then mono-synaptically from the amygdala to the substantia nigra pars compacta (SNpc) (<a id="xref-ref-134-1" class="xref-bibr" href="#ref-134">Poulin et al. 2018</a>), or from the olfactory bulb to the SNpc (<a id="xref-ref-79-1" class="xref-bibr" href="#ref-79">Höglinger et al. 2015</a>), with asymmetric dopamine loss at presentation. In these patients, characteristic nonmotor symptoms including constipation and REM sleep behavior disorder (RBD) would appear after the onset of parkinsonism. Another subtype of the brain-first subtype would include original symmetric pathology in the SNpc or locus coeruleus, in which RBD and parkinsonism would appear coincidentally. In the body-first subtype, pathology is proposed to propagate from the ENS to the vagus to the DMV, and via the sympathetics to the celiac or mesenteric ganglia to the sympathetic trunk to the heart. This would be commensurate with the appearance of autonomic symptoms including constipation and orthostatic hypotension before the onset of RBD or parkinsonism and is supported by evidence of prodromal cardiac denervation by 123I-MIBG scintigraphy (<a id="xref-ref-109-1" class="xref-bibr" href="#ref-109">Miyamoto et al. 2006</a>; <a id="xref-ref-90-1" class="xref-bibr" href="#ref-90">Kashihara et al. 2010</a>; <a id="xref-ref-94-1" class="xref-bibr" href="#ref-94">Knudsen et al. 2018</a>; <a id="xref-ref-115-1" class="xref-bibr" href="#ref-115">Nishikawa et al. 2022</a>), cardiac noradrenergic deficiency by 18F-dopamine positron emission tomography (<a id="xref-ref-68-1" class="xref-bibr" href="#ref-68">Goldstein et al. 2024</a>), and increased colonic transit time (<a id="xref-ref-53-1" class="xref-bibr" href="#ref-53">Fedorova et al. 2022</a>). This symmetry of dopamine loss proposed is supported by the lateralization of the nervous system. Ipsilateral connections outnumber contralateral connections in the brain, whereas there is more substantial right-life overlap in the innervation of the ENS (<a id="xref-ref-15-1" class="xref-bibr" href="#ref-15">Borghammer 2023</a>). One caveat is that hyposmia is more common in the body-first subtype, but the degree of hyposmia may not correlate with disease burden in the olfactory bulb, but rather in the total CNS (<a id="xref-ref-113-1" class="xref-bibr" href="#ref-113">Nag et al. 2019</a>; <a id="xref-ref-157-1" class="xref-bibr" href="#ref-157">Tremblay et al. 2022</a>). </div> <div id="sec-13" class="subsection"> <h3>Summary</h3> In summary, various hypotheses have proposed pathological origins of PD in the olfactory and/or gastrointestinal system (<a id="xref-fig-4-2" class="xref-fig" href="#F4">Fig. 4</a>), with supportive evidence from neuropathology and clinical subtypes. The brain-first clinical phenotype, associated with pathology originating in the olfactory system, is postulated to be characterized by few prodromal symptoms and asymmetric dopamine loss at presentation, whereas a body-first clinical phenotype, associated with pathology originating in the ENS, is postulated to be characterized by prodromal autonomic symptoms, RBD, and more symmetric dopamine loss at presentation. </div> <div id="sec-14" class="subsection"> <h3>Neurodegeneration in the ENS</h3> Loss of dopaminergic neurons in the substantia nigra leads to the cardinal motor symptoms of PD in the brain, and data from patients as well as animal models suggest that PD affects distinct subsets of neurons in the ENS, although further work is needed to determine which enteric neurons are most affected. Although VIP-ergic neurons were originally identified as the major cell type harboring LBs in PD (<a id="xref-ref-169-1" class="xref-bibr" href="#ref-169">Wakabayashi et al. 1990</a>), this finding was not reproduced in a later study (<a id="xref-ref-6-2" class="xref-bibr" href="#ref-6">Annerino et al. 2012</a>). It remains unclear whether PD targets a specific site or neuronal subtype in the ENS the way it targets the substantia nigra dopaminergic neurons in the CNS, and, further, many aspects of enteric neuronal organization remain unknown. Conflicting data also exist regarding potential enteric neuron degeneration in PD. At least two studies have found enteric ganglion cell degeneration (<a id="xref-ref-136-1" class="xref-bibr" href="#ref-136">Qualman et al. 1984</a>; <a id="xref-ref-121-1" class="xref-bibr" href="#ref-121">Ohlsson and Englund 2019</a>), mainly in Auerbach's plexus but also in Meissner's plexus (<a id="xref-ref-13-1" class="xref-bibr" href="#ref-13">Bloch et al. 2006</a>). Atrophic or pyknotic neurons were found both in the myenteric and submucosal plexuses in the jejunum and colon from some PD patients, and degenerative alterations were accompanied by α-synuclein deposits, which were also present in some preserved neurons (<a id="xref-ref-121-2" class="xref-bibr" href="#ref-121">Ohlsson and Englund 2019</a>). However, several others have reported no evidence of neuronal cell loss in the ENS (<a id="xref-ref-167-1" class="xref-bibr" href="#ref-167">Wakabayashi et al. 1988</a>, <a id="xref-ref-169-2" class="xref-bibr" href="#ref-169">1990</a>; <a id="xref-ref-6-3" class="xref-bibr" href="#ref-6">Annerino et al. 2012</a>; <a id="xref-ref-36-1" class="xref-bibr" href="#ref-36">Corbillé et al. 2014</a>; <a id="xref-ref-128-1" class="xref-bibr" href="#ref-128">Pfeiffer 2014</a>). Neurodegeneration may also occur during aging, with loss of neurons in both the submucosal and myenteric plexus, with selective vulnerability of cholinergic and intrinsic sensory neurons (<a id="xref-ref-166-1" class="xref-bibr" href="#ref-166">Wade and Cowen 2004</a>). Overall, it remains to be determined whether there is neuron loss of enteric neurons and which cell types contain Lewy pathology. </div> </div> <div class="section" id="sec-15"> <div class="section-nav"><a href="#sec-9" title="GASTROINTESTINAL PATHOPHYSIOLOGY IN PARKINSON'S DISEASE" class="prev-section-link">Previous Section</a><a href="#sec-19" title="GUT MICROBIOME" class="next-section-link">Next Section</a></div> <h2 class="">α-SYNUCLEIN IN THE ENTERIC NERVOUS SYSTEM</h2> α-Synuclein is a key protein involved in PD pathology. Therefore, it is not surprising that of the various proteins implicated in PD pathology, α-synuclein has been explored most thoroughly in the ENS, although many open questions about its localization and function remain. Here, we review what is known about the physiological and pathological functions of ENS α-synuclein. <div id="sec-16" class="subsection"> <h3>Physiological Functions of ENS α-Synuclein</h3> In the brain, α-synuclein is found in presynaptic terminals and plays critical physiological roles, including SNARE complex assembly and synaptic vesicle clustering (<a id="xref-ref-83-1" class="xref-bibr" href="#ref-83">Iwai et al. 1995</a>; <a id="xref-ref-69-1" class="xref-bibr" href="#ref-69">Gosavi et al. 2002</a>; <a id="xref-ref-3-1" class="xref-bibr" href="#ref-3">Ahn et al. 2006</a>; <a id="xref-ref-24-1" class="xref-bibr" href="#ref-24">Burré et al. 2010</a>; <a id="xref-ref-162-1" class="xref-bibr" href="#ref-162">Varkey et al. 2010</a>; <a id="xref-ref-44-1" class="xref-bibr" href="#ref-44">Diao et al. 2013</a>; <a id="xref-ref-174-1" class="xref-bibr" href="#ref-174">Westphal and Chandra 2013</a>). α-Synuclein adopts various conformations, from an α-helical state on synaptic vesicles, to a largely disordered state in the cytosol (<a id="xref-ref-27-1" class="xref-bibr" href="#ref-27">Bussell et al. 2005</a>; <a id="xref-ref-25-1" class="xref-bibr" href="#ref-25">Burré et al. 2013</a>), to deposits of β-sheet-rich aggregates forming the major components of Lewy bodies (<a id="xref-ref-48-1" class="xref-bibr" href="#ref-48">El-Agnaf et al. 1998</a>; <a id="xref-ref-26-1" class="xref-bibr" href="#ref-26">Burré et al. 2015</a>). Membrane-binding of α-synuclein defines its physiological and pathological roles. Membrane-bound α-helical α-synuclein is protected from aggregation, whereas cytosolic, natively unstructured α-synuclein has a propensity to misfold and aggregate (<a id="xref-ref-26-2" class="xref-bibr" href="#ref-26">Burré et al. 2015</a>). Further, most mutations in α-synuclein associated with disease entities are found in the lipid-binding region of the protein (<a id="xref-ref-84-1" class="xref-bibr" href="#ref-84">Jo et al. 2002</a>; <a id="xref-ref-50-1" class="xref-bibr" href="#ref-50">Fares et al. 2014</a>; <a id="xref-ref-64-1" class="xref-bibr" href="#ref-64">Ghosh et al. 2014</a>; <a id="xref-ref-110-1" class="xref-bibr" href="#ref-110">Mohite et al. 2018</a>). Like in the brain, α-synuclein is abundantly expressed in the human ENS in physiological, nonpathological conditions (<a id="xref-ref-17-1" class="xref-bibr" href="#ref-17">Böttner et al. 2012</a>). However, the localization and function of α-synuclein in the ENS, and whether it plays a critical synaptic role as in the brain, remains largely unknown. The expression of α-synuclein throughout the length of the intestinal tract and in the different layers of the intestinal wall has not been systematically examined, although studies suggest that there are regional differences to be elucidated. In rats, expression of α-synuclein in the myenteric plexus showed a rostral–caudal increase from the stomach to the small intestine (<a id="xref-ref-131-1" class="xref-bibr" href="#ref-131">Phillips et al. 2008</a>), contrary to the rostral–caudal decrease seen in pathological conditions. There was also a regional difference with more α-synuclein colocalization with NOS more proximally in the stomach, and cholinergic neurons more distally. In the human appendix and nonhuman primate cecum, α-synuclein was expressed through the mucosa, submucosal plexus, and myenteric plexus (<a id="xref-ref-181-1" class="xref-bibr" href="#ref-181">Zinnen et al. 2022</a>), and in the human appendix, α-synuclein was particularly enriched in axonal varicosities in the mucosal plexus (<a id="xref-ref-70-1" class="xref-bibr" href="#ref-70">Gray et al. 2014</a>). In human colon samples, α-synuclein was abundantly expressed in neuronal cell bodies and processes throughout the intestinal wall, although most abundantly in the longitudinal and circular muscle and in the submucosa (<a id="xref-ref-17-2" class="xref-bibr" href="#ref-17">Böttner et al. 2012</a>). Concerning cell type, a few studies have suggested that α-synuclein is most highly expressed in cholinergic nerve terminals in the small and large intestines. In guinea pig ileum, α-synuclein colocalization was primarily seen with the majority of vesicular acetylcholine transporter (vAChT) varicosities, also colocalized with varicosities containing 5-HT, calretinin, NOS, TH, and VIP, and rarely colocalized with varicosities containing calbindin, CGRP, somatostatin, and substance P (<a id="xref-ref-145-1" class="xref-bibr" href="#ref-145">Sharrad et al. 2013b</a>). As was seen in the ileum, α-synuclein colocalization in guinea pig rectum was again seen in the majority of vAChT varicosities, which was confirmed in the human colon as well (<a id="xref-fig-5-1" class="xref-fig" href="#F5">Fig. 5</a>, left; <a id="xref-ref-144-1" class="xref-bibr" href="#ref-144">Sharrad et al. 2013a</a>). In the mouse colon, α-synuclein was primarily expressed in cholinergic varicosities (<a id="xref-ref-152-1" class="xref-bibr" href="#ref-152">Swaminathan et al. 2019</a>). <div id="F5" class="fig pos-float odd"> <div class="fig-inline"><a href="a041618/F5.expansion.html"><img alt="Figure 5." src="a041618/F5.small.gif" /></a><div class="callout">View larger version:<ul class="callout-links"> <li><a href="a041618/F5.expansion.html">In this window</a></li> <li><a class="in-nw" href="a041618/F5.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/1/a041618/F5">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption">Figure 5. α-Synuclein (α-Syn) physiology and pathology. (Left) α-Syn physiology. Stomach: α-Syn immunoreactivity in the mucosa of the gastric corpus in a control human subject. (Reprinted, with permission, from <a id="xref-ref-70-2" class="xref-bibr" href="#ref-70">Gray et al. 2014</a>.) Small intestine: α-Syn immunoreactivity in the terminal ileum in a control human subject and α-Syn immunofluorescence (green) in the normal human jejunum myenteric ganglia (white arrows). (Left, reprinted, with permission, from <a id="xref-ref-70-3" class="xref-bibr" href="#ref-70">Gray et al. 2014</a>; right, reprinted, with permission, from <a id="xref-ref-29-1" class="xref-bibr" href="#ref-29">Casini et al. 2021</a>, under the terms of the Creative Commons Attribution NonCommercial 4.0 License [CC BYNC 4.0].) Appendix: α-Syn immunoreactivity in the myenteric ganglia and mucosal plexus of the vermiform appendix in a control human subject. (Left, reprinted, with permission, from <a id="xref-ref-181-2" class="xref-bibr" href="#ref-181">Zinnen et al. 2022</a>, under the terms of the Creative Commons Attribution License; right, reprinted, with permission, from <a id="xref-ref-70-4" class="xref-bibr" href="#ref-70">Gray et al. 2014</a>.) Large intestine: α-Syn immunoreactivity in the ascending colon (left top, reprinted, with permission, from <a id="xref-ref-70-5" class="xref-bibr" href="#ref-70">Gray et al. 2014</a>), colonic myenteric plexus (left middle), and colonic submucosal plexus (left bottom, reprinted, with permission, from <a id="xref-ref-17-3" class="xref-bibr" href="#ref-17">Böttner et al. 2012</a>) from control human subjects. Colocalization of vesicular acetylcholine transport (VAChT) and α-Syn in the human colon. (Top middle and right, reprinted, with permission, from <a id="xref-ref-144-2" class="xref-bibr" href="#ref-144">Sharrad et al. 2013a</a>.) Colocalization of α-Syn and synaptophysin in the enteric ganglia and nerve fiber strands. (Middle middle, middle right, bottom middle, and bottom right, reprinted, with permission, from <a id="xref-ref-18-1" class="xref-bibr" href="#ref-18">Böttner et al. 2015</a>.) (Right) α-Syn pathology. Dorsal motor nucleus of the vagus (DMV): Lewy neurites (arrowheads), Lewy bodies (large arrows), and α-Syn aggregates (small arrows) in cholinergic neurons in Parkinson's disease (PD). (Reprinted, with permission, from <a id="xref-ref-21-1" class="xref-bibr" href="#ref-21">Braak et al. 2004</a>.) Submandibular gland: Phosphorylated α-Syn in PD and Lewy neurites in PD. (Left, reprinted, with permission, from <a id="xref-ref-12-1" class="xref-bibr" href="#ref-12">Beach et al. 2010</a>; right, reprinted, with permission, from <a id="xref-ref-41-1" class="xref-bibr" href="#ref-41">Del Tredici and Duda 2011</a>.) Esophagus: Phosphorylated α-Syn in PD and Lewy body in myenteric plexus of the lower esophagus. (Left, reprinted, with permission, from <a id="xref-ref-12-2" class="xref-bibr" href="#ref-12">Beach et al. 2010</a>; right, reprinted, with permission, from <a id="xref-ref-168-1" class="xref-bibr" href="#ref-168">Wakabayashi et al. 1989</a>.) Stomach: Lewy neurites (left, arrows) and Lewy bodies (right) in myenteric plexus of the gastric cardia. (Reprinted, with permission, from <a id="xref-ref-41-2" class="xref-bibr" href="#ref-41">Del Tredici and Duda 2011</a>.) Small intestine: Phosphorylated α-Syn in PD. (Reprinted, with permission, from <a id="xref-ref-12-3" class="xref-bibr" href="#ref-12">Beach et al. 2010</a>.) Large intestine: Lewy body in submucosal plexus of the rectum and phosphorylated α-Syn in submucosal neurites in PD. (Top, reprinted, with permission, from <a id="xref-ref-168-2" class="xref-bibr" href="#ref-168">Wakabayashi et al. 1989</a>; bottom is reprinted from <a id="xref-ref-101-1" class="xref-bibr" href="#ref-101">Lebouvier et al. 2010</a>, under the terms of the Creative Commons Attribution License.) <div class="sb-div caption-clear"></div> </div> </div> Several studies have suggested a synaptic localization for α-synuclein in the ENS, similar to the brain. In guinea pig ileum, α-synuclein colocalization was seen in the majority of varicosities containing the synaptic proteins synaptobrevin-2, synaptophysin, synaptotagmin-1, and CSPα (<a id="xref-ref-145-2" class="xref-bibr" href="#ref-145">Sharrad et al. 2013b</a>). In rat myenteric plexus culture, α-synuclein was found to colocalize with synaptophysin and accumulate in neuronal varicosities (<a id="xref-ref-18-2" class="xref-bibr" href="#ref-18">Böttner et al. 2015</a>). Colocalization with synaptophysin was also seen in the human colon (<a id="xref-fig-5-2" class="xref-fig" href="#F5">Fig. 5</a>, left; <a id="xref-ref-18-3" class="xref-bibr" href="#ref-18">Böttner et al. 2015</a>). α-Synuclein may be differentially expressed with age. In middle-aged and aged rats, α-synuclein-positive dystrophic axons were found throughout the gastrointestinal (GI) tract in the myenteric plexus, which colocalized with NOS-, calretinin-, calbindin-, or TH-positive swollen neurites (<a id="xref-ref-132-1" class="xref-bibr" href="#ref-132">Phillips et al. 2009</a>). In the colonic submucosal plexus of aging rats, α-synuclein first increased and then decreased over age (<a id="xref-ref-133-1" class="xref-bibr" href="#ref-133">Phillips et al. 2013</a>). In contrast, in surgical samples from human colon, α-synuclein was expressed in all intestinal layers and did not change with age, whereas phosphorylated α-synuclein at the residue serine 129 (S129 α-synuclein), a traditional marker for α-synuclein pathology (<a id="xref-ref-56-1" class="xref-bibr" href="#ref-56">Fujiwara et al. 2002</a>), was seen predominantly in the submucosa and myenteric plexus and increased with age (<a id="xref-ref-23-1" class="xref-bibr" href="#ref-23">Bu et al. 2020</a>). A recent physiological role of phosphorylated S129 α-synuclein has been identified, so its use as a pathological marker may need to be revisited (<a id="xref-ref-124-1" class="xref-bibr" href="#ref-124">Parra-Rivas et al. 2023</a>; <a id="xref-ref-137-1" class="xref-bibr" href="#ref-137">Ramalingam et al. 2023</a>). To examine α-synuclein expression in extrinsic inputs to the ENS, vagal terminals were labeled using a retrograde tracer. Although almost all vagal preganglionic efferents express α-synuclein, both in the axons and terminal varicosities, almost no vagal afferents express α-synuclein (<a id="xref-ref-131-2" class="xref-bibr" href="#ref-131">Phillips et al. 2008</a>). α-Synuclein is also expressed in enteroendocrine cells in the mouse and human intestine (<a id="xref-ref-31-1" class="xref-bibr" href="#ref-31">Chandra et al. 2017</a>), which is presumably a site of vulnerability for initial pathology. In human jejunum samples, α-synuclein was found to be widely expressed and was found to colocalize with enteroendocrine cells expressing 5-HT, but not those expressing choline acetyltransferase (ChAT) (<a id="xref-ref-29-2" class="xref-bibr" href="#ref-29">Casini et al. 2021</a>). All the above studies relied on imaging approaches. Only one study examined α-synuclein biochemically using colonic biopsies taken during routine cancer screening, confirming the expression of α-synuclein and S129-phosphorylated α-synuclein by immunoblotting (<a id="xref-ref-37-1" class="xref-bibr" href="#ref-37">Corbillé et al. 2017</a>). Given its likely role in PD pathophysiology, it will be essential to unravel the still unknown functional impact of α-synuclein on enteric neurotransmission and regulation of GI motility. </div> <div id="sec-17" class="subsection"> <h3>Pathological Functions of ENS Synuclein</h3> Some evidence supports appearance of peripheral Lewy pathology in the olfactory bulb, spinal cord, peripheral autonomic ganglia, submandibular gland, and cardiac nerves, in addition to the ENS before the appearance of neuron loss and Lewy pathology in the SNpc (<a id="xref-ref-42-2" class="xref-bibr" href="#ref-42">Del Tredici et al. 2002</a>, <a id="xref-ref-43-1" class="xref-bibr" href="#ref-43">2010</a>; <a id="xref-ref-19-3" class="xref-bibr" href="#ref-19">Braak et al. 2003a</a>, <a id="xref-ref-22-2" class="xref-bibr" href="#ref-22">2006</a>; <a id="xref-ref-63-1" class="xref-bibr" href="#ref-63">Ghebremedhin et al. 2009</a>; <a id="xref-ref-40-1" class="xref-bibr" href="#ref-40">Del Tredici and Braak 2012</a>). To support an ENS origin of disease, researchers have attempted to identify cases of incidental pathology isolated to the ENS, although there is some controversy about whether a true early-stage “ENS-only” has been convincingly identified (<a id="xref-ref-12-4" class="xref-bibr" href="#ref-12">Beach et al. 2010</a>). However, this study was limited to the examination of a single slide for each ENS subdivision, and relevant regions, including the lumbar prevertebral celiac ganglion, the spinal sympathetic preganglionic neurons, the superior mesenteric ganglion, and the appendix, were not included (<a id="xref-ref-172-2" class="xref-bibr" href="#ref-172">Warnecke et al. 2022</a>). Specifically, through the examination of 92 autopsies, S129-phosphorylated α-synuclein was found in the gastrointestinal tract in ∼65% of cases, in the vagus nerve in ∼73% of cases, and in the sympathetic trunk in ∼80% of PD cases (<a id="xref-ref-12-5" class="xref-bibr" href="#ref-12">Beach et al. 2010</a>). A large study was conducted in which more than 600 whole-body autopsies were screened, nine biopsies were collected in each gastrointestinal tract, and no gut-only cases were identified (<a id="xref-ref-2-1" class="xref-bibr" href="#ref-2">Adler and Beach 2016</a>). However, assuming a small area of involvement and the relative size of the gastrointestinal tract, even with a large number of cases, there is still a high probability of missing a case (<a id="xref-ref-15-2" class="xref-bibr" href="#ref-15">Borghammer 2023</a>). For example, If the area affected is commensurate to the other areas where isolated pathology is found (olfactory bulb, DMV), the size of the affected region would be quite small and methodologically challenging given the large surface area of the ENS (<a id="xref-ref-78-1" class="xref-bibr" href="#ref-78">Helander and Fändriks 2014</a>). Assuming a small area is affected and given the small number of neurons in a given pathological gut section as compared to a brain section (<a id="xref-ref-15-3" class="xref-bibr" href="#ref-15">Borghammer 2023</a>), it is likely that hundreds of slides would have to be examined to identify a gut-only pathology. Some work supports a rostrocaudal gradient of α-synuclein deposition throughout the nervous system (<a id="xref-ref-164-1" class="xref-bibr" href="#ref-164">Visanji et al. 2014</a>). For example, S129-phosphorylated α-synuclein was reported to be highest in the submandibular gland and lower esophagus, lower in the stomach and small intestine, and lowest in the colon and rectum (<a id="xref-ref-12-6" class="xref-bibr" href="#ref-12">Beach et al. 2010</a>), following the pattern of innervation from visceromotor projection neurons, which originate in the DMV, with vagal innervation to the upper gastrointestinal tract and predominant sympathetic and pelvic outflow projections in the lower gastrointestinal tract. </div> <div id="sec-18" class="subsection"> <h3>Summary</h3> In summary, α-synuclein is neuronally expressed throughout the gastrointestinal tract (<a id="xref-fig-5-3" class="xref-fig" href="#F5">Fig. 5</a>), especially in cholinergic neurons, as well as in enteroendocrine cells and vagal efferents. Like in the brain, a synaptic localization of α-synuclein and age-related changes in α-synuclein have been suggested. Pathology containing α-synuclein aggregates is also found throughout the gastrointestinal tract (<a id="xref-fig-5-4" class="xref-fig" href="#F5">Fig. 5</a>, right), but as in the brain, how α-synuclein physiology and pathophysiology relate remains to be determined. </div> </div> <div class="section" id="sec-19"> <div class="section-nav"><a href="#sec-15" title="α-SYNUCLEIN IN THE ENTERIC NERVOUS SYSTEM" class="prev-section-link">Previous Section</a><a href="#sec-20" title="ANIMAL MODELS OF GASTROINTESTINAL DYSFUNCTION IN PARKINSON'S DISEASE" class="next-section-link">Next Section</a></div> <h2 class="">GUT MICROBIOME</h2> There are bidirectional influences between the gastrointestinal tract and the microbial community within. The majority of microorganisms in the gut are found in the large intestine, and most studies of the human microbiome rely on sequencing of bacterial DNA in stool. Determining whether differences in the microbiome are due to lifestyle, disease, or compensatory responses to disease is challenging to unravel. Aging remains the most significant risk factor for developing PD, and affects the microbiome in and of itself, because of changes in gut physiology with aging. Another caveat in interpreting microbiome data is to note that there is likely strain specificity, which cannot be evaluated with genetic data, and, further, that there is limited knowledge of strain-specific function and microbial interactions, as most microbial species identified have not been functionally characterized in culture (<a id="xref-ref-5-1" class="xref-bibr" href="#ref-5">Almeida et al. 2021</a>). That being stated, there are small, but significant, differences in gut microbiome composition between PD and control individuals, which persist even when taking age, diet, constipation, and medication into account (<a id="xref-ref-117-1" class="xref-bibr" href="#ref-117">Nishiwaki et al. 2020b</a>; <a id="xref-ref-153-1" class="xref-bibr" href="#ref-153">Tan et al. 2021</a>). Further, genomic sequencing can distinguish PD from control individuals, even for prodromal individuals with RBD (<a id="xref-ref-77-1" class="xref-bibr" href="#ref-77">Heintz-Buschart et al. 2018</a>). Results among studies vary, but consistent changes include an increased abundance of Akkermansia, Bifidobacterium, Lactobacillus, and reduced abundance of butyrate producers, including Roseburia, Faecalibacterium, and Blautia in PD (<a id="xref-ref-154-1" class="xref-bibr" href="#ref-154">Tan et al. 2022</a>). Measurements of bacterial metabolites and metabolic pathways using transcriptomics, proteomics, and metabolomics can provide insight into the functional contribution of the microbiome. Consistent with the decreased abundance of butyrate producers in taxonomic descriptions, reduction in short-chain fatty acids (SCFAs), including butyrate, acetate, and propionate, have been widely reported (<a id="xref-ref-4-1" class="xref-bibr" href="#ref-4">Aho et al. 2021</a>). Butyrate in particular has been shown to be neuroprotective in animal models of PD (<a id="xref-ref-138-1" class="xref-bibr" href="#ref-138">Rane et al. 2012</a>; <a id="xref-ref-143-1" class="xref-bibr" href="#ref-143">Sharma et al. 2015</a>; <a id="xref-ref-150-1" class="xref-bibr" href="#ref-150">Srivastav et al. 2019</a>). Interestingly, SCFAs are not decreased in prodromal RBD (<a id="xref-ref-116-1" class="xref-bibr" href="#ref-116">Nishiwaki et al. 2020a</a>). Finally, the gut microbiome may affect treatment response because of its role in drug metabolism (<a id="xref-ref-180-1" class="xref-bibr" href="#ref-180">Zimmermann et al. 2019</a>). Bacterial tyrosine decarboxylase, predominantly from Enterococcus faecalis, converts levodopa to dopamine affecting its bioavailability (<a id="xref-ref-104-1" class="xref-bibr" href="#ref-104">Maini Rekdal et al. 2019</a>; <a id="xref-ref-161-1" class="xref-bibr" href="#ref-161">van Kessel et al. 2019</a>), which could thus affect individual response to treatment. Further, dopamine itself acts on gut motility. Microbiome-based treatments, including fecal microbiota transplantation (FMT) (<a id="xref-ref-47-1" class="xref-bibr" href="#ref-47">DuPont et al. 2023</a>), administration of SCFAs, and targeting of levodopa-metabolizing bacterial enzymes, thus represent promising avenues of treatment, although studies exploring these treatments remain preliminary. In summary, elucidation of specific mechanisms remains limited by confounding influences on GI function and the microbiome itself, and functional microbiome data remain limited as most studies rely on genetic sequencing. However, the microbiome and related metabolites and pathways are notably altered in PD, including in the prodromal period. </div> <div class="section" id="sec-20"> <div class="section-nav"><a href="#sec-19" title="GUT MICROBIOME" class="prev-section-link">Previous Section</a><a href="#sec-24" title="DISEASE BIOMARKER AND TREATMENT DEVELOPMENT" class="next-section-link">Next Section</a></div> <h2 class="">ANIMAL MODELS OF GASTROINTESTINAL DYSFUNCTION IN PARKINSON'S DISEASE</h2> Animal models are useful to dissect some of the open questions raised in the previous sections (<a id="xref-ref-127-1" class="xref-bibr" href="#ref-127">Pellegrini and Travagli 2024</a>). Below, we discuss the various animal models of PD that test gastrointestinal involvement, some of which support early gastrointestinal pathophysiology and have investigated the hypothesis of gut-to-brain spread of pathology. <div id="sec-21" class="subsection"> <h3>α-Synuclein Models</h3> α-Synuclein overexpression models, including those driven by the ubiquitous Thy1 promotor (<a id="xref-ref-170-1" class="xref-bibr" href="#ref-170">Wang et al. 2008</a>, <a id="xref-ref-171-1" class="xref-bibr" href="#ref-171">2012</a>; <a id="xref-ref-72-1" class="xref-bibr" href="#ref-72">Hallett et al. 2012</a>), as well as those with pathogenic PD-causing A53T (<a id="xref-ref-98-1" class="xref-bibr" href="#ref-98">Kuo et al. 2010</a>; <a id="xref-ref-120-1" class="xref-bibr" href="#ref-120">Noorian et al. 2012</a>) and A30P mutations (<a id="xref-ref-98-2" class="xref-bibr" href="#ref-98">Kuo et al. 2010</a>), demonstrate gastrointestinal dysfunction and changes in α-synuclein expression. Age-dependent aggregation of α-synuclein in either enteric neurons or varicosities around enteric neurons is associated with GI motility dysfunction, particularly slowed colonic transit (<a id="xref-ref-170-2" class="xref-bibr" href="#ref-170">Wang et al. 2008</a>, <a id="xref-ref-171-2" class="xref-bibr" href="#ref-171">2012</a>; <a id="xref-ref-98-3" class="xref-bibr" href="#ref-98">Kuo et al. 2010</a>; <a id="xref-ref-120-2" class="xref-bibr" href="#ref-120">Noorian et al. 2012</a>). When earlier ages were examined, colonic changes occurred before loss of striatal dopamine (<a id="xref-ref-171-3" class="xref-bibr" href="#ref-171">Wang et al. 2012</a>). Injection of α-synuclein preformed fibrils or viral overexpression of A53T mutant α-synuclein in the colon of rats and stomach of nonhuman primates led to gastrointestinal dysfunction (<a id="xref-ref-105-1" class="xref-bibr" href="#ref-105">Manfredsson et al. 2018</a>). Spread of α-synuclein pathology from gut to brain was demonstrated in rats with intestinal injection of α-synuclein derived from human PD brain lysates and recombinant α-synuclein (<a id="xref-ref-80-1" class="xref-bibr" href="#ref-80">Holmqvist et al. 2014</a>) and mice injected with α-synuclein preformed fibrils (<a id="xref-ref-159-1" class="xref-bibr" href="#ref-159">Uemura et al. 2018</a>). This spread was abolished with truncal vagotomy and required endogenous expression of α-synuclein (<a id="xref-ref-92-1" class="xref-bibr" href="#ref-92">Kim et al. 2019</a>). There is also evidence for the transfer of pathogenic α-synuclein from intestinal epithelial cells to the vagus (<a id="xref-ref-32-1" class="xref-bibr" href="#ref-32">Chandra et al. 2023</a>). Further, aging plays a role in facilitating gut-to-brain propagation (<a id="xref-ref-30-1" class="xref-bibr" href="#ref-30">Challis et al. 2020</a>; <a id="xref-ref-160-1" class="xref-bibr" href="#ref-160">Van Den Berge et al. 2021</a>). </div> <div id="sec-22" class="subsection"> <h3>Other Models</h3> Gut dysfunction and/or dysbiosis were found in several neurotoxin models, including 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (<a id="xref-ref-99-1" class="xref-bibr" href="#ref-99">Lai et al. 2018</a>; <a id="xref-ref-176-1" class="xref-bibr" href="#ref-176">Xie et al. 2020</a>), rotenone (<a id="xref-ref-178-1" class="xref-bibr" href="#ref-178">Zheng et al. 2011</a>; <a id="xref-ref-177-1" class="xref-bibr" href="#ref-177">Yang et al. 2018</a>), and 6-hydroxydopamine (6-OHDA) (<a id="xref-ref-96-1" class="xref-bibr" href="#ref-96">Koutzoumis et al. 2020</a>). Neurotoxin models also support early involvement of gut pathophysiology. In MPTP mice (<a id="xref-ref-99-2" class="xref-bibr" href="#ref-99">Lai et al. 2018</a>), gut features preceded motor features. In 6-OHDA lesioned animals, delayed gastric emptying was prevented by vagotomy (<a id="xref-ref-179-1" class="xref-bibr" href="#ref-179">Zheng et al. 2014</a>). Indeed, neuroanatomical tracing demonstrated a monosynaptic nigro-vagal pathway that modulates gastric tone and is susceptible to both 6-OHDA and paraquat (<a id="xref-ref-7-1" class="xref-bibr" href="#ref-7">Anselmi et al. 2017</a>). Furthermore, in rotenone models, there was increased α-synuclein S129-phosphorylation in the ENS and intermediolateral cell column of the spinal cord (<a id="xref-ref-122-1" class="xref-bibr" href="#ref-122">Pan-Montojo and Funk 2010</a>). Finally, mice lacking mitochondrial transcription factor A in dopaminergic neurons showed gastrointestinal dysfunction preceding motor dysfunction, as well as changes in microbiome composition (<a id="xref-ref-62-1" class="xref-bibr" href="#ref-62">Ghaisas et al. 2019</a>), and a Pink1 knockout rat showed swallowing dysfunction and delayed colonic transit (<a id="xref-ref-97-1" class="xref-bibr" href="#ref-97">Krasko et al. 2023</a>). </div> <div id="sec-23" class="subsection"> <h3>Summary</h3> In summary, both toxin- and α-synuclein-based models show early gut dysfunction, pathological and microbiome changes, and involvement of the vagus nerve in the spread of pathology and are thus useful for further study of early pathophysiological mechanisms. </div> </div> <div class="section" id="sec-24"> <div class="section-nav"><a href="#sec-20" title="ANIMAL MODELS OF GASTROINTESTINAL DYSFUNCTION IN PARKINSON'S DISEASE" class="prev-section-link">Previous Section</a><a href="#sec-25" title="CONCLUSIONS" class="next-section-link">Next Section</a></div> <h2 class="">DISEASE BIOMARKER AND TREATMENT DEVELOPMENT</h2> Current treatments for PD remain symptomatic and do not target the underlying disease physiology. Diagnosis is based on clinical symptoms; although imaging methods can demonstrate dopamine deficiency, they do not elucidate the underlying pathophysiology of the dopamine deficiency and are not useful for distinguishing between different parkinsonisms or predicting disease progression (<a id="xref-ref-151-1" class="xref-bibr" href="#ref-151">Stoessl and Halliday 2014</a>). There is thus a critical need for the development of validated disease biomarkers. Types of useful biomarkers include those that are diagnostic, those that can be used to monitor response to interventions, and those that are predictive and prognostic. Research studies often use clinical end points to measure disease progression and response to treatment. However, the isolated use of clinical evaluation in PD research is limited by the availability of effective treatments for the motor symptoms, treatment-related symptom fluctuations, disease heterogeneity, and slow progression of disease. Although efforts at clinical subtyping have emerged, reliable biomarkers do not exist to validate these subtypes. Further, biomarkers could be helpful in distinguishing between different parkinsonisms, which are currently mostly distinguished by clinical characteristics. Diagnostic biomarkers would also be useful in identifying patients earlier in the disease course, as patients with prodromal or unrecognized disease have been shown to already demonstrate functional impairments in mobility (<a id="xref-ref-108-1" class="xref-bibr" href="#ref-108">Miller-Patterson et al. 2023</a>). Finally, although movement disorders specialists can diagnose PD and parkinsonisms with a high degree of accuracy (<a id="xref-ref-81-1" class="xref-bibr" href="#ref-81">Hughes et al. 2002</a>), in the United States, >90% of patients with PD are not seen by a movement disorders specialist (<a id="xref-ref-126-1" class="xref-bibr" href="#ref-126">Pearson et al. 2023</a>). Biomarkers could thus serve to identify patients throughout the disease course, to track disease progression, and to monitor treatment response. Because of the convincing involvement of the gastrointestinal system in disease physiology, especially early in the disease course, the gut is an attractive target for the development of disease biomarkers and disease-modifying treatment and warrants further research and development. Previous work exploring the use of colonic mucosal α-synuclein and S129-phosphorylated α-synuclein as a biomarker was not advanced further because of the lack of specificity (<a id="xref-ref-165-1" class="xref-bibr" href="#ref-165">Visanji et al. 2015</a>). However, these studies were limited by methodology and extent of tissue sampled. More recently, aggregated α-synuclein was identified in duodenal biopsies of living patients with various stages of disease (<a id="xref-ref-49-1" class="xref-bibr" href="#ref-49">Emmi et al. 2023</a>). Seeding of aggregated α-synuclein has also been explored in the human GI tract. In a small study of gastrointestinal biopsies from the stomach (antrum), sigmoid colon, and rectum, biopsies from PD patients were able to seed α-synuclein aggregation, mostly from the sigmoid colon (<a id="xref-ref-54-1" class="xref-bibr" href="#ref-54">Fenyi et al. 2019</a>). Another study showed α-synuclein seeding from duodenal biopsies in 22/23 PD patients and 0/6 controls (<a id="xref-ref-163-1" class="xref-bibr" href="#ref-163">Vascellari et al. 2023</a>). These studies also have the advantage of being conducted in living patients. Other peripheral α-synuclein-based biomarkers are currently under development, and advances in peripheral biomarkers have been made with α-synuclein seeding, detection of S129-phosphorylated α-synuclein, and identification of α-synuclein strains (<a id="xref-ref-55-1" class="xref-bibr" href="#ref-55">Fricova et al. 2020</a>; <a id="xref-ref-38-1" class="xref-bibr" href="#ref-38">Coughlin and Irwin 2023</a>). There is now a commercially available skin biomarker based on S129-phosphorylation of α-synuclein (<a id="xref-ref-65-1" class="xref-bibr" href="#ref-65">Gibbons et al. 2024</a>), and significant advances have been made using α-synuclein seeding assays, especially in the cerebrospinal fluid (CSF), and including prodromal patients (<a id="xref-ref-147-1" class="xref-bibr" href="#ref-147">Siderowf et al. 2023</a>). The α-synuclein seeding assay is based on the demonstration that fluids and other tissues from PD patients can seed aggregation of recombinant α-synuclein in vitro (<a id="xref-ref-89-1" class="xref-bibr" href="#ref-89">Kang et al. 2019</a>), thought to model the prion-like propagation of pathogenic oligomers from native α-synuclein (<a id="xref-ref-86-1" class="xref-bibr" href="#ref-86">Jucker and Walker 2013</a>). However, α-synuclein seeding activity has mainly been tested with CSF as this assay currently relies on CSF sampling, and although demonstrating a high diagnostic performance for differentiating synucleinopathies with Lewy bodies from controls, results for the diagnosis of multiple system atrophy have been less robust (<a id="xref-ref-71-1" class="xref-bibr" href="#ref-71">Grossauer et al. 2023</a>). In summary, biomarkers are essential to advance the development of disease-modifying treatments. Peripheral biomarker development remains in early stages for PD, but holds promise for future research and clinical utility. Further work remains to be done to develop an accessible, sensitive, and specific GI biomarker. </div> <div class="section" id="sec-25"> <div class="section-nav"><a href="#sec-24" title="DISEASE BIOMARKER AND TREATMENT DEVELOPMENT" class="prev-section-link">Previous Section</a><a href="#ack-1" title="ACKNOWLEDGMENTS" class="next-section-link">Next Section</a></div> <h2 class="">CONCLUSIONS</h2> Gastrointestinal dysfunction is an early manifestation of PD, occurs throughout the GI tract, and includes difficulty swallowing, gastroparesis, and constipation. These symptoms contribute to disease morbidity; both affect and are affected by treatments for motor symptoms, and are important to treat. However, there are currently no PD-specific treatments for gastrointestinal dysfunction. PD-specific mechanisms are important to understand as typical neuropathology is seen throughout the ENS. ENS function is governed by both intrinsic circuits and extrinsic modulation from the CNS. Much progress has been made in understanding neuronal populations and physiology in the ENS, but many open questions remain, including how PD neuropathology contributes to ENS dysfunction, how neuropathology spreads between the ENS and CNS, and how microbiome changes contribute to disease pathophysiology. PD is the fastest-growing disease of the brain worldwide, and multiple lines of evidence suggest that the gut is involved in early disease pathophysiology. It is thus an important target when considering both biomarker development and disease-modifying treatment, which remain lacking in PD. Further research on the gut–brain axis and its role in PD pathophysiology is of critical importance. </div> <div class="section ack" id="ack-1"> <div class="section-nav"><a href="#sec-25" title="CONCLUSIONS" class="prev-section-link">Previous Section</a><a href="#fn-group-1" title="Footnotes" class="next-section-link">Next Section</a></div> <h2 class="">ACKNOWLEDGMENTS</h2> This work was supported by funding from the Leon Levy Fellowship in Neuroscience and the McGraw Fellowship in Neurology Research (to V.G.) and the NIH (R01NS113960, R01NS121077, RF1NS1263422, and UL1TR002384 subaward to J.B.). </div> <div class="section fn-group" id="fn-group-1"> <div class="section-nav"><a href="#ack-1" title="ACKNOWLEDGMENTS" class="prev-section-link">Previous Section</a><a href="#ref-list-1" title="REFERENCES" class="next-section-link">Next Section</a></div> <h2>Footnotes</h2> <ul> <li class="fn" id="fn-1"> Editors: Stanley Fahn and Serge Przedborski </li> <li class="fn" id="fn-2"> Additional Perspectives on Parkinson's Disease available at <a href="http://www.perspectivesinmedicine.org">www.perspectivesinmedicine.org</a> </li> </ul> </div> <ul class="copyright-statement"> <li class="fn" id="copyright-statement-1"><a href="http://www.perspectivesinmedicine.org/site/misc/terms.xhtml">Copyright © 2025 Cold Spring Harbor Laboratory Press; all rights reserved</a></li> </ul> <div class="section ref-list" id="ref-list-1"> <div class="section-nav"><a href="#fn-group-1" title="Footnotes" class="prev-section-link">Previous Section</a><div class="nav-placeholder"> </div> </div> <h2 class="">REFERENCES</h2> <ol class="cit-list ref-use-labels"> <li><a class="rev-xref-ref" href="#xref-ref-1-1" title="View reference in text" id="ref-1">↵</a><div class="cit ref-cit ref-journal" id="cit-15.1.a041618.1" data-doi="10.1136/jnnp-2015-311680"> <div class="cit-metadata"><cite>Adams-Carr KL, Bestwick JP, Shribman S, Lees A, Schrag A, Noyce AJ. 2016. 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Article</h3> <div class="cb-section" id="cb-art-nav"> <ol> <li><a href="#content-block">Top</a></li> <li><a href="#abstract-1">Abstract</a></li> <li><a href="#sec-2">GASTROINTESTINAL DYSFUNCTION IN PARKINSON'S DISEASE</a></li> <li><a href="#sec-3">NEUROANATOMY OF THE ENS</a></li> <li><a href="#sec-9">GASTROINTESTINAL PATHOPHYSIOLOGY IN PARKINSON'S DISEASE</a></li> <li><a href="#sec-15">α-SYNUCLEIN IN THE ENTERIC NERVOUS SYSTEM</a></li> <li><a href="#sec-19">GUT MICROBIOME</a></li> <li><a href="#sec-20">ANIMAL MODELS OF GASTROINTESTINAL DYSFUNCTION IN PARKINSON'S DISEASE</a></li> <li><a href="#sec-24">DISEASE BIOMARKER AND TREATMENT DEVELOPMENT</a></li> <li><a href="#sec-25">CONCLUSIONS</a></li> <li><a href="#ack-1">ACKNOWLEDGMENTS</a></li> <li><a href="#fn-group-1">Footnotes</a></li> <li><a href="#ref-list-1">REFERENCES</a></li> </ol> </div> </div> </div> </div> <div id="col-3"> <div class="content-box" id="sidebar-current-issue"> <div class="cb-contents"> <h3 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