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NATURE REVIEWS | NEUROLOGY ADVANCE ONLINE PUBLICATION | 1

Department of Neurology, Technical University Dresden, Fetscherstrasse 74, 01307 Dresden, Germany (L.K., H.R.)

Correspondence to: H.R. [email protected]

Pathogenesis of Parkinson disease—the gut–brain axis and environmental factorsLisa Klingelhoefer and Heinz Reichmann

Abstract | Parkinson disease (PD) follows a defined clinical pattern, and a range of nonmotor symptoms precede the motor phase. The predominant early nonmotor manifestations are olfactory impairment and constipation. The pathology that accompanies these symptoms is consistent with the Braak staging system: α-synuclein in the dorsal motor nucleus of the vagus nerve, the olfactory bulb, the enteric nervous system (ENS) and the submandibular gland, each of which is a gateway to the environment. The neuropathological process that leads to PD seems to start in the ENS or the olfactory bulb and spreads via rostrocranial transmission to the substantia nigra and further into the CNS, raising the intriguing possibility that environmental substances can trigger pathogenesis. Evidence from epidemiological studies and animal models supports this hypothesis. For example, in mice, intragastric administration of the pesticide rotenone can almost completely reproduce the typical pathological and clinical features of PD. In this Review, we present clinical and pathological evidence to support the hypothesis that PD starts in the gut and spreads via trans-synaptic cell-to-cell transfer of pathology through the sympathetic and parasympathetic nervous systems to the substantia nigra and the CNS. We also consider how environmental factors might trigger pathogenesis, and the potential for therapeutically targeting the mechanisms of these initial stages.

Klingelhoefer, L. & Reichmann, H. Nat. Rev. Neurol. advance online publication 27 October 2015; doi:10.1038/nrneurol.2015.197

IntroductionPatients with Parkinson disease (PD) are known to experience both motor and nonmotor symptoms. However, according to the UK Brain Bank Criteria,1 diagnosis of PD is precluded until motor symptoms such as bradykinesia, rigidity, tremor and postural instability are clinically evident. Nevertheless, some nonmotor symptoms, such as olfactory disturbances,2 sleep disorders (especially REM sleep behaviour dis order),3 autonomic dysfunction (especially constipation)4–7 and depression8 can precede the onset of motor symptoms by over a decade. Such nonmotor symptoms have a major impact on healthrelated quality of life in patients with PD,9–11 raising the question of whether patients with premotor symptoms of PD should be recognized as having the disease, and whether patients at risk of developing PD should be offered treatment.12,13

Key features of PD pathogenesis (selective degeneration of dopaminergic neurons, nigral Lewy bodies, reactive gliosis and initiation of degeneration in the ventral tier of the substantia nigra pars compacta followed by spread to the dorsal tier)14 were identified before premotor symptoms, such as hyposmia and constipation, were recognized as such. Constipation was considered

to be an autonomic symptom that develops during PD. At that time, no evidence suggested that PD is a neurodegenerative disorder of both the brain and the gut, especi ally one that affects the brain–gut connection via the vagus nerve (Figure 1). Yet, remarkably, new evidence strongly suggests that the pathogenesis involves transsynaptic celltocell transmission of PD pathology from the enteric nervous system (ENS)—sometimes referred to as the little brain of the gut—via the vagus nerve and the olfactory bulb to the substantia nigra and further areas of the CNS.15,16 When combined with the fact that the ENS and the olfactory bulb are gateways to the environment, this evidence suggests that the pathogenesis of PD is triggered and maintained by environmental factors.17

In this Review, we focus on emerging evidence that the neurodegenerative process that leads to PD starts in the ENS and spreads via the vagus nerve to the lower brainstem, a process that precedes degeneration of the dopaminergic nigrostriatal system. We provide an overview of clinical and pathological studies that support this hypothesis, as well as data from animal models of PD. We also discuss the evidence that pathogenesis is triggered by environmental factors, and consider therapeutic approaches that could target the earliest stages of PD.

Gastrointestinal symptoms of PDGastrointestinal impairments are commonly observed at all stages of PD:18 ~30% of patients with the disease report gastrointestinal symptoms.19,20 Previously, motility disturbances—particularly constipation—were

Competing interestsH.R. has served on the advisory boards of, given lectures for and received research grants from Abbott, Abbvie, Bayer Health Care, Boehringer Ingelheim, Brittania Pharmaceuticals, Cephalon, Desitin, GlaxoSmithKline, Lundbeck, Medtronic, MerckSerono, Novartis, Orion Pharma, Pfizer, Teva Pharmaceutical Industries, UCB, Valeant Pharmaceutical International, and Zambon. L.K. declares no competing interests.

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considered to be nonmotor symptoms of advanced PD, but we now know that the whole gastrointestinal tract can be affected in the premotor stage;6,21,22 gastro intestinal symptoms subsequently become more prominent in advanced PD.23 These symptoms are often underreported in patient interviews, especially in early stages of PD;24 a higher percentage of complaints are observed in advanced stages of PD.25–27

Constipation is one of the most common nonmotor symptoms of PD, with a prevalence of 28–80%.23,28–31 In the PRIAMO study,32 which included 1,072 patients with PD, 28% of patients reported constipation, 25% experienced fewer than three evacuations per week, and 11% reported incomplete bowel emptying. Furthermore, evidence suggests that the prevalence of constipation is up to 6fold greater among patients with PD than among agematched and sexmatched controls.7,23,28,33

Many studies have shown that constipation precedes the development of PD.4,6,7,34,35 In one of these studies, 6,790 men without PD at baseline and who were enrolled in the Honolulu Heart Program were monitored for incidence of PD over 24 years.4 96 participants developed PD after an average time of 12 years. After adjustment for various factors that might influence constipation, such as age and consumption of nicotine and coffee, men who experienced fewer bowel movements than one per day had a 2.7fold, 4.1fold and 4.5fold greater risk of PD than men who experienced one, two or more than two bowel movements per day, respectively. These findings demonstrate that infrequent bowel movements are associated with an elevated risk of developing PD and, together with other evidence (Box 1), suggests that constipation is an early clinical manifestation of PD. The likely cause of constipation in PD is neuro degeneration of autonomic centres of the ENS and—in advanced disease—CNS degeneration.36

Constipation associated with PD can be classified as either ‘slowtransit’ constipation, caused by prolonged intestinal passage,23,37,38 or ‘outlet’ constipation, caused by anorectal dysfunction; patients can experience one or both.39–41 Reported colonic transit times in patients with

Key points

■ Nonmotor symptoms, particularly hyposmia and constipation, precede the motor symptoms of Parkinson disease (PD) by many years, and the lifetime risk of PD negatively correlates with the frequency of bowel movements

■ Neurodegeneration in PD seems to start in the olfactory bulb, the enteric nervous system, the dorsal motor nucleus of the vagus nerve and the intermediolateral nucleus in the thoracic and sacral spinal cord

■ Evidence suggests that environmental factors have an important role in triggering and/or propagating the pathology of PD; the olfactory and gastrointestinal systems are gateways to the environment

■ Chronic intragastral administration of rotenone in mice has resulted in neuropathology and symptoms typical of PD that developed in a chronological and regional sequence that corresponds to the Braak staging system

■ PD pathology that involves α-synuclein spreads from the enteric nervous system to the CNS by trans-synaptic cell-to-cell transmission in intact sympathetic and parasympathetic nerves

■ α-Synuclein impairs mitochondrial activity and causes oxidative stress in neurons, especially dopaminergic neurons in the substantia nigra and noradrenergic neurons in the locus coeruleus

PD vary widely, but demonstrate markedly longer transit times in patients with PD (44–130 h, or ~89 h in de novo patients) than in controls (20–39 h).30,37,38,42 An estimated 80% of patients with PD have a prolonged transit time,43 and the pathophysiological basis is impaired colonic motility.37,44 Prolonged colonic transit has also been observed in patients who have PD but no symptomatic constipation; in this study, patients did not selfreport increases of up to 50% in colonic transit time.34

Outlet constipation occurs in up to twothirds of patients with PD.30,45 The disorder can be caused by paradoxical anal sphincter muscle contraction during defecation (a type of focal dystonia),42,46–48 involuntary and uncoordinated contractions of the pelvic floor,46,48 or reduced anorectal sensitivity owing to disturbance of afferent pathways.46,47

Pathological progression of PDThe pathognomonic histological features of PD are Lewy bodies in neuronal somata, Lewy neurites in dendrites and axons, loss of catecholaminergic neurons in the locus coeruleus, and loss of dopaminergic neurons in the sub stantia nigra. Lewy bodies and Lewy neurites are intra cytoplasmic accumulations of proteins, mainly comprising αsynuclein.49 Pathological investigations have indicated that the neuropathological changes in PD follow a specific chronological and regional pattern.50,51

The Braak staging systemBraak and colleagues developed a pathological staging system for PD, which correlates well with the clinical presentation at the different stages of the disease.52–54 Originally, the Braak staging system identified the olfactory bulb and the dorsal motor nucleus of the vagus (DMNV) as the sites at which the neurodegenerative process in PD starts before spreading to the brainstem and cortical areas of the brain.52,55,56 Involvement of both the olfactory bulb and the DMNV was explained by a proposed dualhit mechanism, involving anterograde progression of pathology from the olfactory system into the temporal lobe, and retrograde progression to the brainstem from the gut following ingestion of a neurotropic pathogen.17,57

Studies have shown that the presence of αsynuclein in the olfactory bulb alone predicted neuropathologically confirmed advanced PD and dementia with Lewy bodies (DLB) with a sensitivity and specificity greater than 90%, and correlated with the severity of synucleinopathy in other brain regions. These findings do not, however, contradict the Braak hypothesis, as they do not preclude the possibility of a ‘second hit’ that allows the pathology to reach the brain via the gut, nor do they indicate a specific chronology of disease process.

The Braak stages were adapted following subsequent pathological studies. Lewy bodies and Lewy neurites were found not only in the CNS but also in the PNS of the gut and in sympathetic and parasympathetic ganglia (Figure 2).59–62 Both pathologies were detected in the Auerbach plexus, the Meissner plexus and the olfactory bulb in people with PD, but also in apparently healthy

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people without typical motor symptoms or CNS pathology of PD.59,63–68 Furthermore, autopsies have shown that latelife constipation in people with no clin ical signs of parkinsonism or dementia before death is associated with incidental Lewy bodies in the sub stantia nigra and the locus coeruleus, and with low neuron density in the substantia nigra.69,70 Lewy bodies and Lewy neurites have also

been detected in the intermedio lateral nucleus (IML) of the spinal cord in early stages of PD.64 To cover the pathological distributions and the timing of presentation, the Braak stages were therefore adjusted to incorporate the onset of neuropathological changes in the olfactory bulb, the ENS, the IML of the spinal cord and the DMNV.64,71,72 The neurodegenerative process is thought to then spread

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Figure 1 | Vagal parasympathetic innervation of the gastrointestinal tract and connection of the ENS and CNS. a | Vagal innervation of the digestive system. b | Schematic representation of the vagal nerve fibres between the ENS and CNS. c | Transverse brainstem section through the middle of the olivary nucleus. Abbreviation: ENS, enteric nervous system. Permission for part b obtained from Springer © Braak, H. & Del Tredici, K. Adv. Anat. Embryol. Cell Biol. 201, 1–119 (2009). Permission for part c obtained from M. Meinhardt and G. Baretton, Neuropathology, Institute of Pathology, Technical University Dresden, Germany.

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through anatomically connected structures in a caudorostral direction to the brain and also from the brainstem into the spinal cord.64 The diseasedefining typical motor symptoms of PD, such as rigidity and hypokinesia, only emerge after the loss of >80% of dopaminergic neurons in the substantia nigra and dysfunction of the nigrostriatal dopamin ergic pathway.73 Further neurodegeneration leads to dys function of higher cortical structures, which manifests clinically as cognitive decline.74

Challenges to the Braak staging systemThe findings of several studies challenge the validity of the Braak staging system. Retrospective autopsy studies have found that in up to half of the patients studied, patho logical findings do not conform to the Braak staging system.75–80 Conversely, one study showed that 7% of patients with PD exhibited no αsynuclein in the DMNV despite the fact that αsynuclein was present in the substantia nigra and cortical regions.75 In another study, the DMNV did not exhibit αsynuclein pathology in 8.3% of patients with PD.76

Furthermore, the relationship between PDspecific pathology and impaired gastrointestinal motility in patients with PD is poorly understood. Studies that have focused on Lewy pathology in the ENS of patients with Lewy body diseases have found αsynuclein in the ENS of nearly every included patient with PD,81,82 but neither neuronal loss in the Auerbach plexus nor alterations in the abundance of neurochemicals such as nitric oxide, vasoactive intestinal peptide and tyrosine hydroxylase (a crucial enzyme in dopamine synthesis) were found in patients with PD when compared with healthy controls.83 By contrast, a 15% decrease in the number of Meissner plexus neurons per ganglion has been observed in colon biopsy samples from patients with PD.84 Neurochemical changes—such as low levels of glutathione and prostaglandins85 and high expression levels of glial fibrillary acidic protein and SOX1086—in patients with PD also suggest dysregulation and loss of enteric glial cells.86–88 A positive correlation between gut permeability, which is regulated by enteric glial cells, and intestinal levels of αsynuclein was observed in untreated patients with early PD.89 Enteric glial cells might, therefore, be involved in gastrointestinal dysfunction and PD initia tion and develop ment.90 Levels of glial markers reduce with longer durations of PD, suggesting that the reaction of glial cells to disease onset is strong but decreases over time.86

Involvement of enteric glial cells in PD and their changing responses over the course of PD might, there fore, partly explain the variation in the extent of enteric neuronal loss and neurochemical changes in differ ent studies that are based on autopsies of patients with advanced PD.83,84,91

Any staging scheme is likely to be imperfect, and deviations should always be expected. The diversity of Lewy body distribution in PD might be greater than expected; however, the diversity could reflect differences between the cohorts studied and the techniques applied, or the inclusion of patients with incidental Lewy body disease rather than PD.16 Crosssectional studies suggest that incidental Lewy bodies are present in ~8% of elderly people,79,92,93 but, whereas Lewy pathology is essential for pathological diagnosis of PD, it is not specific for prodromal PD.16

Environmental factors and PDWhen combined with the fact that the olfactory bulb and the ENS are exposed to substances from the environment through inhalation or ingestion, the possibility that PD pathogenesis starts in the olfactory and gastro intestinal systems agrees with the hypothesis that environmental factors have an important role in triggering and propagating PD pathology in the CNS.

The risk of PDEpidemiological and sociological studies have shown that exposure to toxic environmental substances (such as drinking well water and exposure to agricultural chemicals) and specific living conditions (such as rural living and farming) increase the risk of developing PD or parkinsonism.94–97 Environmental factors such as pesticides,94,98,99 herbicides96,100,101 and metals94,102 have been linked to high levels of αsynuclein in the brain and to parkinsonian symptoms. A postmortem study that included brain samples from 20 patients with PD, seven patients with Alzheimer disease and 14 people with no neurological disease revealed a highly significant association between exposure to dieldrin (a lipidsoluble, longlasting mitochondrial poison that has been used as an insecticide) and a diagnosis of PD.99 Another study has shown that PD is associated with exposure to pesticides that impair mitochondrial function by inhibiting mitochondrial complex I or that increase oxidative stress.103

The role of the microbiomeSome environmental factors, such as cigarette smoking and caffeine consumption, are associated with a reduced risk of PD.104–107 One proposed explanation for this effect is that cigarette smoking and caffeine consumption change the composition of the microbiota in the gut in a way that mitigates intestinal inflammation.106 This, in turn, leads to less aggregation of αsynuclein in the ENS, thereby reducing the risk of PD. This hypothesis is consistent with findings of altered intestinal microbiomes in patients with PD and an influence of gut microbiota on the activity of enteric neurons.108–110

Comparison of the gut microbiomes of patients with PD with those of sexmatched and agematched

Box 1 | Clinical evidence that Parkinson disease starts in the gut

■ Constipation clearly precedes the motor stage of Parkinson disease6 and worsens with disease progression23,186

■ Studies have shown prolonged colon transit times in untreated patients with Parkinson disease,5,187 indicating that constipation is intrinsic to the disease

■ The occurrence of constipation in Parkinson disease is independent of age, physical activity and medication;4,43 it is more common in idiopathic Parkinson disease than in other parkinsonian syndromes188

■ Evidence indicates a substantial burden of α-synuclein neuropathology in the upper gut (symptoms such as dry mouth, drooling and dysphagia), but only constipation and defecatory dysfunction are prominent premotor gastrointestinal symptoms of PD7

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controls revealed that the mean abundance of the bacterial family Prevotellaceae was 78% lower in the faeces of patients with PD than in that of controls.108 Five other bacterial families (Lactobacillaceae, Bradyrhizobiaceae, Clostridiales Incertae Sedis IV, Verrucomicrobiaceae and

Ruminococcaceae) were more abundant in patients with PD than in controls. Furthermore, the composition of the gut micro biome was associated with the PD motor phenotype: Enterobacteriaceae were more abundant in patients with nontremordominant PD than in patients with tremordominant PD, and the concentration of the bacteria corre lated positively with the severity of postural instability and gait difficulties, and with akinetic–rigid subscores. This finding is of special interest because nontremordominant PD is associated with a more extensive αsynuclein pathology in the ENS than in other forms of PD; its clinical progression is also faster and the associ ated prognosis is worse.84,111,112 Evidence suggests that the abundance of specific bacterial families, together with the severity of constipation, identifies patients with PD with a sensitivity of 67% and a specificity of 90%.108–110 Nevertheless, whether changes in the gut microbiome are a risk factor for or a consequence of PD is unclear; to determine the causal relation ship, a prospective study is needed in which the gut microbiome and dietary habits are monitored in de novo patients with PD with different motor phenotypes. To date, several studies have proposed microbiome–gut–brain communication that involves caudorostral propagation of pathology via the vagus nerve.113–116

Interactions between antiparkinsonian medication and the gut microbiome are currently unclear. Bacterial over growth in the small intestines of patients with PD has been associated with worse motor function117,118 and a high prevalence of unpredictable motor fluctuations.118 This worsening of motor function might be caused by mal absorption of antiparkinsonian medication, as eradicating bacterial overgrowth in the small intestine improved motor fluctuations.118 Furthermore, gastrointestinal infection with Helicobacter pylori has been associated with a deterioration of motor function in PD119–121 and limited evidence indicates that eradication of the infection improves absorption of levodopa and consequently improves motor function.120,122 An increased abundance of Enterobacteriaceae has been associated with the use of catechol O‑methyltransferase inhibitors, although not with use of levodopa, dopamine agonists, monoamine oxidase inhibitors or anticholinergic medication.108

Diet and interactionsStudies of the relationship between PD and dietary fat intake have produced contradictory results: some have suggested that higher fat intake increases the risk of PD,123,124 whereas others have reported no association or an inverse association.125–130 A 2014 study indicated that a higher intake of dietary fats, particularly N3 polyunsaturated fatty acids, is associated with a lower risk of PD.130 This finding is supported by evidence that unsaturated fatty acids are important constituents of neuronal cell membranes and have neuroprotective, antioxidant, and antiinflammatory properties.127

Furthermore, intake of dietary fats modified the association of exposure to pesticides with the risk of PD.130 A high intake of unsaturated fats attenuated the associa tion of the pesticide N,N'dimethyl4,4'bipyridinium dichloride (Paraquat™) with PD, whereas a high intake

Figure 2 | Enteric nervous system of the gut. a | Anatomy of the intestinal wall with the Auerbach plexus between the longitudinal and circular muscles and the Meissner plexus in the submucosa. b | Histological section of the intestinal wall (left) and magnification of the Meissner plexus (middle and right) that contains α-synuclein inclusions (stained dark red with AEC-chromogen, middle) that are similar to Lewy bodies and resistant to proteinase K (right), so are classified as α-synuclein aggregates. c | Histological section of the intestinal wall (left) and magnification of the Auerbach plexus (middle and right) that contains α-synuclein inclusions (stained dark red with AEC-chromogen, middle) that are similar to Lewy bodies and resistant to proteinase K (right) and are, thus, classified as α-synuclein aggregates. Abbreviation: AEC, 3-amino-9-ethylcarbazole. Part a reproduced from Wikimedia Commons/Goran tek-en under the Creative Commons Attribution-Share Alike 3.0 Unported license. Permission for parts b and c obtained from W. J. Schultz-Schaeffer, Prion and Dementia Research Unit, Neuropathology, University Medical Center, Göttingen, Germany.

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of saturated fat intensified this association and that of the pesticide rotenone with PD. Such synergistic effects of interacting factors might explain the inconsistency between studies that have investigated environmental risk factors for PD.

Insights from animal models of PDNo animal model on its own recapitulates the entire disease process of PD. Some models reproduce individual or combined clinical features (for example, parkinsonism with hypokinesia, rigidity and tremor or a symptomatic response to levodopa and dopamine agonists), whereas others reproduce pathological features (for example, loss of tyrosine hydroxylasepositive neurons and loss of dopaminergic cells in the nigrostriatal region, loss of tyrosine hydroxylasepositive neurons in the ENS, or αsynuclein inclusions in the substantia nigra and the ENS). Nevertheless, the complete chronological and topographical expansion pattern of PD pathology proposed by the Braak staging system has not be reproduced in any single model.

Toxin-induced modelsSeveral toxininduced animal models that are generated by exposure to different environmental factors that are administered via different routes can reproduce aspects of PD pathology. The most commonly used neurotoxins in this context are 6hydroxydopamine, 1methyl4phenyl1,2,3,6tetrahydropyridine (MPTP) and the pesticide rotenone.131–133 These neurotoxins cause specific clinical and neuropathological abnormalities, but each model has advantages and disadvantages. For example, systemic application of rotenone causes the PDlike pathology of nigro striatal neurodegeneration with formation of αsynuclein inclusions that are similar to Lewy bodies,134 but also leads to degeneration in CNS structures that are typically not affected in PD, and this degeneration does not progress.135

Cues for the route of exposureTo be absorbed, pathogenic environmental factors must be capable of overcoming physiological defence mechan isms, such as the mucosal barrier of the nasopharyngeal and gastrointestinal tracts, so the route by which neurotoxins are administered could be important in determining whether they realistically reproduce pathogenesis of PD. The importance of this consideration is demonstrated by a mouse study in which chronic intranasal inoculation of MPTP caused motor deficits, depletion of striatal dopamine levels and loss of tyrosine hydroxylase from the substantia nigra and striatum,136 but chronic inhalation of rotenone failed to cause a clinical or pathological presentation of PD, and inhalation of N,N'dimethyl4,4'bipyridinium dichloride induced severe hypokinesia but did not alter the nigrostriatal system.

Rotenone models of PDPanMontojo et al.137 used chronic intragastric administration of low doses of rotenone to trigger neuropatho logical

changes typical of PD in wildtype mice (the Dresden Parkinson Model; Box 2). Rotenone was administered via a gastric tube in such low doses that only local effects on the ENS, and no systemic effects, were expected. Highperformance liquid chromatographic analysis of blood, brain and brainstem samples from the animals and measurements of mitochondrial complex I activity (which rotenone inhibits) in brain and muscle samples confirmed that rotenone was not distributed systemically. In mice that were treated with rotenone for 1.5 months, patho logical changes typical of PD, such as αsynuclein aggregation, were observed in the ENS, IML and DMNV, but were not accompanied by changes in substantia nigra dopaminergic cells or motor dysfunction assessed with the rotarod test.137 By contrast, in mice that were treated for 3 months, αsynuclein aggregation and loss of dopamin ergic neurons was observed in the substantia nigra pars compacta, and motor disability was observed.137 The spatio temporal development of pathological manifes tations and clinical symptoms in the rotenonetreated mice corresponded well to current theories of the neurodegenerative process and timings of clinical motor symptom presentation in patients with PD.

In an earlier study, Inden et al.138 found that chronic oral administration of rotenone in mice induced dosedependent, selective nigrostriatal dopamin ergic neurodegeneration, motor deficits and cyto plasmic accumulation of αsynuclein in surviving dopamin ergic neurons. Furthermore, in many mice, dopamin ergic neuronal loss in the substantia nigra pars compacta occurred asymmetrically, similar to that in early PD neuro pathology. However, no degeneration of nondopamin ergic neurons or activation of astrocytes and microglia was observed. Tasselli et al.139 replicated the neurodegeneration of the substantia nigra in mice by using 4 weeks of chronic oral treatment with rotenone, but observed no changes of gastro intestinal motility or neuropathological changes in the ENS. Nevertheless, several other studies from different groups have provided further evidence that administration of rotenone leads to αsynuclein accumulation.134,137,138,140–143

Spread of pathology from the ENS to the CNSIf environmental toxins can trigger the development of PD pathology in the ENS, the question remains of how this pathology spreads to the CNS. One likely mech anism is the propagation of αsynuclein accumulation via sympathetic and parasympathetic nerves.

Several studies have shown that αsynuclein can be transported between neurons. The protein can be released from neurons into the extracellular space, where it can be either free or associated with exosomes,144 and transported via endocytosis to neighbouring neurons and neuronal precursor cells.145,146 In a transgenic mouse model of PDlike pathology, αsynuclein was transmitted to engrafted neuronal precursor cells, where it accumulated and formed inclusions that were similar to Lewy bodies.146,147 Similarly, in autopsy studies of patients with PD who had received fetal mesencephalic transplants, αsynuclein had accumulated in the grafted neurons and must, therefore, have spread from host to graft cells.148,149

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In one mouse study, disrupting the connection between enteric neurons and sympathetic or parasympa thetic neurons halted the progression of PDlike pathology.150 Hemivagotomy or partial sympathectomy before gastric rotenone treatment delayed the development of motor symptoms, but not of gastro intestinal symptoms, relative to that observed with rotenone treatment alone. Gastrointestinal symptoms were caused by rotenoneinduced decreases in gut motility.150 In mice that underwent surgery and were treated with rotenone, accumulation of αsynuclein in choline acetyltransferase (ChAT)positive neurons was greater in the DMNV contra lateral to the hemivagotomy than in that ipsi lateral to the hemivagotomy (Figure 3).150 This asymmetry could not be attributed to neuronal death in the ipsi lateral DMNV, which is a consequence of hemivagotomy.151 Therefore, hemivagotomy seemed to stop progression of PDlike pathology that is mediated by propagation of αsynuclein accumulation from the ENS via the vagus nerve into the central DMNV.150

This finding is supported by evidence from another study in rats that showed active transport of αsynuclein from the intestine to the DMNV via the vagus nerve in a timedependent manner after injection of monomeric, oligomeric or fibrillar αsynuclein into the intestinal wall.152 All αsynuclein forms were transported in a mechanism that involved the slow and fast components of axonal transport. By contrast, results of another study showed that transport of αsynuclein did not result in neuronal cell death, nor could exogenous αsynuclein be observed in the DMNV or SN.152 An outstanding question is whether the discrepancy between studies is attribu table to a dosedependent effect of injected αsynuclein, an incubation time after injection of αsynuclein that was too short for these effects to develop, or a missing ‘seeding’ effect (aggregation of

endogenous αsynuclein in neurons that is started by an exogenous αsynuclein ‘seed’).145,153

The findings of a large epidemiological study support the evidence from these animal studies.116 The results of this study, which were adjusted for possible confounders such as smoking and comorbidities, showed that patients who underwent truncal vagotomy, but not superselective vagotomy, are at lower risk of PD than are the general population. The incidence of PD among people with a followup period >20 years after vagotomy was 0.65 per 1,000 personyears, compared with 1.28 per 1,000 personyears in controls who had not undergone vagotomy and who were matched for year of birth, gender and indexdate (that is, the controls had not undergone vagotomy at the surgery date of the corresponding patient or later). These findings are in line with the suspected long premotor period of PD and implicate the vagus nerve in caudorostral propagation of PD pathology to the CNS.

Evidence from animal models also supports the hypothesis that once PD pathology has propagated to the DMNV, it is subsequently transferred from there into further areas of the CNS. After 4 months of rotenone treatment in the Dresden Parkinson Model, vagotomized mice exhibited less dopaminergic cell death in the substantia nigra pars compacta ipsilateral to the hemivagotomy than did mice that were not vagotomized.150

Evidence suggests that the propagation of PD pathology relies on intact synaptic connections. Only neurons with synaptic connections to the ENS exhibited pathological changes after gastric rotenone treatment.137 In agreement with these observations are the findings that in humans with pathologically confirmed PD and in mice treated with rotenone, the only spinal cord neurons affected by PD pathology were preganglionic sympathetic neurons in the IML and lamina I of the posterior horn, owing to the axonal connections that exist here; motor neurons of the anterior horn were unaffected.64,137

Role of α-synuclein in PD progressionMitochondrial dysfunction that results from complex I defects,154–156 oxidative stress,157 inflammation and protein mishandling158,159 has been proposed as an important mechanism in the pathogenesis of PD. Environmental toxins such as rotenone trigger exocytosis of αsynuclein from enteric and sympathetic neurons into the extracellular space.150,160,161 Subsequent endocytosis of the released αsynuclein into neighbouring neurons can be followed by its retrograde transport into the somata of these neurons.150,162,163 The protein can also be transferred in the same way to nonneuronal cells. Once transferred, αsynuclein can act as a seed for aggregation of endo genous αsynuclein in the recipient neuron.145 Aggregates of αsynuclein impair mitochondrial complex I activity, reduce mitochondrial function and cause oxidative stress in the recipient neuron.157,164,165

Several findings indicate that dopaminergic neurons of the substantia nigra have an intrinsic sensitivity to mitochondrial complex I defects. For example, in cultured mesencephalic cells from mice and rats, and in the substantia nigra pars compacta of mice, rotenone and

Box 2 | The Dresden Parkinson Model

The Dresden Parkinson Model137,150 is generated by chronic intragastric administration of the pesticide rotenone to wild-type mice. The model reproduces many aspects of Parkinson disease (PD), from clinical motor symptoms to spatiotemporal pathological progression that corresponds to the Braak stages. This model provides compelling proof of several concepts in the pathogenesis of PD: ■ Chronic local administration of environmental toxins, such as rotenone, can

cause parkinsonism with typical motor symptoms, laterality of motor symptom presentation and PD-like pathology

■ Locally administered rotenone induces α-synuclein release from enteric neurons into the extracellular space

■ Released α-synuclein is taken up by non-neuronal cells or presynaptic neurons and retrogradely transported to the somata of neurons, where it accumulates

■ α-Synuclein pathology propagates by trans-synaptic cell-to-cell transmission via sympathetic and parasympathetic nerves from the enteric nervous system to the CNS

■ Progression of PD pathology relies on an intact multisynaptic pathway via the dorsal motor nucleus of the vagus nerve and the intermediolateral nucleus of the spinal cord; nerve interruption halts the pathological process116

■ Transferred α-synuclein impairs mitochondrial complex I activity and causes inflammation

■ Dopaminergic neurons of the substantia nigra have an intrinsic sensitivity to complex I defects, leading to selective neurodegeneration

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the presence of endogenous dopamine caused selective toxicity of dopaminergic neurons.134,166 Similarly, central dopaminergic neurons seem to have a higher sensitivity to accumulation of intracellular αsynuclein than do neurons in the DMNV and IML.137 In the rotenone model of PD, even a modest systemic defect of complex I caused neurodegeneration only in the substantia nigra.167

Furthermore, a proinflammatory effect of αsynuclein might exacerbate the degeneration of dopaminergic neurons. Extracellular αsynuclein triggers the release of inflammatory mediators, such as cytokines and activated microglia, leading to inflammation.168–170 Ultimately, cells that are exposed to neuronderived αsynuclein show signs of apoptosis, such as nuclear fragmentation and caspase 3 activation.146,164 In one study, low concentrations of rotenone in combination with an inflammogen worked in synergy to induce selective degeneration of dopamin ergic neurons, demonstrating that inflammation can worsen degeneration.159

Implications for interventionNo current therapeutic strategies directly target the gut–brain axis to prevent the initiation and spread of PD pathology. The current body of evidence suggests three possible approaches: reduction of intracellular or extracellular levels of αsynuclein, and preservation of mitochondrial activity.

Several trials have aimed to reduce intracellular αsynuclein by either inhibition of its accumulation and aggregation or by acceleration of its depletion.171–177 A novel synthetic oligomer modulator called anle138b, which blocks the formation of pathological protein aggregates by targeting structuredependent epitopes, has been used in vitro and in vivo to prevent intracellular αsynuclein aggregation and inhibit the formation and accumulation of pathological oligomers.171 Anle138b strongly inhibited αsynuclein accumulation, neuronal degeneration and disease progression in three different mouse models of PD. Furthermore, anle138b caused no

toxicity at therapeutic doses and displayed excellent oral bioavailability and penetration of the blood–brain barrier. Oligomer modulators therefore seem promising for the treatment of protein aggregation diseases and could represent a diseasemodifying therapy for PD.

Levels of extracellular αsynuclein could be reduced by using monoclonal antibodies against the protein.178–181 In one study, antiαsynuclein antibodies reduced Lewy body and Lewy neurite formation and dopaminergic neuron loss in the substantia nigra of mice by preventing uptake of αsynuclein into neurons and consequently preventing transsynaptic celltocell transmission of αsynuclein pathology.182

Mitochondrial function can be protected by antioxidants, such as coenzyme Q10, that oppose inhibition of the respiratory chain by environmental toxins that induce apoptosis. Coenzyme Q10 produced promising results in cell cultures,183 but did not affect symptoms in patients with PD.184 New evidence suggests that polyphenols, which are ubiquitous in fruits and vegetables, can modulate mitochondrial activity and mitochondria triggered cell death.185 These compounds might, therefore, offer new treatment options that target the gut–brain axis in patients with PD.

ConclusionsThe motor symptoms of PD only become apparent after degeneration of >80% of dopaminergic neurons in the substantia nigra, so pathogenesis could commence decades before the clinical onset of motor PD. Clinical presentation of nonmotor symptoms long before the onset of motor PD supports this hypothesis. Hyposmia and constipation are especially important symptoms because the olfactory and gastrointestinal systems represent gateways to the environment, and evidence suggests that environmental factors contribute to the patho genesis of PD. Direct contact between environmental toxins and neurons in the olfactory bulb and ENS—through inhalation or ingestion—has been associated with the


a cb

ChATα-synuclein

DAPI

ChATα-synuclein

DAPI

ChATα-synuclein

DAPI

A

P

A

P

A

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L R L R L R

Vagotomy

Non-vagotomy

Figure 3 | Hemivagotomy prevents α-synuclein accumulation in the ipsilateral DMNV. Confocal images (single plane) of DMNV sections from mice, stained with anti-α-synuclein (green) and anti-ChAT antibodies (red) and DAPI (blue). Scale bar 60 nm. a | The DMNV of an untreated mouse. b | The DMNV of a mouse that was treated with rotenone for 4 months but did not undergo hemivagotomy. c | The DMNV of a mouse that was treated with rotenone for 4 months and underwent hemivagotomy. Rotenone markedly increased the amount of α-synuclein in ChAT+ neurons on the intact (right) side relative to the vagotomized side (left). Abbreviations: A, anterior; ChAT, choline acetyltransferase; DAPI, 4,6-diamino-2-phenylindole; DMNV, dorsal motor nucleus of the vagus; L, left; P, posterior; R, right. Permission obtained from Nature Publishing Group © Pan-Montojo, F. et al. Sci. Rep. 2, 898 (2012).

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develop ment of nonmotor PD symptoms, and the clinical and pathological presentation in this context corresponds to that described by spatiotemporal Braak staging of PD.

Current evidence indicates that PD pathology that involves αsynuclein propagates from the ENS by transsynaptic celltocell transmission through sympathetic and parasympathetic nerves to the DMNV and IML into the CNS. Intact synaptic pathways seem to be important, as disruption of nerve connections stops the caudorostral progression of pathology. Variability in the initial phenotype of PD and involvement of different neurotransmitters and brain regions in the progression of the disease in different patients supports the hypothesis that a combination of external environmental factors and individual susceptibility triggers pathogenesis. An understanding of the roles that environmental and genetic factors play in the pathogenesis of PD is crucial for the identification

of risk factors and early disease. Such an understanding could help in defining criteria for categorizing patients in the premotor stage of PD according to their risk of developing motor PD. Such risk stratification could then enable the application of preventative and interventional therapeutic strategies for targeting the premotor stage. Strategies for primary prevention of PD development could include preventative lifestyle advice, regular control of gut microbiome composition and regulation of stool frequency. Targets for delaying or stopping disease progression via the gut–brain axis might include αsynuclein, enteric glial cells and neurochemical alterations (for example, enzymes of dopamine metabolism). Greater understanding of the exact interactions between multifactorial causes of PD that converge on a common pathogenetic pathway will help in the development of such strategies and offer new paradigms for understanding and treating PD and other Lewy body diseases.

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AcknowledgementsThe authors are very thankful for the provision of Figure 1c by M. Meinhardt and G. Baretton at Neuropathology, Institute of Pathologie, Technical University Dresden, Germany and of Figure 2b and 2c by W. J. Schulz-Schaeffer at the Prion and Dementia Research Unit, Neuropathology, University Medical Center Göttingen, Germany.

Author contributionsBoth authors contributed equally to all aspects of the article.

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Pathogenesis of Parkinson disease—the gut–brain axis and environmental factorsLisa Klingelhoefer and Heinz ReichmannKey pointsIntroductionGastrointestinal symptoms of PDPathological progression of PDEnvironmental factors and PDInsights from animal models of PDImplications for interventionConclusionsFigure 1 | Vagal parasympathetic innervation of the gastrointestinal tract and connection of the ENS and CNS. a | Vagal innervation of the digestive system. b | Schematic representation of the vagal nerve fibres between the ENS and CNS. c | Transverse braFigure 2 | Enteric nervous system of the gut. a | Anatomy of the intestinal wall with the Auerbach plexus between the longitudinal and circular muscles and the Meissner plexus in the submucosa. b | Histological section of the intestinal wall (left) and maFigure 3 | Hemivagotomy prevents α‑synuclein accumulation in the ipsilateral DMNV. Confocal images (single plane) of DMNV sections from mice, stained with anti‑α‑synuclein (green) and anti‑ChAT antibodies (red) and DAPI (blue). Scale bar 20 nm. a | The DMBox 1 | Clinical evidence that Parkinson disease starts in the gutBox 2 | The Dresden Parkinson ModelAcknowledgementsAuthor contributions

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