Highlights
- •Parkinsons disease patients suffer from imbalanced microbial colonisation of the gut.
- •Some of the PD non motor symptoms are also associated with microbial imbalance.
- •Gastrointestinal disturbances occur in PD and often precede motor symptoms.
- •α-synuclein is present in the enteric nervous system prior to their appearance in the brain.
- •Microbiota manipulation may relieve non motor symptoms and improve quality of life.
Abstract
Parkinson's disease is the second most common neurodegenerative disorder, affecting
1–2% of the population over 65 years of age. The primary neuropathology is the loss
of midbrain dopaminergic neurons, resulting in characteristic motor deficits, upon
which the clinical diagnosis is based. However, a number of significant non-motor
symptoms (NMS) are also evident that appear to have a greater impact on the quality
of life of these patients.
In recent years, it has become increasingly apparent that neurobiological processes
can be modified by the bi-directional communication that occurs along the brain-gut
axis. The microbiota plays a key role in this communication throughout different routes
in both physiological and pathological conditions. Thus, there has been an increasing
interest in investigating how microbiota changes within the gastrointestinal tract
may be implicated in health and disease including PD.
Interestingly α-synuclein-aggregates, the cardinal neuropathological feature in PD,
are present in both the submucosal and myenteric plexuses of the enteric nervous system,
prior to their appearance in the brain, indicating a possible gut to brain route of
“prion-like” spread. In this review we highlight the potential importance of gut to
brain signalling in PD with particular focus on the role of the microbiota as major
player in this communication.
Keywords
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References
- Parkinson's disease.Lancet. 2009; 373: 2055-2066
- Progress in Parkinson's disease-where do we stand?.Prog. Neurobiol. 2008; 85: 376-392
- Parkinson's disease.Lancet (London, England). 2004; 363: 1783-1793
- Lewy bodies in the enteric nervous system in Parkinson's disease.Arch. Histol. Cytol. 1989; 52: 191-194
- The importance of non-motor disturbances to quality of life in Parkinson's disease.J. Neurol. Sci. 2011; 310: 12-16
- A clinical overview of non-motor symptoms in Parkinson's disease.Arch. Ital. Biol. 2013; 151: 148-168
- Where does parkinson disease pathology begin in the brain?.J. Neuropathol. Exp. Neurol. 2002; 61: 413-426
- Gut Microbes and the Brain: Paradigm Shift in Neuroscience. vol. 34. 2014: 15490-15496
- Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour.Nat. Rev. Neurosci. 2012; 13: 701-712
- Brain-gut-microbiota axis in Parkinson's disease.World J. Gastroenterol. 2015; 21: 10609-10620
- Delineating nonmotor symptoms in early Parkinson's disease and first-degree relatives.Mov. Disord. 2015; 30: 1759-1766
- Gastrointestinal dysfunction in Parkinson's disease.Lancet. Neurol. 2015; 14: 625-639
- Frequency of bowel movements and the future risk of Parkinson's disease.Neurology. 2001; 57: 456-462
- Medical records documentation of constipation preceding Parkinson disease: a case-control study.Neurology. 2009; 73: 1752-1758
- Alimentary, my dear Watson? The challenges of enteric alpha-synuclein as a Parkinson's disease biomarker.Mov. Disord. Off. J. Mov. Disord. Soc. 2014; 29: 444-450
- Pathological correlates of gastrointestinal dysfunction in Parkinson's disease.Neurobiol. Dis. 2012; 46: 559-564
- Parkinson's disease is not associated with gastrointestinal myenteric ganglion neuron loss.Acta Neuropathol. 2012; 124: 665-680
- Appraisal of the dopaminergic and noradrenergic innervation of the submucosal plexus in PD.J. Parkinson's Dis. 2014; 4: 571-576
- Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats.Acta Neuropathol. 2014; 128: 805-820
- Causes and consequences of degeneration of the dorsal motor nucleus of the vagus nerve in Parkinson's disease.Antioxid. Redox Signal. 2014; 21: 649-667
- Gastrointestinal dysfunction in idiopathic Parkinson's disease.Der Nervenarzt. 2012; 83: 1282-1291
- The role of the vagal pathway and gastric dopamine in the gastroparesis of rats after a 6-hydroxydopamine microinjection in the substantia nigra.Acta physiol. Oxf. (Oxford, England). 2014; 211: 434-446
- Colonic inflammation in Parkinson's disease.Neurobiol. Dis. 2013; 50: 42-48
- Enteric GFAP expression and phosphorylation in Parkinson's disease.J. Neurochem. 2014; 130: 805-815
- Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease.PloS One. 2011; 6: e28032
- Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease.Mov. Disord. 2014; 29: 999-1009
- Colonic bacterial composition in Parkinson's disease.Mov. Disord. 2015; 30: 1351-1360
- Gut microbiota are related to Parkinson's disease and clinical phenotype.Mov. Disord. Off. J. Mov. Disord. Soc. 2015; 30: 350-358
- Increased urinary indoxyl sulfate (indican): new insights into gut dysbiosis in Parkinson's disease.Park. Relat. Disord. 2015; 21: 389-393
- An Essay on the Shaking Palsy.Sherwood, Nealy, Jones, London1817
- Pain in Parkinson disease: a review of the literature.Park. Relat. Disord. 2013; 19 (discussion 285): 285-294
- Evidence that the substantia nigra is a component of the endogenous pain suppression system in the rat.Brain Res. 1988; 447: 116-121
- Pains in Parkinson disease–many syndromes under one umbrella.Nat. Rev. Neurol. 2012; 8: 284-294
- Musculoskeletal problems in Parkinson's disease.J. Neural Transm. 2013; 120: 537-542
- Primary sensory symptoms in parkinsonism.Neurology. 1976; 26: 423-429
- Levodopa raises objective pain threshold in Parkinson's disease: a RIII reflex study.J. Neurol. Neurosurg. Psychiatry. 2007; 78: 1140-1142
- Noradrenergic pain modulation.Prog. Neurobiol. 2006; 80: 53-83
- Apomorphine effect on pain threshold in Parkinson's disease: a clinical and positron emission tomography study.Mov. Disord. 2011; 26: 153-157
- Parkinson's disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons.Acta Neuropathol. 2007; 113: 421-429
- Symptoms and duration of the prodromal phase in Parkinson's disease.Mov. Disord. Off. J. Mov. Disord. Soc. 1997; 12: 871-876
- Parkinson disease: depression and anxiety in Parkinson disease.Nat. Rev. Neurol. 2010; 6: 243-245
- Depression in Parkinson disease–epidemiology, mechanisms and management.Nat. Rev. Neurol. 2012; 8: 35-47
- Anxiety disorders in Parkinson's disease: prevalence and risk factors.Mov. Disord. Off. J. Mov. Disord. Soc. 2010; 25: 838-845
- Glucocorticoids, depression, and mood disorders: structural remodeling in the brain.Metab. Clin. Exp. 2005; 54: 20-23
- Depressive-like phenotype induced by AAV-mediated overexpression of human α-synuclein in midbrain dopaminergic neurons.Exp. Neurol. 2015; 273: 243-252
- Antidepressant-like effect of brain-derived neurotrophic factor (BDNF).Pharmacol. Biochem. Behav. 1997; 56: 131-137
- Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression.J. Neurosci. Off. J. Soc. Neurosci. 2002; 22: 3251-3261
- Pain and its relationship to depression in Parkinson disease.Am. J. Geriatr. Psychiatry Off. J. Am. Assoc. Geriatr. Psychiatry. 2009; 17: 269-275
- The microbiome-gut-brain axis: from bowel to behavior.Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 2011; 23: 187-192
- The microbiota-gut-brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both?.J. Physiol. 2014; 592: 2989-2997
- Review article: modulation of the brain–gut axis as a therapeutic approach in gastrointestinal disease.Aliment. Pharmacol. Ther. 2006; 24: 919-933
- Gut microbiota and gastrointestinal health: current concepts and future directions.Neurogastroenterol. Motil. 2013; 25: 4-15
- Brain-gut interactions in inflammatory bowel disease.Gastroenterology. 2013; 144: 36-49
- Probiotics treatment improves diabetes-induced impairment of synaptic activity and cognitive function: behavioral and electrophysiological proofs for microbiome-gut-brain axis.Neuroscience. 2013; 240: 287-296
- Brain-gut-microbe communication in health and disease.Front. Physiol. 2011; 2: 94
- Gut feelings: the emerging biology of gut-brain communication.Nat. Rev. Neurosci. 2011; 12: 453-466
- The gut microbiota and nonalcoholic fatty liver disease.Semin. Liver Dis. 2015; 35: 262-269
- The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.Mol. Psychiatry. 2013; 18: 666-673
- Serotonin, tryptophan metabolism and the brain-gut-microbiome axis.Behav. Brain Res. 2015; 277: 32-48
- The microbiota-gut-brain axis: learning from intestinal bacteria?.Gut. 2011; 60: 288-289
- The interplay between the intestinal microbiota and the brain.Nat. Rev. Microbiol. 2012; 10: 735-742
- Principles and clinical implications of the brain-gut-enteric microbiota axis.Nat. Rev. Gastroenterol. Hepatol. 2009; 6: 306-314
- Maternal separation as a model of brain-gut axis dysfunction.Psychopharmacology (Berl). 2011; 214: 71-88
- The brain-gut axis in abdominal pain syndromes.Annu. Rev. Med. 2011; 62: 381-396
- Colonic bacterial composition in Parkinson's disease.Mov. Disord. Off. J. Mov. Disord. Soc. 2015; 30: 1351-1360
- Protective effect of vagotomy suggests source organ for Parkinson disease.Ann. Neurol. 2015; 78: 834-835
- Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 16050-16055
- Use of probiotics for the treatment of constipation in Parkinson's disease patients.Minerva Gastroenterol. Dietol. 2011; 57: 117-121
- The impact of gut microbiota on brain and behaviour: implications for psychiatry.Curr. Opin. Clin. Nutr. Metab. Care. 2015; 18: 552-558
- Prevalence of small intestinal bacterial overgrowth in Parkinson's disease.Mov. Disord. 2011; 26: 889-892
- Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 2: response of facets of clinical idiopathic parkinsonism to Helicobacter pylori eradication. A randomized, double-blind, placebo-controlled efficacy study.Helicobacter. 2005; 10: 276-287
- The role of small intestinal bacterial overgrowth in Parkinson's disease.Mov. Disord. 2013; 28: 1241-1249
- Reduced L-dopa absorption and increased clinical fluctuations in Helicobacter pylori-infected Parkinson's disease patients.Neurol. Sci. Off. J. Ital. Neurol. Soc. Ital. Soc. Clin. Neurophysiol. 2001; 22: 89-91
- Differential effect of Helicobacter pylori eradication on time-trends in brady/hypokinesia and rigidity in idiopathic parkinsonism.Helicobacter. 2010; 15: 279-294
- Antimicrobial surveillance in idiopathic parkinsonism: indication-specific improvement in hypokinesia following Helicobacter pylori eradication and non-specific effect of antimicrobials for other indications in worsening rigidity.Helicobacter. 2013; 18: 187-196
- Peripheral aetiopathogenic drivers and mediators of Parkinson’s disease and co-morbidities: role of gastrointestinal microbiota.J. Neurovirol. 2015; : 1-11
- Influence of microbial species on small intestinal myoelectric activity and transit in germ-free rats.Am. J. Physiol. Gastrointest. Liver Physiol. 2001; 280: G368-G380
- Microflora modulation of motility.J. Neurogastroenterol. Motil. 2011; 17: 140
- Gastroparesis and Parkinson's disease: a systematic review.Park. Relat. Disord. 2012; 18: 433-440
- Potential role of gut microbiota and tissue barriers in Parkinson's disease and amyotrophic lateral sclerosis.Int. J. Neurosci. 2015; : 1-18
- Microbiota-host interactions in irritable bowel syndrome: epithelial barrier, immune regulation and brain-gut interactions.World J. Gastroenterol. 2014; 20: 8859-8866
- Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice.Gut Microbes. 2014; 0
- Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats.Neuroscience. 2014; 277: 885-901
- Effect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome.Gut Microbes. 2014; 5: 430-436
- Commensal microbiota is fundamental for the development of inflammatory pain.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 2193-2197
- Migraine associated with gastrointestinal disorders: review of the literature and clinical implications.Front. Neurol. 2014; 5: 241
- Does the microbiota play a role in the pathogenesis of autoimmune diseases?.Gut. 2015; 64: 332-341
- An osteopathic approach to gastrointestinal disease: somatic clues for diagnosis and clinical challenges associated with Helicobacter pylori antibiotic resistance.J. Am. Osteopath Assoc. 2013; 113: 404-416
- Gastrointestinal bacterial overgrowth: pathogenesis and clinical significance.Ther. Adv. Chronic Dis. 2013; 4: 223-231
- Helicobacter pylori infection and Parkinson's disease: apoptosis as an underlying common contributor.Eur. J. Neurol. 2012; 19: e56
- The role of microbiome in central nervous system disorders.Brain Behav. Immun. 2014; 38: 1-12
- Brain-gut microbiome interactions and functional bowel disorders.Gastroenterology. 2014; 146: 1500-1512
- The relevance of pre-motor symptoms in Parkinson's disease.Expert Rev. Neurother. 2015; 15: 1205-1217
- Normal gut microbiota modulates brain development and behavior.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 3047-3052
- Reduced anxiety-like behavior and central neurochemical change in germ-free mice.Neurogastroenterol. Motil. 2010; 23 (255–264, e119)
- Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats.Psychoneuroendocrinology. 2014; https://doi.org/10.1016/j.psyneuen.2014.1001.1014
- The intestinal microbiota affect Central levels of brain-derived neurotropic factor and behavior in mice.Gastroenterology. 2011; 141 (599–609.e593)
- Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior.Brain Behav. Immun. 2008; 22: 354-366
- Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium.Physiol. Behav. 2006; 89: 350-357
- Anxiogenic effect of subclinical bacterial infection in mice in the absence of overt immune activation.Physiol. Behav. 1998; 65: 63-68
- The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication.Neurogastroenterol. Motil. 2011; 23: 1132-1139
- Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve.Proc. Natl. Acad. Sci. 2011; 108: 16050-16055
- Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.Gastroenterology. 2010; 139 (2102–2112. e2101)
- Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.Biol. Psychiatry. 2009; 65: 263-267
- Altered colonic function and microbiota profile in a mouse model of chronic depression.Neurogastroenterol. Motil. 2013; 25 (733–e575)
- Melancholic microbes: a link between gut microbiota and depression?.Neurogastroenterol. Motil. 2013; 25: 713-719
- The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat.J. Psychiatr. Res. 2008; 43: 164-174
- Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.Br. J. Nutr. 2011; 105: 755-764
- Novel therapeutic targets in depression: minocycline as a candidate treatment.Behav. Brain Res. 2012; 235: 302-317
- Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study.Prog. Neuropsychopharmacol. Biol. Psychiatry. 2012; 37: 222-226
- The potential of minocycline for neuroprotection in human neurologic disease.Clin. Neuropharmacol. 2004; 27: 293-298
- Gut feelings about smoking and coffee in Parkinson's disease.Mov. Disord. 2014; 29: 976-979
- Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles.Gastroenterology. 2005; 128: 541-551
- Consumption of fermented milk product with probiotic modulates brain activity.Gastroenterology. 2013; 144 (1401 e1391–1394): 1394-1401
- A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome.Gut Pathog. 2009; 1: 6
- Major nutritional issues in the management of Parkinson's disease.Mov. Disord. 2009; 24: 1881-1892
- Mediterranean diet polyphenols reduce inflammatory angiogenesis through MMP-9 and COX-2 inhibition in human vascular endothelial cells: a potentially protective mechanism in atherosclerotic vascular disease and cancer.Arch. Biochem. Biophys. 2012; 527: 81-89
- Intestinal microbiota, probiotics and mental health: from Metchnikoff to modern advances: part III - convergence toward clinical trials.Gut Pathog. 2013; 5: 4
- Consumption of dairy products and risk of Parkinson's disease.Am. J. Epidemiol. 2007; 165: 998-1006
- Effect of probiotic species on irritable bowel syndrome symptoms: a bring up to date meta-analysis.Rev. Esp. Enferm. Dig. 2013; 105: 19-36
- An update on the use and investigation of probiotics in health and disease.Gut. 2013; 62: 787-796
- Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders.Front. Cell. Neurosci. 2015; 9: 392
- High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway.PloS One. 2012; 7: e47713
- Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 9066-9071
- Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats.Psychoneuroendocrinology. 2014; 42: 207-217
- Normal gut microbiota modulates brain development and behavior.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 3047-3052
- Neurotrophic factors: from neurodevelopmental regulators to novel therapies for Parkinson's disease.Neural Regen. Res. 2014; 9: 1708-1711
- Viral vector delivery of neurotrophic factors for Parkinson's disease therapy.Expert Rev. Mol. Med. 2015; 17: e8
Article info
Publication history
Published online: March 16, 2016
Accepted:
March 15,
2016
Received in revised form:
February 15,
2016
Received:
November 5,
2015
Footnotes
Editor's Comment: There has been a veritable explosion of information in recent years examining and linking changes in the gut with changes in the brain in Parkinson's disease (PD). The latest frontier in this exploration is the recognition that changes in the microbiome of the gut are present in patients with PD. Felice and colleagues provide an in-depth and up-to-date review of these changes and the potential implications they may have, not only for gastrointestinal function in Parkinson's disease but also for other non-motor PD features. This is a revealing and fascinating exposition that is a must-read!
Ronald F. Pfeiffer, Editor-in-Chief, Dept. of Neurology, Oregon Health and Science University (OHSU), 3181 SW Sam Jackson Park Rd, Portland, OR 97201-3098, Oregon, USA
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