Gut Microbiota Dysfunction as Reliable Non-invasive Early Diagnostic Biomarkers in the Pathophysiology of Parkinson's Disease: A Critical Review

Arun T Nair, Vadivelan Ramachandran, Nanjan M Joghee, Shanish Antony, Gopalakrishnan Ramalingam, Arun T Nair, Vadivelan Ramachandran, Nanjan M Joghee, Shanish Antony, Gopalakrishnan Ramalingam

Abstract

Recent investigations suggest that gut microbiota affects the brain activity through the microbiota-gut-brain axis under both physiological and pathological disease conditions like Parkinson's disease. Further dopamine synthesis in the brain is induced by dopamine producing enzymes that are controlled by gut microbiota via the microbiota-gut-brain axis. Also alpha synuclein deposition and the associated neurodegeneration in the enteric nervous system that increase intestinal permeability, oxidative stress, and local inflammation, accounts for constipation in Parkinson's disease patients. The trigger that causes blood brain barrier leakage, immune cell activation and inflammation, and ultimately neuroinflammation in the central nervous system is believed to be due to the chronic low-grade inflammation in the gut. The non-motor symptoms that appear years before motor symptoms could be reliable early biomarkers, if they could be correlated with the established and reliable neuroimaging techniques or behavioral indices. The future directions should therefore, focus on the exploration of newer investigational techniques to identify these reliable early biomarkers and define the specific gut microbes that contribute to the development of Parkinson's disease. This ultimately should pave the way to safer and novel therapeutic approaches that avoid the complications of the drugs delivered today to the brain of Parkinson's disease patients.

Keywords: Biomarkers; Constipation; Gastrointestinal microbiome; Humans alpha synuclein; Parkinson disease.

Conflict of interest statement

Conflicts of interest: None.

Figures

Figure
Figure
Gut inflammation driven gastrointestinal dysfunction mediated Parkinson’s disease (PD) pathogenesis model. BBB, blood brain barrier. Adapted from Yarandi et al and Houser and Tansey.

References

    1. Tysnes OB, Storstein A. Epidemiology of Parkinson’s disease. J Neural Transm. 2017;124:901–905. doi: 10.1007/s00702-017-1686-y.
    1. Statistics on Parkinson’s disease. Parkinson Association of the Carolinas; [accessed 11 December, 2017]. Available from URL:
    1. Schapira AH. Recent developments in biomarkers in Parkinson disease. Curr Opin Neurol. 2013;26:395–400. doi: 10.1097/WCO.0b013e3283633741.
    1. Kalia LV, Lang AE. Parkinson’s disease. Lancet. 2015;386:896–912. doi: 10.1016/S0140-6736(14)61393-3.
    1. Garcia-Ruiz PJ, Chaudhuri KR, Martinez-Martin P. Non-motor symptoms of parkinson’s disease a review from the past. J Neurol Sci. 2014;338:30–33. doi: 10.1016/j.jns.2014.01.002.
    1. Dietert J, Dietert R. The sum of our parts. Scientist. 2015;29:44–49.
    1. Fond G, Boukouaci W, Chevalier G, et al. The “psychomicrobiotic”: targeting microbiota in major psychiatric disorders: a systematic review. Pathol Biol (Paris) 2015;63:35–42. doi: 10.1016/j.patbio.2014.10.003.
    1. Forsythe P, Sudo N, Dinan T, Taylor VH, Bienenstock J. Mood and gut feelings. Brain Behav Immun. 2010;24:9–16. doi: 10.1016/j.bbi.2009.05.058.
    1. Shakir R. Neurodegenerative noncommunicable diseases (Neurology NCDs). Where are we now? J Neurol Sci. 2015;356:1–2. doi: 10.1016/j.jns.2015.07.005.
    1. Silberberg D, Anand NP, Michels K, Kalaria RN. Brain and other nervous system disorders across the lifespan - global challenges and opportunities. Nature. 2015;527:S151–S154. doi: 10.1038/nature16028.
    1. Wolters ECh, Braak H. Parkinson’s disease: premotor clinico-pathological correlations. J Neural Transm Suppl. 2006;70:309–319. doi: 10.1007/978-3-211-45295-0_47.
    1. Sulzer D. Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci. 2007;30:244–250. doi: 10.1016/j.tins.2007.03.009.
    1. Doudet D, Ruth T. Imaging the brain in Parkinson’s disease. BC Med. 2001;3:148–152.
    1. Rascol O, Payoux P, Ory F, Ferreira JJ, Brefel-Courbon C, Montastruc JL. Limitations of current Parkinson’s disease therapy. Ann Neuro. 2003;53:S3–12. doi: 10.1002/ana.10513. discussion S12–S15.
    1. Murman DL. Early treatment of Parkinson’s disease: opportunities for managed care. Am J Manag Care. 2012;18:S183–S188.
    1. Lancet Neurology. Building on 50 years of levodopa therapy. Lancet Neurol. 2016;15:1. doi: 10.1016/S1474-4422(15)00349-X.
    1. Picillo M, Moccia M, Spina E, Barone P, Pellecchia MT. Biomarkers of Parkinson’s disease: recent insights, current challenges, and future prospects. J Parkinsonism Restless Legs Syndr. 2016;6:1–13.
    1. DeKosky ST, Marek K. Looking backward to move forward: early detection of neurodegenerative disorders. Science. 2003;302:830–834. doi: 10.1126/science.1090349.
    1. Scherzer C. Interview-Searching for biomarkers in Parkinson’s disease. Biomark Med. 2009;3:1134. doi: 10.2217/bmm.09.10.
    1. O’Sullivan SS, Williams DR, Gallagher DA, Massey LA, Silveira-Moriyama L, Lees AJ. Nonmotor symptoms as presenting complaints in Parkinson’s disease: a clinico pathological study. Mov Disord. 2008;23:101–106. doi: 10.1002/mds.21813.
    1. Barber TR, Klein JC, Mackay CE, Hu MTM. Neuroimaging in pre-motor Parkinson’s disease. Neuroimage Clin. 2017;15:215–227. doi: 10.1016/j.nicl.2017.04.011.
    1. Cryan JF, O’Mahony SM. The microbiome-gut-brain axis: from bowel to behavior. Neurogastroenterol Motil. 2011;23:187–192. doi: 10.1111/j.1365-2982.2010.01664.x.
    1. De Palma G, Collins SM, Bercik P, Verdu EF. The microbiota-gut-brain axis in gastrointestinal disorders: stressed bugs, stressed brain or both? J Physiol. 2014;592:2989–2997. doi: 10.1113/jphysiol.2014.273995.
    1. Mayer EA, Tillisch K, Bradesi S. Review article: modulation of the brain–gut axis as a therapeutic approach in gastrointestinal disease. Aliment Pharmacol Ther. 2006;24:919–933. doi: 10.1111/j.1365-2036.2006.03078.x.
    1. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13:701–712. doi: 10.1038/nrn3346.
    1. Aziz Q, Doré J, Emmanuel A, Guarner F, Quigley EM. Gut micro-biota and gastrointestinal health: current concepts and future directions. Neurogastroenterol Motil. 2013;25:4–15. doi: 10.1111/nmo.12046.
    1. Bonaz BL, Bernstein CN. Brain-gut interactions in inflammatory bowel disease. Gastroenterology. 2013;144:36–49. doi: 10.1053/j.gastro.2012.10.003.
    1. Davari S, Talaei SA, Alaei H, Salami M. 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. doi: 10.1016/j.neuroscience.2013.02.055.
    1. Grenham S, Clarke G, Cryan JF, Dinan TG. Brain-gut-microbe communication in health and disease. Front Physiol. 2011;2:94. doi: 10.3389/fphys.2011.00094.
    1. Mayer EA. Gut feelings: the emerging biology of gut-brain communication. Nat Rev Neurosci. 2011;12:453–466. doi: 10.1038/nrn3071.
    1. Quigley EM, Monsour HP. The gut microbiota and nonalcoholic fatty liver disease. Semin Liver Dis. 2015;35:262–269. doi: 10.1055/s-0035-1562946.
    1. O’Mahony SM, Hyland NP, Dinan TG, Cryan JF. Maternal separation as a model of brain-gut axis dysfunction. Psychopharmacology (Berl) 2011;214:71–88. doi: 10.1007/s00213-010-2010-9.
    1. Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol. 2009;6:306–314. doi: 10.1038/nrgastro.2009.35.
    1. Thakur AK, Shakya A, Husain GM, Emerald M, Kumar V. Gut-microbiota and mental health: current and future perspectives. J Pharmacol Clin Toxicol. 2014;2:1016.
    1. Blekhman R, Goodrich JK, Huang K, et al. Host genetic variation impacts microbiome composition across human body sites. Genome Biol. 2015;16:191. doi: 10.1186/s13059-015-0759-1.
    1. Bäckhed F, Roswall J, Peng Y, et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe. 2015;17:690–703. doi: 10.1016/j.chom.2015.04.004.
    1. Debnath M, Venkatasubramanian G, Berk M. Fetal programming of schizophrenia: select mechanisms. Neurosci Biobehav Rev. 2015;49:90–104. doi: 10.1016/j.neubiorev.2014.12.003.
    1. Dominguez-Bello MG, Blaser MJ. Asthma: undoing millions of years of coevolution in early life? Sci Transl Med. 2015;7:307fs39. doi: 10.1126/scitranslmed.aad2741.
    1. Van Opstal EJ, Bordenstein SR. Rethinking heritability of the microbiome. Science. 2015;349:1172–1173. doi: 10.1126/science.aab3958.
    1. Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med. 2016;22:250–253. doi: 10.1038/nm.4039.
    1. Gomez de Agüero M, Ganal-Vonarburg SC, Fuhrer T, et al. The maternal microbiota drives early postnatal innate immune development. Science. 2016;351:1296–1302. doi: 10.1126/science.aad2571.
    1. Al-Asmakh M, Hedin L. Microbiota and the control of blood-tissue barriers. Tissue Barriers. 2015;3:e1039691. doi: 10.1080/21688370.2015.1039691.
    1. McKenney PT, Pamer EG. From hype to hope: the gut microbiota in enteric infectious disease. Cell. 2015;163:1326–1332. doi: 10.1016/j.cell.2015.11.032.
    1. Scharschmidt TC, Vasquez KS, Truong HA, et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity. 2015;43:1011–1021. doi: 10.1016/j.immuni.2015.10.016.
    1. Wang Z, Roberts AB, Buffa JA, et al. Non-lethal inhibition of gut microbial tri methylamine production for the treatment of atherosclerosis. Cell. 2015;163:1585–1595. doi: 10.1016/j.cell.2015.11.055.
    1. Yang I, Corwin EJ, Brennan PA, Jordan S, Murphy JR, Dunlop A. The infant microbiome: Implications for infant health and neurocognitive development. Nurs Res. 2016;65:76–88. doi: 10.1097/NNR.0000000000000133.
    1. Hinde K, Lewis ZT. Mother’s littlest helpers. Science. 2015;348:1427–1428. doi: 10.1126/science.aac7436.
    1. Meadow JF, Altrichter AE, Bateman AC, et al. Humans differ in their personal microbial cloud. Peer J. 2015;3:e1258. doi: 10.7717/peerj.1258.
    1. Zeevi D, Korem T, Zmora N, et al. Personalized nutrition by prediction of glycemic responses. Cell. 2015;163:1079–1094. doi: 10.1016/j.cell.2015.11.001.
    1. Zuker CS. Food for the brain. Cell. 2015;161:9–11. doi: 10.1016/j.cell.2015.03.016.
    1. Collins SM, Surette M, Bercik P. The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol. 2012;10:735–742. doi: 10.1038/nrmicro2876.
    1. Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest. 2015;125:926–938. doi: 10.1172/JCI76304.
    1. Sampson TR, Mazmanian SK. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe. 2015;17:565–576. doi: 10.1016/j.chom.2015.04.011.
    1. Friedland RP. Mechanisms of molecular mimicry involving the micro-biota in neurodegeneration. J Alzheimers Dis. 2015;45:349–362.
    1. Del Tredici K, Rüb U, De Vos RA, Bohl JR, Braak H. Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol. 2002;61:413–426. doi: 10.1093/jnen/61.5.413.
    1. Ueki A, Otsuka M. Life style risks of Parkinson’s disease: association between decreased water intake and constipation. J Neurol. 2004;251(suppl 7):vII18–vII23. doi: 10.1007/s00415-004-1706-3.
    1. Cersosimo MG, Benarroch EE. Pathological correlates of gastrointestinal dysfunction in Parkinson’s disease. Neurobiol Dis. 2012;46:559–564. doi: 10.1016/j.nbd.2011.10.014.
    1. Forsyth CB, Shannon KM, Kordower JH, et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early parkinson’s disease. PLoS One. 2011;6:e28032. doi: 10.1371/journal.pone.0028032.
    1. Devos D, Lebouvier T, Lardeux B, et al. Colonic inflammation in parkinson’s disease. Neurobiol Dis. 2013;50:42–48. doi: 10.1016/j.nbd.2012.09.007.
    1. Poewe W. Non-motor symptoms in Parkinson’s disease. Eur J Neurol. 2008;15(suppl 1):14–20. doi: 10.1111/j.1468-1331.2008.02056.x.
    1. Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in meissner’s and auerbach’s plexuses in cases staged for parkinson’s disease related brain pathology. Neurosci Lett. 2006;396:67–72. doi: 10.1016/j.neulet.2005.11.012.
    1. Shannon KM, Keshavarzian A, Dodiya HB, Jakate S, Kordower JH. Is alpha-synuclein in the colon a biomarker for premotor Parkinson’s disease? Evidence from 3 cases. Mov Disord. 2012;27:716–719. doi: 10.1002/mds.25020.
    1. Kieburtz K, Wunderle KB. Parkinson’s disease: evidence for environmental risk factors. Mov Disord. 2013;28:8–13. doi: 10.1002/mds.25150.
    1. Savica R, Carlin JM, Grossardt BR, et al. Medical records documentation of constipation preceding Parkinson disease: a case-control study. Neurology. 2009;73:1752–1758. doi: 10.1212/WNL.0b013e3181c34af5.
    1. Çamci G, Oğuz S. Association between Parkinson’s disease and helicobacter pylori. J Clin Neurol. 2016;12:47–50. doi: 10.3988/jcn.2016.12.2.147.
    1. Fasano A, Bove F, Gabrielli M, et al. The role of small intestinal bacterial overgrowth in Parkinson’s disease. Mov Disord. 2013;28:1241–1249. doi: 10.1002/mds.25522.
    1. Tan AH, Mahadeva S, Thalha AM, et al. Small intestinal bacterial overgrowth in Parkinson’s disease. Parkinsonism Relat Disord. 2014;20:535–540. doi: 10.1016/j.parkreldis.2014.02.019.
    1. Keshavarzian A, Green SJ, Engen PA, et al. Colonic bacterial composition in Parkinson’s disease. Mov Disord. 2015:1351–1360. doi: 10.1002/mds.26307.
    1. Eisenhofer G, Aneman A, Friberg P, et al. Substantial production of dopamine in the human gastrointestinal tract. J Clin Endocrinol Metab. 1997;82:3864–3871. doi: 10.1210/jcem.82.11.4339.
    1. Wall R, Cryan JF, Ross RP, Fitzgerald GF, Dinan TG, Stanton C. Bacterial neuroactive compounds produced by psychobiotics. Adv Exp Med Biol. 2014;817:221–239. doi: 10.1007/978-1-4939-0897-4_10.
    1. Brenner SR. Blue-green algae or cyanobacteria in the intestinal micro-flora may produce neurotoxins such as Beta-N-Methylamino-L-Alanine (BMAA) which may be related to development of Amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson-dementia-complex in humans and equine motor neuron disease in horses. Med Hypotheses. 2013;80:103. doi: 10.1016/j.mehy.2012.10.010.
    1. Edelblum KL, Turner JR. The tight junction in inflammatory disease: communication breakdown. Curr Opin Pharmacol. 2009;9:715–720. doi: 10.1016/j.coph.2009.06.022.
    1. Scher JU, Ubeda C, Artacho A, et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol. 2015;67:128–139. doi: 10.1002/art.38892.
    1. Rana SV. Small intestinal bacterial overgrowth and orocecal transit time in patients of inflammatory bowel disease. Dig Dis Sci. 2013;58:2594–2598. doi: 10.1007/s10620-013-2694-x.
    1. Kelly LP, Carvey PM, Keshavarzian A, et al. Progression of intestinal permeability changes and alphasynuclein expression in a mouse model of Parkinson’s disease. Mov Disord. 2014;29:999–1009. doi: 10.1002/mds.25736.
    1. Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2:a008888. doi: 10.1101/cshperspect.a008888.
    1. Fraher MH, O’Toole PW, Quigley EM. Techniques used to characterize the gut microbiota : a guide for the clinician. Nat Rev Gastroenterol Hepatol. 2012;9:312–322. doi: 10.1038/nrgastro.2012.44.
    1. Dutkiewicz J, Szlufik S, Nieciecki M, et al. Small intestine dysfunction in Parkinson’s disease. J Neural Transm (Vienna) 2015;122:1659–1661. doi: 10.1007/s00702-015-1442-0.
    1. Sakakibara R, Odaka T, Uchiyama T, et al. Colonic transit time and rectoanal video manometry in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2003;74:268–272. doi: 10.1136/jnnp.74.2.268.
    1. Goldman JG, Postuma R. Premotor and non-motor features of Parkin-son’s disease. Curr Opin Neurol. 2014;27:434–441. doi: 10.1097/WCO.0000000000000112.
    1. Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology. 2001;57:456–462. doi: 10.1212/WNL.57.3.456.
    1. Gao X, Chen H, Schwarzschild MA, Ascherio A. A prospective study of bowel movement frequency and risk of Parkinson’s disease. Am J Epidemiol. 2011;174:546–551. doi: 10.1093/aje/kwr119.
    1. Chen H, Zhao EJ, Zhang W, et al. Meta-analyses on prevalence of selected Parkinson’s non motor symptoms before and after diagnosis. Transl Neurodegener. 2015;4:1. doi: 10.1186/2047-9158-4-1.
    1. Adams-Carr KL, Bestwick JP, Shribman S, Lees A, Schrag A, Noyce AJ. Constipation preceding Parkinson’s disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2015;87:710–716. doi: 10.1136/jnnp-2015-311680.
    1. Postuma RB, Gagnon JF, Pelletier A, Montplaisir J. Prodromal autonomic symptoms and signs in parkinson’s disease and dementia with lewy bodies. Mov Disord. 2013;28:597–604. doi: 10.1002/mds.25445.
    1. Gold A, Turkalp ZT, Munoz DG. Enteric alpha-synuclein expression is increased in Parkinson’s disease but not Alzheimer’s disease. Mov Disord. 2013;28:237–240. doi: 10.1002/mds.25298.
    1. Hilton D, Stephens M, Kirk L, et al. Accumulation of alpha-synuclein in the bowel of patients in the pre-clinical phase of Parkinson’s disease. Acta Neuropathol. 2014;127:235–241. doi: 10.1007/s00401-013-1214-6.
    1. Shannon KM, Keshavarzian A, Mutlu E, et al. Alpha-synuclein in colonic submucosa in early untreated parkinson’s disease. Mov Disord. 2012;27:709–715. doi: 10.1002/mds.23838.
    1. Wang L, Fleming SM, Chesselet MF, Taché Y. Abnormal colonic motility in mice over expressing human wild-type alpha-synuclein. Neuroreport. 2008;19:873–876. doi: 10.1097/WNR.0b013e3282ffda5e.
    1. Hallett PJ, McLean JR, Kartunen A, Langston JW, Isacson O. Alpha-synuclein over expressing transgenic mice shows internal organ pathology and autonomic deficits. Neurobiol Dis. 2012;47:258–267. doi: 10.1016/j.nbd.2012.04.009.
    1. Beach TG, Adler CH, Sue LI, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with lewy body disorders. Acta Neuropathol. 2010;119:689–702. doi: 10.1007/s00401-010-0664-3.
    1. Lebouvier T, Neunlist M, Bruley des Varannes S, et al. Colonic biopsies to assess the neuropathology of parkinson’s disease and its relationship with symptoms. PLoS One. 2010;5:e12728. doi: 10.1371/journal.pone.0012728.
    1. Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F. Parkin-son’s disease: the presence of lewy bodies in auerbach’s and meissner’s plexuses. Acta Neuropathol. 1988;76:217–221. doi: 10.1007/BF00687767.
    1. Lebouvier T, Chaumette T, Damier P, et al. Pathological lesions in colonic biopsies during parkinson’s disease. Gut. 2008;57:1741–1743. doi: 10.1136/gut.2008.162503.
    1. Clairembault T, Leclair-Visonneau L, Coron E, et al. Structural alterations of the intestinal epithelial barrier in parkinson’s disease. Acta Neuropathol Commun. 2015;3:12. doi: 10.1186/s40478-015-0196-0.
    1. Shaikh M, Rajan K, Forsyth CB, Voigt RM, Keshavarzian A. Simultaneous gas-chromatographic urinary measurement of sugar probes to assess intestinal permeability: use of time course analysis to optimize its use to assess regional gut permeability. Clin Chim Acta. 2015;442:24–32. doi: 10.1016/j.cca.2014.12.040.
    1. Hasegawa S, Goto S, Tsuji H, et al. Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in parkinson’s disease. PLoS One. 2015;10:e0142164. doi: 10.1371/journal.pone.0142164.
    1. Salat-Foix D, Tran K, Ranawaya R, Meddings J, Suchowersky O. Increased intestinal permeability and Parkinson disease patients: chicken or egg? Can J Neurol Sci. 2012;39:185–188. doi: 10.1017/S0317167100013202.
    1. Gabrielli M, Bonazzi P, Scarpellini E, et al. Prevalence of small intestinal bacterial overgrowth in parkinson’s disease. Mov Disord. 2011;26:889–892. doi: 10.1002/mds.23566.
    1. Cassani E, Barichella M, Dancello R, et al. Increased urinary indoxyl sulfate (indican): new insights into gut dysbiosis in Parkinson’s disease. Parkinsonism Relat Disord. 2015;21:389–393. doi: 10.1016/j.parkreldis.2015.02.004.
    1. Scheperjans F, Aho V, Pereira PA, et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord. 2015;30:350–358. doi: 10.1002/mds.26069.
    1. Soret R, Chevalier J, De Coppet P, et al. Short-chain fatty acids regulate the enteric neurons and control gastrointestinal motility in rats. Gastroenterology. 2010;138:1772–1782. doi: 10.1053/j.gastro.2010.01.053.
    1. Unger MM, Spiegel J, Dillmann KU, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord. 2016;32:66–72. doi: 10.1016/j.parkreldis.2016.08.019.
    1. Mukherjee A, Biswas A, Das SK. Gut dysfunction in Parkinson’s disease. World J Gastroenterol. 2016;22:5742–5752. doi: 10.3748/wjg.v22.i25.5742.
    1. Förster C. Tight junctions and the modulation of barrier function in disease. Histochem Cell Biol. 2008;130:55–70. doi: 10.1007/s00418-008-0424-9.
    1. Dobbs RJ, Charlett A, Dobbs SM, et al. Leukocyte-subset counts in idiopathic Parkinsonism provide clues to a pathogenic pathway involving small intestinal bacterial over growth. A surveillance study. Gut Pathog. 2012;4:12. doi: 10.1186/1757-4749-4-12.
    1. Charlett A, Dobbs RJ, Purkiss AG, et al. Cortisol is higher in Parkin-sonism and associated with gait deficit. Acta Neurol Scand. 1998;97:77–85. doi: 10.1111/j.1600-0404.1998.tb00614.x.
    1. Dobbs RJ, Charlett A, Purkiss AG, Dobbs SM, Weller C, Peterson DW. Association of circulating TNF-alpha and IL-6 with ageing and Parkinsonism. Acta Neurol Scand. 1999;100:34–41. doi: 10.1111/j.1600-0404.1999.tb00721.x.
    1. Reale M, Iarlori C, Thomas A, et al. Peripheral cytokines profile in parkinson’s disease. Brain Behav Immun. 2009;23:55–63. doi: 10.1016/j.bbi.2008.07.003.
    1. Chen H, O’Reilly EJ, Schwarzschild MA, Ascherio A. Peripheral inflammatory biomarkers and risk of Parkinson’s disease. Am J Epidemiol. 2008;167:90–95. doi: 10.1093/aje/kwm260.
    1. Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota regulates host serotonin biosynthesis. Cell. 2015;161:264–276. doi: 10.1016/j.cell.2015.02.047.
    1. Hsu YT, Liao CC, Chang SN, et al. Increased risk of depression in patients with Parkinson disease: a nationwide cohort study. Am J Geriatr Psychiatry. 2015;23:934–940. doi: 10.1016/j.jagp.2014.10.011.
    1. Tong Q, Zhang L, Yuan Y, et al. Reduced plasma serotonin and 5-hy-droxyindoleacetic acid levels in Parkinson’s disease are associated with nonmotor symptoms. Parkinsonism Relat Disord. 2015;21:882–887. doi: 10.1016/j.parkreldis.2015.05.016.
    1. Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: Intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008;29:117–124.
    1. Schicho R, Shaykhutdinov R, Ngo J, et al. Quantitative metabolomic profiling of serum, plasma, and urine by H NMR spectroscopy discriminates between patients with inflammatory bowel disease and healthy individuals. J Proteome Res. 2012;11:3344–3357. doi: 10.1021/pr300139q.
    1. Van Berkel JJ, Dallinga JW, Möller GM, et al. A profile of volatile organic compounds in breath discriminates COPD patients from controls. Respir Med. 2010;104:557–563. doi: 10.1016/j.rmed.2009.10.018.
    1. Szczesniak O, Hestad KA, Hanssen JF, Rudi K. Isovaleric acid in stool correlates with human depression. Nutr Neurosci. 2016;19:279–283. doi: 10.1179/1476830515Y.0000000007.
    1. Liepelt-Scarfone I, Gauss K, Maetzler W, et al. Evaluation of progression markers in the premotor phase of Parkinson’s disease: the progression markers in the premotor phase study. Neuroepidemiology. 2013;41:174–182. doi: 10.1159/000353560.
    1. Saeed U, Compagnone J, Aviv RI, et al. Imaging biomarkers in Parkinson’s disease and Parkinsonian symptoms: current and emerging concepts. Transl Neurodegener. 2017;6:8. doi: 10.1186/s40035-017-0076-6.
    1. Sharma S, Moon CS. Biomarkers in Parkinson’s disease (recent update) Neurochem Int. 2013;63:201–229. doi: 10.1016/j.neuint.2013.06.005.
    1. Berg D, Godau J, Walter U. Transcranial sonography in movement disorders. Lancet Neurol. 2008;7:1044–1055. doi: 10.1016/S1474-4422(08)70239-4.
    1. Gaig C, Tolosa E. When does Parkinson’s disease begin? Mov Disord. 2009;24(suppl 2):S656–S664. doi: 10.1002/mds.22672.
    1. Tuite PJ, Mangia S. Magnetic resonance imaging (MRI) in Parkinson’s disease. J Alzheimers Dis Parkinsonism. 2013;(suppl 1):001.
    1. Poewe W, Mahlknecht P. Combined assessment of midbrain hyperechogenicity, hyposmia and motor asymmetry improves diagnostic accuracy in early Parkinson’s disease. Expert Rev Neurother. 2012;12:911–914. doi: 10.1586/ern.12.75.
    1. Shao N, Yang J, Li J, Shang HF. Voxelwise meta-analysis of gray matter anomalies in progressive supranuclear palsy and parkinson’s disease using anatomic likelihood estimation. Front Hum Neurosci. 2014;8:63. doi: 10.3389/fnhum.2014.00063.
    1. Berg D, Lang AE, Postuma RB, et al. Change the research criteria for the diagnosis of Parkinson’s disease: obstacles and opportunities. Lancet Neurol. 2013;12:514–524. doi: 10.1016/S1474-4422(13)70047-4.
    1. Berg D, Marek K, Ross GW, Poewe W. Defining at-risk populations for Parkinson ‘s disease: lessons from ongoing studies. Mov Disord. 2012;27:656–665. doi: 10.1002/mds.24985.
    1. Lerche S, Hobert M, Brochmann K, et al. Mild parkinsonian signs in the elderly – Is there an association with PD? Crossectional findings in 992 individuals. PLoS One. 2014;9:e92878. doi: 10.1371/journal.pone.0092878.
    1. Noyce AJ, Bestwick JP, Silveira-Moriyam L, et al. PREDICT-PD: Identifying risk of Parkinson’s disease in the community: methods and baseline results. J Neurol Neurosur Psychiatry. 2014;85:31–37. doi: 10.1136/jnnp-2013-305420.
    1. Berg D, Postuma RB, Bloem B, et al. Time to redefine PD? Introductory statement of the MDS task force on the definition of Parkinson’s disease. Mov Disord. 2014;29:454–462. doi: 10.1002/mds.25844.
    1. Bhidayasiri R, Reichmann H. Different diagnostic criteria for Parkinson disease: what are the pitfalls? J Neural Transm (Vienna) 2013;120:619–625. doi: 10.1007/s00702-013-1007-z.
    1. Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet. 2009;373:2055–2066. doi: 10.1016/S0140-6736(09)60492-X.
    1. Deutch AY. Parkinson’s disease redefined. Lancet Neurol. 2013;12:422–423. doi: 10.1016/S1474-4422(13)70052-8.
    1. Wang N, Gibbons CH, Lafo J, Freeman R. α-synuclein in cutaneous autonomic nerves. Neurol. 2013;81:1604–1610. doi: 10.1212/WNL.0b013e3182a9f449.
    1. del Campo M, Mollenhauer B, Bertolotto A. Recommendations to standardize preanalytical confounding factors in Alzheimer’s and Parkinson’s disease cerebrospinal fluid biomarkers: an update. Biomark Med. 2012;6:419–430. doi: 10.2217/bmm.12.46.
    1. Van Dijk KD, Teunissen CE, Drukarch B, et al. Diagnostic cerebrospinal fluid biomarkers for Parkinson’s disease: a pathogenetically based approach. Neurobiol Dis. 2010;39:229–241. doi: 10.1016/j.nbd.2010.04.020.
    1. Mielke MM, Maetzler W. A ‘bird’s eye’ view on the current status and potential benefits of blood biomarkers for Parkinson’s disease. Biomarkers Med. 2014;8:225–227. doi: 10.2217/bmm.13.139.
    1. Saracchi E, Fermi S, Brighina L. Emerging candidate biomarkers for Parkinson’s disease: a review. Aging Dis. 2013;5:27–34. doi: 10.14336/AD.2014.050027.
    1. Rappaport SM. Biomarkers intersect with the exposome. Biomarkers. 2012;17:483–489. doi: 10.3109/1354750X.2012.691553.
    1. Bogdanov M, Matson WR, Wang L, et al. Metabolomic profiling to develop blood biomarkers for Parkinson’s disease. Brain. 2008;131(pt 2):389–396. doi: 10.1093/brain/awm304.
    1. Rappaport SM, Barupal DK, Wishart D, Vineis P, Scalbert A. The blood exposome and its role in discovering causes of disease. Environ Health Perspect. 2014;122:769–774.
    1. Ahmed SS, Santosh W, Kumar S, Christlet HTT. Metabolic profiling of Parkinson’s disease: evidence of biomarker from gene expression analysis and rapid neural network detection. J Biomed Sci. 2009;16:63. doi: 10.1186/1423-0127-16-63.
    1. Burgos K, Malenica I, Metpally R, et al. Profiles of extracellular miR-NA in cerebrospinal fluid and serum from patients with Alzheimer’s and Parkinson’s diseases correlate with disease status and features of pathology. PLoS One. 2014;9:e94839. doi: 10.1371/journal.pone.0094839.
    1. DeKosky ST, Gandy S. Environmental exposures and the risk for Alzheimer disease: can we identify the smoking guns? JAMA Neurol. 2014;71:273–275. doi: 10.1001/jamaneurol.2013.6031.
    1. Mulak A, Bonaz B. Brain-gut-microbiota axis in Parkinson’s disease. World J Gastroenterol. 2015;21:10609–10620. doi: 10.3748/wjg.v21.i37.10609.
    1. Principi N, Esposito S. Gut microbiota and central nervous system development. J Infect. 2016;73:536–546. doi: 10.1016/j.jinf.2016.09.010.
    1. Yarandi SS, Peterson DA, Treisman GJ, Moran TH, Pasricha PJ. Modulatory effects of gut microbiota on the central nervous system: how gut could play a role in neuropsychiatric health and diseases. J Neurogastroenterol Motil. 2016;22:201–212. doi: 10.5056/jnm15146.
    1. Houser MC, Tansey MG. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? NPJ Parkinson’s Dis. 2017;3:3. doi: 10.1038/s41531-016-0002-0.

Source: PubMed

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