{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T14:35:28Z","timestamp":1787668528971,"version":"build-2736575974"},"reference-count":130,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T00:00:00Z","timestamp":1774742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T00:00:00Z","timestamp":1774742400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["124098"],"award-info":[{"award-number":["124098"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH2110915"],"award-info":[{"award-number":["W81XWH2110915"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Comprehensive Physiology"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Parkinson's disease, characterized by the motor deficits that result from the loss of dopaminergic neurons in the Substantia Nigra pars compacta, is the second most common neurodegenerative disorder worldwide. Parkinson's disease is also commonly associated with severe non\u2010motor symptoms, including hyposmia and sleep disorders, as well as gastrointestinal dysfunction and dysregulation of the brain\u2010gut axis. Increasing evidence indicates that pathology in the \u201cbody\u2010first\u201d subtype of Parkinson's disease may originate in the gastrointestinal (GI) tract and then spread to the brain via the vagus nerve. GI dysfunction may also arise, however, from \u201ctop\u2010down\u201d or \u201cbrain\u2010first\u201d mechanisms, reflecting bidirectional brain\u2010gut interactions. Systemic environmental factors, such as exposure to pesticides and heavy metals, are hypothesized to initiate this pathology and promote \u03b1\u2010synuclein (\u03b1\u2010syn) misfolding and the formation of Lewy Bodies. A growing body of evidence suggests, however, that oxidative stress and glial activation may emerge in the enteric nervous system and the dorsal motor nucleus of the vagus long before the onset of neurodegeneration, and that these early changes may be sufficient to drive the retrograde spread of pathology to higher brain regions. The purpose of this review is to discuss the progression of PD pathology across the brain\u2010gut axis, providing insights into the contribution of oxidative stress and glial activation to neuronal loss, and highlighting the importance of these mechanisms for potential therapeutic intervention at the earliest stages of PD.<\/jats:p>","DOI":"10.1002\/cph4.70137","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T02:26:47Z","timestamp":1774837607000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Brain\u2010Gut Axis in Parkinson's Disease Pathology"],"prefix":"10.1002","volume":"16","author":[{"given":"Kudret Selin","family":"Ozkaya","sequence":"first","affiliation":[{"name":"Department of Neuroscience and Experimental Therapeutics Penn State University\u2014College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsteen N.","family":"Browning","sequence":"additional","affiliation":[{"name":"Department of Neuroscience and Experimental Therapeutics Penn State University\u2014College of Medicine  Hershey Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,29]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.81453"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2007.05.010"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-1040-2"},{"key":"e_1_2_12_5_1","article-title":"Ingestion of Subthreshold Doses of Environmental Toxins Induces Ascending Parkinsonism in the Rat. Npj","volume":"4","author":"Anselmi L.","year":"2018","journal-title":"Parkinson's Disease"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2017.08.069"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-017-0428-y"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2019.08.048"},{"issue":"2","key":"e_1_2_12_9_1","first-page":"II0","article-title":"Pathoanatomy of Parkinson's Disease","volume":"247","author":"Braak H.","year":"2000","journal-title":"Journal of Neurology"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00296485"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01276421"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(02)00065-9"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2014.tb00587.x"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0000000000000449"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21541"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.14.4546"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2018.02.008"},{"issue":"5","key":"e_1_2_12_18_1","article-title":"Gastrointestinal Manifestations in Parkinson's Disease: Prevalence and Occurrence Before Motor Symptoms","volume":"260","author":"Cersosimo M. G.","year":"2012","journal-title":"Journal of Neurology"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2013.02.009"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd3994"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.autneu.2025.103339"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0020401"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00432.2014"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1781(79)90006-4"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.09.007"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(86)92471-2"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.06.017"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/297409a0"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0028032"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0773.1990.tb00833.x"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-1838(00)00127-2"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.56.1.33"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.12995"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5493.985"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3209"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.3949\/ccjm.74.Suppl_1.S91"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1841"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.1987.253.6.G726"},{"issue":"1","key":"e_1_2_12_39_1","article-title":"Astrocytic Expression of Parkinson's Disease\u2010Related A53T \u03b1\u2010Synuclein Causes Neurodegeneration in Mice. Molecular","volume":"3","author":"Gu X.\u2010L.","year":"2010","journal-title":"Brain"},{"issue":"11","key":"e_1_2_12_40_1","article-title":"Novel Functional Roles for Enteric Glia in the Gastrointestinal Tract. Nature Reviews","volume":"9","author":"Gulbransen B. D.","year":"2012","journal-title":"Gastroenterology & Hepatology"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-008-0412-0"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2519-09.2009"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.98.18_supplement.946"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0142164"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2024.111024"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.181.4098.456"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/mdc3.13687"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27217414"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2118819119"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.21769"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1343-6"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(95)90302-X"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(94)00395-5"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2008.07.006"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/286736a0"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2990.2007.00923.x"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.05.035"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1353-8020(99)00022-X"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1747"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-021-00178-7"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(199910)46:4<598::AID-ANA7>3.0.CO;2-F"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012728"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.081125"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.3858\/emm.2011.43.4.026"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1746"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-020-00145-8"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2024.1390310"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-022-02574-z"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adi8716"},{"key":"e_1_2_12_70_1","first-page":"153","article-title":"Vesicular Monoamine Transporter 2 (VMAT2) Level Regulates MPTP Vulnerability and Clearance of Excess Dopamine in Mouse Striatal Terminals","volume":"10","author":"Lohr K. M.","year":"2016","journal-title":"Toxicological Sciences"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04569-y"},{"key":"e_1_2_12_72_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.38.8.1285"},{"key":"e_1_2_12_73_1","doi-asserted-by":"publisher","DOI":"10.1007\/s100720300035"},{"key":"e_1_2_12_74_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-025-01142-5"},{"key":"e_1_2_12_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.01.033"},{"key":"e_1_2_12_76_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-015-1577-2"},{"key":"e_1_2_12_77_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI127330"},{"key":"e_1_2_12_78_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28119"},{"key":"e_1_2_12_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02358-9"},{"key":"e_1_2_12_80_1","first-page":"26","article-title":"Progression of Parkinson's Disease Pathology Is Reproduced by Intragastric Administration of Rotenone in Mice","volume":"5","author":"Pan\u2010Montojo F.","year":"2010","journal-title":"Nature Precedings"},{"key":"e_1_2_12_81_1","doi-asserted-by":"publisher","DOI":"10.1176\/jnp.14.2.223"},{"key":"e_1_2_12_82_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1984.sp015428"},{"key":"e_1_2_12_83_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44328-024-00023-w"},{"key":"e_1_2_12_84_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(82)90390-1"},{"key":"e_1_2_12_85_1","doi-asserted-by":"publisher","DOI":"10.1586\/ern.12.17"},{"key":"e_1_2_12_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.adgen.2025.02.001"},{"key":"e_1_2_12_87_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncom.2013.00013"},{"key":"e_1_2_12_88_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-1331.2008.02056.x"},{"key":"e_1_2_12_89_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5290.1197"},{"key":"e_1_2_12_90_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2982.2012.01887.x"},{"key":"e_1_2_12_91_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells14231910"},{"key":"e_1_2_12_92_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12989-020-00358-y"},{"key":"e_1_2_12_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(84)90079-9"},{"key":"e_1_2_12_94_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nurt.2010.07.001"},{"issue":"3","key":"e_1_2_12_95_1","first-page":"S175","article-title":"Subthalamic Nucleus\u2010Mediated Excitotoxicity in Parkinson's Disease: A Target for Neuroprotection","volume":"44","author":"Rodriguez M. C.","year":"1998","journal-title":"Annals of Neurology"},{"key":"e_1_2_12_96_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0983-17.2017"},{"key":"e_1_2_12_97_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1093133"},{"key":"e_1_2_12_98_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1989.tb11759.x"},{"key":"e_1_2_12_99_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-019-05693-5"},{"key":"e_1_2_12_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.11.018"},{"key":"e_1_2_12_101_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-017-0032-2"},{"key":"e_1_2_12_102_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1990.tb02325.x"},{"key":"e_1_2_12_103_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nly024"},{"key":"e_1_2_12_104_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00018.2022"},{"key":"e_1_2_12_105_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-34-10756.2003"},{"key":"e_1_2_12_106_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox9090852"},{"key":"e_1_2_12_107_1","doi-asserted-by":"publisher","DOI":"10.1016\/0301-0082(85)90015-2"},{"key":"e_1_2_12_108_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)92707-7"},{"key":"e_1_2_12_109_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2024-080952"},{"key":"e_1_2_12_110_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2024.107020"},{"key":"e_1_2_12_111_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24448"},{"key":"e_1_2_12_112_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2011-2040"},{"key":"e_1_2_12_113_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.281.4.341"},{"key":"e_1_2_12_114_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2015.06.010"},{"key":"e_1_2_12_115_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00258.2014"},{"key":"e_1_2_12_116_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2016.76"},{"issue":"11","key":"e_1_2_12_117_1","first-page":"17","article-title":"Parkinson Disease and the Gut: New Insights Into Pathogenesis and Clinical Relevance. Nature Reviews","volume":"17","author":"Travagli R. A.","year":"2020","journal-title":"Gastroenterology & Hepatology"},{"key":"e_1_2_12_118_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-018-0257-5"},{"key":"e_1_2_12_119_1","doi-asserted-by":"publisher","DOI":"10.1159\/000118533"},{"key":"e_1_2_12_120_1","first-page":"11","article-title":"Dopamine Autoxidation Is Controlled by Acidic pH","volume":"18","author":"Umek N.","year":"2018","journal-title":"Frontiers in Molecular Neuroscience"},{"key":"e_1_2_12_121_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.parkreldis.2016.08.019"},{"key":"e_1_2_12_122_1","doi-asserted-by":"publisher","DOI":"10.1002\/jmr.747"},{"key":"e_1_2_12_123_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1011456"},{"key":"e_1_2_12_124_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-315666"},{"key":"e_1_2_12_125_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00007400"},{"key":"e_1_2_12_126_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(96)13080-9"},{"key":"e_1_2_12_127_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00687767"},{"key":"e_1_2_12_128_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-022-00430-8"},{"key":"e_1_2_12_129_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0314fje"},{"key":"e_1_2_12_130_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.1940.sp000824"},{"key":"e_1_2_12_131_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12640-013-9435-y"}],"container-title":["Comprehensive Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cph4.70137","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cph4.70137","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cph4.70137","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T07:20:13Z","timestamp":1777015213000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cph4.70137"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,29]]},"references-count":130,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/cph4.70137"],"URL":"https:\/\/doi.org\/10.1002\/cph4.70137","archive":["Portico"],"relation":{},"ISSN":["2040-4603","2040-4603"],"issn-type":[{"value":"2040-4603","type":"print"},{"value":"2040-4603","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,29]]},"assertion":[{"value":"2025-12-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70137"}}