{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:06:32Z","timestamp":1784700392935,"version":"3.55.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Parkinson\u2019s disease (PD)-related constipation represents a prevalent and disabling non-motor symptom that imposes a substantial and growing health and economic burden worldwide. Current management strategies, including dietary modification, probiotics, and pharmacological therapies, often provide limited benefit, with potential adverse effects and minimal improvement in other PD-related symptoms. Acupuncture has emerged as a promising complementary therapeutic approach and has demonstrated preliminary clinical efficacy. However, the underlying biological mechanisms and the potential contribution of placebo responses to therapeutic effects remain insufficiently understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This randomized controlled clinical trial will enroll 66 patients with PD\u2013related constipation and randomly assign them in a 1:1 ratio to the real acupuncture group or the sham acupuncture group. Participants, acupuncturists, outcome assessors, and statisticians will be blinded to group allocation. The 8-week trial consists of a 4-week treatment period followed by a 4-week follow-up period. The primary outcome is the longitudinal change in the Chronic Constipation Severity Score (CCS) over time. Secondary clinical outcomes include weekly complete spontaneous bowel movements (CSBMs), spontaneous bowel movements (SBMs), Bristol Stool Scale (BSS) scores, and Unified Parkinson\u2019s Disease Rating Scale (UPDRS) scores. In addition, exploratory outcomes include levels of short-chain fatty acids (SCFAs), histone deacetylase 1 (HDAC1), and phosphorylated\n                      <jats:italic>\u03b1<\/jats:italic>\n                      -synuclein at serine 129 (pS129-\u03b1-syn) measured in biofluid samples. Adverse events will be systematically monitored throughout the trial. The study is conducted in accordance with the SPIRIT guidelines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      This trial is designed to evaluate the clinical efficacy of acupuncture for PD-related constipation using a rigorously implemented double-blind, sham acupuncture-controlled design. Although the sham acupuncture procedure may itself induce nonspecific physiological and contextual effects, the use of a standardized double-blind control is intended to reduce expectancy-related bias and improve methodological rigor in the assessment of acupuncture-related outcomes. In addition to clinical symptom evaluation, the integration of SCFAs, HDAC1, and pS129-\n                      <jats:italic>\u03b1<\/jats:italic>\n                      -syn allows exploratory investigation of potential biological changes associated with treatment. This trial aims to provide multidimensional evidence regarding possible gut\u2013brain axis\u2013related mechanisms involved in acupuncture treatment for PD-related constipation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      The study protocol was registered with the International Traditional Medicine Clinical Trial Registry (ITMCTR 2026000107) on December 7, 2025. The publicly accessible website is:\n                      <jats:ext-link>https:\/\/itmctr.ccebtcm.org.cn\/mgt\/search<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1840324","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:52:56Z","timestamp":1784699576000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Efficacy of acupuncture for patients with Parkinson\u2019s disease\u2013related constipation: study protocol for a randomized controlled, double-blind trial"],"prefix":"10.3389","volume":"20","author":[{"given":"Shumin","family":"Lin","sequence":"first","affiliation":[{"name":"The First Clinical School of Medicine, Guangzhou University of Chinese Medicine","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwei","family":"Lin","sequence":"additional","affiliation":[{"name":"Faculty of Geology, Lomonosov Moscow State University","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Li","sequence":"additional","affiliation":[{"name":"The First Clinical School of Medicine, Guangzhou University of Chinese Medicine","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Guangzhou University of Chinese Medicine","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danxia","family":"Gu","sequence":"additional","affiliation":[{"name":"The First Clinical School of Medicine, Guangzhou University of Chinese Medicine","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Clinical School of Medicine, Guangzhou University of Chinese Medicine","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Wu","sequence":"additional","affiliation":[{"name":"The First Clinical School of Medicine, Guangzhou University of Chinese Medicine","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Wang","sequence":"additional","affiliation":[{"name":"Shenzhen Hospital (Fu Tian) of Guangzhou University of Chinese Medicine","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingqi","family":"Fan","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Guangzhou University of Chinese Medicine","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixing","family":"Zhuang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Guangzhou University of Chinese Medicine","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1136\/jnnp-2015-311680","article-title":"Constipation preceding Parkinson's disease: a systematic review and meta-analysis","volume":"87","author":"Adams-Carr","year":"2016","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"23095","DOI":"10.1038\/s41598-024-74400-w","article-title":"Synbiotic supplementation may globally improve non-motor symptoms in patients with stable Parkinson's disease: results from an open label single-arm study","volume":"14","author":"Andreozzi","year":"2024","journal-title":"Sci. Rep."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41531-021-00191-w","article-title":"Early constipation predicts faster dementia onset in Parkinson's disease","volume":"7","author":"Camacho","year":"2021","journal-title":"NPJ Parkinson's Dis."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1001\/jama.2025.4486","article-title":"SPIRIT 2025 statement: updated guideline for protocols of randomized trials","volume":"334","author":"Chan","year":"2025","journal-title":"JAMA"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"973","DOI":"10.3760\/cma.j.cn113694-20200331-00233","article-title":"Chinese Society of Neurology, Parkinson\u2019s Disease and Movement Disorders Group; Parkinson\u2019s Disease and Movement Disorders Group of the Neurology Branch of the Chinese Medical Doctor Association. Chinese guideline for the treatment of Parkinson\u2019s disease (Fourth Edition)","volume":"53","author":"Chen","year":"2020","journal-title":"Chin J Neurol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"67","DOI":"10.14802\/jmd.18067","article-title":"Altered gut microbiome and intestinal pathology in Parkinson's disease","volume":"12","author":"Chiang","year":"2019","journal-title":"J. Mov. Disord."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1002\/mds.25979","article-title":"Enteric glial cells: new players in Parkinson's disease?","volume":"30","author":"Clairembault","year":"2015","journal-title":"Mov. Disord."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.3390\/cells14171338","article-title":"HDACs in the brain: from chromatin remodeling to neurodegenerative disease","volume":"14","author":"Diniz","year":"2025","journal-title":"Cells"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.immuni.2024.01.002","article-title":"Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity","volume":"57","author":"Eshleman","year":"2024","journal-title":"Immunity"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"e70540","DOI":"10.1002\/mco2.70540","article-title":"Parkinson's disease: the epidemiology, risk factors, molecular pathogenesis, prevention, and therapy","volume":"6","author":"Guo","year":"2025","journal-title":"MedComm."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1080\/00365521.2021.1961307","article-title":"Chronic constipation is negatively associated with colonic diverticula","volume":"56","author":"Higashimori","year":"2021","journal-title":"Scand. J. Gastroenterol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1007\/s00394-024-03398-8","article-title":"Acacia fiber or probiotic supplements to relieve gastrointestinal complaints in patients with constipation-predominant IBS: a 4-week randomized double-blinded placebo-controlled intervention trial","volume":"63","author":"Janssen Duijghuijsen","year":"2024","journal-title":"Eur. J. Nutr."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1111\/j.1365-2036.2006.03238.x","article-title":"Chronic constipation: a survey of the patient perspective","volume":"25","author":"Johanson","year":"2007","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1002\/mds.26866","article-title":"Constipation in parkinson's disease: subjective symptoms, objective markers, and new perspectives","volume":"32","author":"Knudsen","year":"2017","journal-title":"Mov. Disord."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1111\/codi.13388","article-title":"Effectiveness of percutaneous tibial nerve stimulation in managing refractory constipation","volume":"19","author":"Kumar","year":"2017","journal-title":"Colorectal Dis."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"2197837","DOI":"10.1080\/19490976.2023.2197837","article-title":"Effects of dietary fibers or probiotics on functional constipation symptoms and roles of gut microbiota: a double-blinded randomized placebo trial","volume":"15","author":"Lai","year":"2023","journal-title":"Gut Microbes"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"749","DOI":"10.16780\/j.cnki.sjssgncj.20200767","article-title":"Clinical efficacy observation of acupuncture in treating functional constipation in Parkinson\u2019s disease","volume":"15","author":"Lei","year":"2020","journal-title":"Neural Injury and Functional Reconstruction."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1126080","DOI":"10.3389\/fnins.2023.1126080","article-title":"Efficacy of acupuncture for the treatment of Parkinson's disease-related constipation (PDC): a randomized controlled trial","volume":"17","author":"Li","year":"2023","journal-title":"Front. Neurosci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"101814","DOI":"10.1016\/j.eclinm.2022.101814","article-title":"Electroacupuncture for motor dysfunction and constipation in patients with Parkinson's disease: a randomised controlled multi-Centre trial","volume":"56","author":"Li","year":"2023","journal-title":"EClinicalMedicine"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"268","DOI":"10.3760\/cma.j.issn.1006-7876.2016.04.002","article-title":"Chinese Society of Neurology, Parkinson\u2019s Disease and Movement Disorders Group; Parkinson\u2019s Disease and Movement Disorders Group of the Neurology Branch of the Chinese Medical Doctor Association. Diagnostic criteria for Parkinson\u2019s disease in China (2016 edition)","volume":"49","author":"Liu","year":"2016","journal-title":"Chin J Neurol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"37130","DOI":"10.1038\/srep37130","article-title":"Phosphorylation induces distinct alpha-synuclein strain formation","volume":"6","author":"Ma","year":"2016","journal-title":"Sci. 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Record specification on adverse events in clinical trials of acupuncture and moxibustion (T\/CAAM 0002-2022)","year":"2022"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"772133","DOI":"10.3389\/fnut.2021.772133","article-title":"Assessment of the methodology that is used to determine the nutritional sustainability of the Mediterranean diet-a scoping review","volume":"8","author":"Portugal-Nunes","year":"2021","journal-title":"Front. Nutr."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1097\/DCR.0b013e318223fd7b","article-title":"Bowel biofeedback treatment in patients with multiple sclerosis and bowel symptoms","volume":"54","author":"Preziosi","year":"2011","journal-title":"Dis. Colon Rectum"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1038\/ismej.2017.196","article-title":"Specific substrate-driven changes in human faecal microbiota composition contrast with functional redundancy in short-chain fatty acid production","volume":"12","author":"Reichardt","year":"2018","journal-title":"ISME J."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.nbd.2018.03.001","article-title":"Inflammation kinase PKR phosphorylates \u03b1-synuclein and causes \u03b1-synuclein-dependent cell death","volume":"115","author":"Reimer","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1016\/j.cell.2016.11.018","article-title":"Gut microbiota regulate motor deficits and Neuroinflammation in a model of Parkinson's disease","volume":"167","author":"Sampson","year":"2016","journal-title":"Cell"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1002\/mds.26069","article-title":"Gut microbiota are related to Parkinson's disease and clinical phenotype","volume":"30","author":"Scheperjans","year":"2015","journal-title":"Mov. Disord."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1002\/mds.28016","article-title":"Plasma short-chain fatty acids in patients with Parkinson's disease","volume":"35","author":"Shin","year":"2020","journal-title":"Mov. Disord."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/s0140-6736(95)92707-7","article-title":"Dopaminergic defect of enteric nervous system in Parkinson's disease patients with chronic constipation","volume":"346","author":"Singaram","year":"1995","journal-title":"Lancet"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"e772","DOI":"10.1212\/wnl.0000000000010998","article-title":"Probiotics for constipation in Parkinson disease: a randomized placebo-controlled study","volume":"96","author":"Tan","year":"2021","journal-title":"Neurology"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"6137450","DOI":"10.1155\/2020\/6137450","article-title":"The effectiveness of acupuncture in Management of Functional Constipation: a systematic review and Meta-analysis","volume":"2020","author":"Wang","year":"2020","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/s40168-022-01255-6","article-title":"The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids","volume":"10","author":"Xiao","year":"2022","journal-title":"Microbiome."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"579","DOI":"10.13703\/j.0255-2930.20220117-k0001","article-title":"Interpretation of China national standard nomenclature and location of Meridian points (GB\/T 12346-2021)","volume":"42","author":"Xiaodong","year":"2022","journal-title":"Zhongguo Zhen Jiu"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1159\/000527513","article-title":"Constipation in Parkinson's disease: a systematic review and Meta-analysis","volume":"86","author":"Yao","year":"2023","journal-title":"Eur. Neurol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1038928","DOI":"10.3389\/fcimb.2022.1038928","article-title":"Probiotics for constipation in Parkinson's: a systematic review and meta-analysis of randomized controlled trials","volume":"12","author":"Yin","year":"2022","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"2754","DOI":"10.1007\/s10620-018-5139-8","article-title":"Probiotics ameliorate stool consistency in patients with chronic constipation: a randomized, double-blind, placebo-controlled study","volume":"63","author":"Yoon","year":"2018","journal-title":"Dig. Dis. Sci."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1253874","DOI":"10.3389\/fneur.2023.1253874","article-title":"Acupuncture for Parkinson's disease-related constipation: current evidence and perspectives","volume":"14","author":"Zhang","year":"2023","journal-title":"Front. Neurol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s40035-023-00392-8","article-title":"Parkinson's disease and gut microbiota: from clinical to mechanistic and therapeutic studies","volume":"12","author":"Zhang","year":"2023","journal-title":"Transl. Neurodegener."},{"key":"ref43","first-page":"317","article-title":"Observation on the therapeutic effect of Jiajian Dihuang Yinzi on constipation in elderly patients with Parkinson's disease","volume":"27","author":"Zhen","year":"2021","journal-title":"Laonian Yi Xue Yu Baojian."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1016\/j.cell.2018.08.041","article-title":"Personalized gut mucosal colonization resistance to empiric probiotics is associated with unique host and microbiome features","volume":"174","author":"Zmora","year":"2018","journal-title":"Cell"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2026.1840324\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:53:01Z","timestamp":1784699581000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2026.1840324\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":44,"alternative-id":["10.3389\/fnins.2026.1840324"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2026.1840324","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]},"article-number":"1840324"}}