{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:10:38Z","timestamp":1791418238344,"version":"4.3.3"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"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. Nutr."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Functional constipation is a common disorder of gut\u2013brain interaction that substantially affects bowel function, psychological well-being, and quality of life. Probiotic supplementation represents a microbiota-targeted nutritional strategy for functional constipation, but associated host-response signals remain incompletely understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This single-center, randomized, double-blind, placebo-controlled trial enrolled 104 adults who met the Rome IV criteria for functional constipation. Participants received either\n                      <jats:italic>Lactiplantibacillus plantarum<\/jats:italic>\n                      Probio87 or placebo for 8\u202fweeks, followed by a 4-week post-intervention follow-up. The primary endpoint was weekly complete spontaneous bowel movements. Secondary outcomes included Rome IV symptom scores, PAC-QOL, HAMD-24, safety parameters, and exploratory whole-blood gene-expression profiles related to inflammation, immune regulation, neuroendocrine signaling, and gut motility. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2300075360).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Probio87 supplementation significantly increased weekly complete spontaneous bowel movements compared with placebo at Week 8 and Week 12. Improvements were also observed in Rome IV symptom scores, constipation-related quality of life, and HAMD-24 domains related to anxiety, sleep, and retardation. Exploratory whole-blood gene-expression analysis showed differential host-response signals after intervention, characterized by increased BDNF expression and reduced expression of IL-1\u03b2, CD117, CXCR5, IDO1, DBH, and MLNR in the probiotic group relative to placebo. No intervention-related adverse events or clinically relevant abnormalities in hematological, hepatic, or renal safety parameters were observed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      <jats:italic>L. plantarum<\/jats:italic>\n                      Probio87 supplementation was associated with sustained improvement in bowel function, constipation-related quality of life, and psychological well-being in adults with functional constipation. Exploratory peripheral gene-expression findings suggest that inflammatory, immune, neuroendocrine, and motility-related host-response pathways may be involved, although causal mechanisms require further validation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.chictr.org.cn\/showproj.html?proj=205514<\/jats:ext-link>\n                      , identifier (ChiCTR2300075360).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnut.2026.1876944","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T15:49:56Z","timestamp":1784303396000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Lactiplantibacillus plantarum Probio87 supplementation improves functional constipation and is associated with peripheral gene-expression responses related to inflammation and the gut\u2013brain axis: a randomized, double-blind, placebo-controlled trial"],"prefix":"10.3389","volume":"13","author":[{"given":"Fan","family":"Zheng","sequence":"first","affiliation":[{"name":"Deyang People\u2019s Hospital of Chengdu University of Traditional Chinese Medicine","place":["Deyang, China"]},{"name":"School of Medical Sciences, Universiti Sains Malaysia","place":["Kota Bharu, Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Yang","sequence":"additional","affiliation":[{"name":"Deyang People\u2019s Hospital of Chengdu University of Traditional Chinese Medicine","place":["Deyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhan","sequence":"additional","affiliation":[{"name":"Chengdu Integrated TCM & Western Medicine Hospital","place":["Chengdu, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe Wen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Key Laboratory of Bioinformatics and Molecular Imaging, Center for Artificial Intelligence Biology, Department of Bioinformatics and Systems Biology, College of Life Science and Technology, Huazhong University of Science and Technology","place":["Wuhan, Hubei, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanting","family":"Lu","sequence":"additional","affiliation":[{"name":"Deyang People\u2019s Hospital of Chengdu University of Traditional Chinese Medicine","place":["Deyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daoyuan","family":"Xie","sequence":"additional","affiliation":[{"name":"Deyang People\u2019s Hospital of Chengdu University of Traditional Chinese Medicine","place":["Deyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Ming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Deyang People\u2019s Hospital of Chengdu University of Traditional Chinese Medicine","place":["Deyang, China"]},{"name":"School of Medicine and Life Sciences, Chengdu University of Traditional Chinese Medicine","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma","family":"Mageswary","sequence":"additional","affiliation":[{"name":"School of Industrial Technology, Universiti Sains Malaysia","place":["Penang, Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeong-Yeh","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Universiti Sains Malaysia","place":["Kota Bharu, Malaysia"]},{"name":"GI Function and Motility Unit, Hospital Pakar Universiti Sains Malaysia","place":["Kota Bharu, Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Tze","family":"Liong","sequence":"additional","affiliation":[{"name":"School of Industrial Technology, Universiti Sains Malaysia","place":["Penang, Malaysia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1053\/j.gastro.2016.03.035","article-title":"Rome IV-functional GI disorders: disorders of gut-brain interaction","volume":"150","author":"Drossman","year":"2016","journal-title":"Gastroenterology"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1053\/j.gastro.2016.02.031","article-title":"Bowel disorders","volume":"150","author":"Mearin","year":"2016","journal-title":"Gastroenterology"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.bpg.2010.12.010","article-title":"Epidemiology of constipation in children and adults: a systematic review","volume":"25","author":"Mugie","year":"2011","journal-title":"Best Pract Res Clin Gastroenterol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e143771","DOI":"10.1172\/JCI143771","article-title":"Gastrointestinal motility disorders in neurologic disease","volume":"131","author":"Camilleri","year":"2021","journal-title":"J Clin Invest"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"6917","DOI":"10.3390\/ijms23136917","article-title":"The role of inflammatory mediators in the development of gastrointestinal motility disorders","volume":"23","author":"Docsa","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"269","DOI":"10.3390\/metabo15040269","article-title":"Metabolomics insights into gut microbiota and functional constipation","volume":"15","author":"Zheng","year":"2025","journal-title":"Meta"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"3704","DOI":"10.3390\/nu14183704","article-title":"Crosstalk between the gut microbiome and colonic motility in chronic constipation: potential mechanisms and microbiota modulation","volume":"14","author":"Pan","year":"2022","journal-title":"Nutrients"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"203","DOI":"10.20524\/aog.2015.0016","article-title":"The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems","volume":"28","author":"Carabotti","year":"2015","journal-title":"Ann Gastroenterol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1016\/j.chom.2018.05.003","article-title":"Gut microbiota regulation of tryptophan metabolism in health and disease","volume":"23","author":"Agus","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"892","DOI":"10.3390\/life11090892","article-title":"Gut hormones as potential therapeutic targets or biomarkers of response in depression: the case of motilin","volume":"11","author":"Rajkumar","year":"2021","journal-title":"Life (Basel)"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.1053\/j.gastro.2020.10.066","article-title":"The microbiota-gut-brain axis: from motility to mood","volume":"160","author":"Margolis","year":"2021","journal-title":"Gastroenterology"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"e2436888","DOI":"10.1001\/jamanetworkopen.2024.36888","article-title":"Eight-week supplementation with Bifidobacterium lactis HN019 and functional constipation: a randomized clinical trial","volume":"7","author":"Cheng","year":"2024","journal-title":"JAMA Netw Open"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"8244","DOI":"10.1038\/s41598-025-92783-2","article-title":"Poly-gamma-glutamic acid alleviates slow transit constipation by regulating aquaporin and gut microbes","volume":"15","author":"Wang","year":"2025","journal-title":"Sci Rep"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"350","DOI":"10.5851\/kosfa.2018.38.2.350","article-title":"Lactobacillus plantarum DR7 reduces cholesterol via phosphorylation of AMPK that down-regulated the mRNA expression of HMG-CoA reductase","volume":"38","author":"Lew","year":"2018","journal-title":"Korean J Food Sci Anim Resour"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3920\/BM2017.0063","article-title":"Bifidobacterium longum BB536 alleviated upper respiratory illnesses and modulated gut microbiota profiles in Malaysian pre-school children","volume":"9","author":"Lau","year":"2018","journal-title":"Benef Microbes"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/jmf.2018.4229","article-title":"Lactobacillus strains alleviated aging symptoms and aging-induced metabolic disorders in aged rats","volume":"22","author":"Hor","year":"2019","journal-title":"J Med Food"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e70142","DOI":"10.1002\/mnfr.70142","article-title":"Impact of the probiotic on the modulation of vaginal bacterial and fungal microbiota in HPV-positive women","volume":"69","author":"Xu","year":"2025","journal-title":"Mol Nutr Food Res"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1163\/18762891-bja00079","article-title":"Probiotic reduces vaginal HPV abundance, improves immunity and quality of life in HPV-positive women: a randomised, placebo-controlled and double-blind study","volume":"16","author":"Xu","year":"2025","journal-title":"Benef Microbes."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1163\/18762891-bja00061","article-title":"Probiotic enhanced immunity and mental wellbeing of generally healthy women: a randomised, placebo-controlled and double-blind study","volume":"16","author":"Nisaa","year":"2025","journal-title":"Benef Microbes."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"106755","DOI":"10.1016\/j.phrs.2023.106755","article-title":"Effect of the probiotic strain, Lactiplantibacillus plantarum P9, on chronic constipation: a randomized, double-blind, placebo-controlled study","volume":"191","author":"Ma","year":"2023","journal-title":"Pharmacol Res"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1093\/ajcn\/nqac184","article-title":"The effect of fiber supplementation on chronic constipation in adults: an updated systematic review and meta-analysis of randomized controlled trials","volume":"116","author":"van der Schoot","year":"2022","journal-title":"Am J Clin Nutr"},{"key":"ref22","volume-title":"A Global Cascade Approach to Diagnosis and Management of Chronic Constipation","year":"2025"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1101\/gr.215087.116","article-title":"Canu: scalable and accurate long-read assembly via adaptive k-mer weighting and repeat separation","volume":"27","author":"Koren","year":"2017","journal-title":"Genome Res"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2068","DOI":"10.1093\/bioinformatics\/btu153","article-title":"Prokka: rapid prokaryotic genome annotation","volume":"30","author":"Seemann","year":"2014","journal-title":"Bioinformatics"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"D690","DOI":"10.1093\/nar\/gkac920","article-title":"CARD 2023: expanded curation, support for machine learning, and resistome prediction at the comprehensive antibiotic resistance database","volume":"51","author":"Alcock","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"3491","DOI":"10.1093\/jac\/dkaa345","article-title":"ResFinder 4.0 for predictions of phenotypes from genotypes","volume":"75","author":"Bortolaia","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"D912","DOI":"10.1093\/nar\/gkab1107","article-title":"VFDB 2022: a general classification scheme for bacterial virulence factors","volume":"50","author":"Liu","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"btaf129","DOI":"10.1093\/bioinformatics\/btag129","article-title":"Whole-genome prediction of bacterial pathogenic capacity on novel bacteria using protein language models with PathogenFinder2","volume":"42","author":"Ferrer Florensa","year":"2026","journal-title":"Bioinformatics"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e13294","DOI":"10.1111\/nmo.13294","article-title":"Recommendations for pharmacological clinical trials in children with functional constipation: the Rome foundation pediatric subcommittee on clinical trials","volume":"30","author":"Koppen","year":"2018","journal-title":"Neurogastroenterol Motil"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1053\/j.gastro.2016.02.009","article-title":"Functional anorectal disorders","volume":"150","author":"Rao","year":"2016","journal-title":"Gastroenterology"},{"key":"ref31","first-page":"209","article-title":"Evaluation of the Chinese version of the patient assessment of constipation quality of life scale","volume":"19","author":"Jin","year":"2011","journal-title":"World Chin J Digestol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1016\/j.jad.2013.04.028","article-title":"Severity classification on the Hamilton Depression Rating Scale","volume":"150","author":"Zimmerman","year":"2013","journal-title":"J Affect Disord"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"e0223065","DOI":"10.1371\/journal.pone.0223065","article-title":"Gene expression profiling of whole blood: a comparative assessment of RNA-stabilizing collection methods","volume":"14","author":"Donohue","year":"2019","journal-title":"PLoS One"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1165\/rcmb.2017-0230OC","article-title":"Whole-blood gene expression in pulmonary nontuberculous mycobacterial infection","volume":"58","author":"Cowman","year":"2018","journal-title":"Am J Respir Cell Mol Biol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"237","DOI":"10.14670\/HH-25.237","article-title":"BDNF function and intracellular signaling in neurons","volume":"25","author":"Numakawa","year":"2010","journal-title":"Histol Histopathol"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"e62462","DOI":"10.1371\/journal.pone.0062462","article-title":"Reference gene selection for real-time quantitative PCR analysis of the mouse uterus in the peri-implantation period","volume":"8","author":"Lin","year":"2013","journal-title":"PLoS One"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"16153","DOI":"10.1038\/s41598-022-20615-8","article-title":"Identification and verification of CCNB1 as a potential prognostic biomarker by comprehensive analysis","volume":"12","author":"Zeng","year":"2022","journal-title":"Sci Rep"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1666","DOI":"10.1136\/ard-2024-225812","article-title":"Helicobacter pylori upregulates PAD4 expression via stabilising HIF-1alpha to exacerbate rheumatoid arthritis","volume":"83","author":"Wu","year":"2024","journal-title":"Ann Rheum Dis"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1373\/clinchem.2008.112797","article-title":"The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments","volume":"55","author":"Bustin","year":"2009","journal-title":"Clin Chem"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1080\/00365520510012208","article-title":"Development and validation of the patient assessment of constipation quality of life questionnaire","volume":"40","author":"Marquis","year":"2005","journal-title":"Scand J Gastroenterol"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.13703\/j.0255-2930.20210902-k0007","article-title":"Minimal clinically important difference of the frequency of bowel movement for patients with chronic severe functional constipation treated with acupuncture","volume":"42","author":"Ai","year":"2022","journal-title":"Zhongguo Zhen Jiu"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0163-4453(96)80003-X","article-title":"Mechanisms of glycopeptide resistance in enterococci","volume":"32","author":"Arthur","year":"1996","journal-title":"J Infect"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"767456","DOI":"10.3389\/fimmu.2021.767456","article-title":"IL-1beta and the intestinal epithelial tight junction barrier","volume":"12","author":"Kaminsky","year":"2021","journal-title":"Front Immunol"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.neubiorev.2019.03.023","article-title":"Prebiotics and probiotics for depression and anxiety: a systematic review and meta-analysis of controlled clinical trials","volume":"102","author":"Liu","year":"2019","journal-title":"Neurosci Biobehav Rev"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/nri.2015.5","article-title":"The role of inflammation in depression: from evolutionary imperative to modern treatment target","volume":"16","author":"Miller","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1152\/physrev.00018.2018","article-title":"The microbiota-gut-brain Axis","volume":"99","author":"Cryan","year":"2019","journal-title":"Physiol Rev"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/s41574-019-0164-1","article-title":"Motilin: from gastric motility stimulation to hunger signalling","volume":"15","author":"Deloose","year":"2019","journal-title":"Nat Rev Endocrinol"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"652363","DOI":"10.3389\/fendo.2021.652363","article-title":"Versatile functions of somatostatin and somatostatin receptors in the gastrointestinal system","volume":"12","author":"Shamsi","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/10408398.2024.2448562","article-title":"Advancements in Lactiplantibacillus plantarum: probiotic characteristics, gene editing technologies and applications","author":"Zhang","year":"2025","journal-title":"Crit Rev Food Sci Nutr"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.3945\/ajcn.114.089151","article-title":"The effect of probiotics on functional constipation in adults: a systematic review and meta-analysis of randomized controlled trials","volume":"100","author":"Dimidi","year":"2014","journal-title":"Am J Clin Nutr"}],"container-title":["Frontiers in Nutrition"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1876944\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T15:49:58Z","timestamp":1784303398000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnut.2026.1876944\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":51,"alternative-id":["10.3389\/fnut.2026.1876944"],"URL":"https:\/\/doi.org\/10.3389\/fnut.2026.1876944","relation":{},"ISSN":["2296-861X"],"issn-type":[{"value":"2296-861X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]},"article-number":"1876944"}}