{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:40:53Z","timestamp":1780447253776,"version":"3.54.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T00:00:00Z","timestamp":1762473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["SQ2025YFC3500142"],"award-info":[{"award-number":["SQ2025YFC3500142"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017958","name":"Health Commission of Hubei Province","doi-asserted-by":"publisher","award":["ZY 2025D002"],"award-info":[{"award-number":["ZY 2025D002"]}],"id":[{"id":"10.13039\/100017958","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018806","name":"Department of Science and Technology of Hubei Province","doi-asserted-by":"publisher","award":["2023BCB031"],"award-info":[{"award-number":["2023BCB031"]}],"id":[{"id":"10.13039\/501100018806","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Constipation is a prevalent gastrointestinal disorder with limited therapeutic options that often lead to laxative dependence. Gut microbiota and their metabolic regulation represent promising therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      In this study, we isolated and characterized exosome-like nanovesicles from the traditional Chinese herb\n                      <jats:italic>Cistanche deserticola<\/jats:italic>\n                      (CELNs) and evaluated their efficacy in a loperamide-induced mouse model of constipation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that CELNs administration significantly alleviated constipation phenotypes, as evidenced by increased fecal output, water content, and intestinal transit rate, alongside the restoration of colonic histology and goblet cell function. Multiomic analyses revealed that CELNs remodeled the gut microbiota by enriching GABA-producing genera, such as\n                      <jats:italic>Lactobacillus<\/jats:italic>\n                      and\n                      <jats:italic>Bacteroides<\/jats:italic>\n                      , consequently elevating intestinal GABA levels. This increased GABA specifically activated GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptor subunits \u03b12 and \u03b22\/3, thereby enhancing intestinal smooth muscle contraction. Crucially, the therapeutic effects of CELNs were entirely abolished by a GABA\n                      <jats:sub>A<\/jats:sub>\n                      R antagonist, confirming that their action is dependent on GABA\n                      <jats:sub>A<\/jats:sub>\n                      R signaling activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>In summary, our study reveals a novel mechanism through which CELNs enhance intestinal motility via the microbiota\u2013metabolite\u2013host axis, offering a conceptual foundation and a potential nanotherapeutic strategy for the targeted treatment of constipation by modulating microbial homeostasis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1693366","type":"journal-article","created":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T05:21:01Z","timestamp":1762492861000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Cistanche deserticola-derived exosome-like nanovesicles target the Microbiota-GABA signaling axis to ameliorate loperamide-induced constipation"],"prefix":"10.3389","volume":"16","author":[{"given":"Xiaoyu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keqiu","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinkun","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dequn","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbo","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangjun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aizhen","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"102339","DOI":"10.1016\/j.jaut.2019.102339","article-title":"The immunobiology of autoimmune encephalitides","volume":"104","author":"Alexopoulos","year":"2019","journal-title":"J. Autoimmun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.ejphar.2014.03.003","article-title":"Opposite role played by GABAA and GABAB receptors in the modulation of peristaltic activity in mouse distal colon","volume":"731","author":"Auteri","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.phrs.2014.12.001","article-title":"GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation","volume":"93","author":"Auteri","year":"","journal-title":"Pharmacol. Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"4996","DOI":"10.2174\/1381612821666150914121518","article-title":"The GABAergic system and the gastrointestinal physiopathology","volume":"21","author":"Auteri","year":"","journal-title":"Curr. Pharm. Des."},{"key":"B5","doi-asserted-by":"publisher","first-page":"113627","DOI":"10.1016\/j.biopha.2022.113627","article-title":"Shouhui tongbian capsule ameliorates constipation via gut microbiota-5-HT-intestinal motility axis","volume":"154","author":"Bai","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"B6","doi-asserted-by":"publisher","first-page":"277","DOI":"10.23736\/S2724-5985.22.03335-6","article-title":"Chronic constipation: from pathophysiology to management","volume":"69","author":"Barbara","year":"2023","journal-title":"Minerva Gastroentero"},{"key":"B7","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1038\/ajg.2011.30","article-title":"Opioid-induced constipation: challenges and therapeutic opportunities","volume":"106","author":"Camilleri","year":"2011","journal-title":"Am. J. Gastroenterol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1163\/18762891-20230025","article-title":"Gut production of GABA by a probiotic formula: an in vitro study","volume":"15","author":"Casertano","year":"2024","journal-title":"Benef. Microbes"},{"key":"B9","doi-asserted-by":"publisher","first-page":"16568","DOI":"10.1021\/acs.jafc.3c04150","article-title":"Broccoli-derived exosome-like nanoparticles alleviate loperamide-induced constipation, in correlation with regulation on gut microbiota and tryptophan metabolism","volume":"71","author":"Duan","year":"2023","journal-title":"J. Agr Food Chem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1017\/S0007114522003853","article-title":"Functional constipation and the effect of prebiotics on the gut microbiota: a review","volume":"130","author":"Erhardt","year":"2023","journal-title":"Brit J. Nutr."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1539277","DOI":"10.3389\/fcimb.2025.1539277","article-title":"Gut-brain axis mediated by intestinal content microbiota was associated with zhishi daozhi decoction on constipation","volume":"15","author":"Fang","year":"2025","journal-title":"Front. Cell Infect. Mi"},{"key":"B12","doi-asserted-by":"publisher","first-page":"108759","DOI":"10.1016\/j.pharmthera.2024.108759","article-title":"Peripheral GABA(A) receptors - physiological relevance and therapeutic implications","volume":"266","author":"Gajic Bojic","year":"2025","journal-title":"Pharmacol. Ther."},{"key":"B13","doi-asserted-by":"publisher","first-page":"12810","DOI":"10.3390\/ijms252312810","article-title":"A potential use of vidarabine: alleviation of functional constipation through modulation of the adenosine A2A Receptor-MLC signaling pathway and the gut microbiota","volume":"25","author":"Gao","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/164_2016_118","article-title":"Gastrointestinal physiology and function","volume":"239","author":"Greenwood-Van Meerveld","year":"2017","journal-title":"Handb. Exp. Pharmacol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"3429","DOI":"10.3390\/jcm10153429","article-title":"Neurotransmitter dysfunction in irritable bowel syndrome: emerging approaches for management","volume":"10","author":"Gros","year":"2021","journal-title":"J. Clin. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"98","DOI":"10.3168\/jds.2019-16856","article-title":"Use of Streptococcus thermophilus for the in situ production of gamma-aminobutyric acid-enriched fermented milk","volume":"103","author":"Han","year":"2020","journal-title":"J. Dairy Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e2413197","DOI":"10.1002\/advs.202413197","article-title":"Advances in fecal microbiota transplantation for gut dysbiosis-related diseases","volume":"12","author":"Hou","year":"2025","journal-title":"Adv. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"124","DOI":"10.3389\/fphar.2010.00124","article-title":"A gut feeling about GABA: Focus on GABA(B) receptors","volume":"1","author":"Hyland","year":"2010","journal-title":"Front. Pharmacol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.ajps.2021.05.006","article-title":"Plant-derived exosome-like nanoparticles and their therapeutic activities","volume":"17","author":"Kim","year":"2022","journal-title":"Asian J. Pharm. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1111\/j.1365-2982.2006.00784.x","article-title":"Role of TNF-\u03b1 in muscularis inflammation and motility disorder in a TNBS-Induced colitis model: clues from TNF-\u03b1-deficient mice","volume":"18","author":"Kinoshita","year":"2006","journal-title":"Neurogastroent Motil."},{"key":"B21","doi-asserted-by":"publisher","first-page":"3993","DOI":"10.1039\/d2fo00008c","article-title":"Microbiome-metabolomics deciphers the effects of Cistanche deserticola polysaccharides on aged constipated rats","volume":"13","author":"Liu","year":"2022","journal-title":"Food Funct."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2561803","DOI":"10.1080\/07853890.2025.2561803","article-title":"Association between constipation and risk of cardiovascular or all-cause mortality: a meta-analysis","volume":"57","author":"Liu","year":"2025","journal-title":"Ann. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"7228","DOI":"10.1021\/acs.jafc.4c11506","article-title":"Garlic-derived exosome-like nanoparticles enhance gut homeostasis in stressed piglets: involvement of Lactobacillus reuteri modulation and Indole-3-propionic acid induction","volume":"73","author":"Liu","year":"2025","journal-title":"J. Agr Food Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.3390\/nu17091501","article-title":"Bioactive components, pharmacological properties, and applications of Cistanche deserticola Y. C. Ma: a comprehensive review","volume":"17","author":"Liu","year":"2025","journal-title":"Nutrients"},{"key":"B25","doi-asserted-by":"publisher","first-page":"900","DOI":"10.3390\/foods14050900","article-title":"L-Arabinose alleviates functional constipation in mice by regulating gut microbiota and metabolites","volume":"14","author":"Liu","year":"2025","journal-title":"Foods"},{"key":"B26","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1186\/s12876-025-03774-6","article-title":"Clinical practice guidelines for the diagnosis of constipation-predominant irritable bowel syndrome and functional constipation in adults: a scoping review","volume":"25","author":"Luo","year":"2025","journal-title":"Bmc Gastroenterol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2442528","DOI":"10.1080\/19490976.2024.2442528","article-title":"T cells regulate intestinal motility and shape enteric neuronal responses to intestinal microbiota","volume":"17","author":"Marques de Souza","year":"2025","journal-title":"Gut Microbes"},{"key":"B28","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1038\/s41586-018-0832-5","article-title":"GABA(A) receptor signalling mechanisms revealed by structural pharmacology","volume":"565","author":"Masiulis","year":"2019","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","first-page":"590","DOI":"10.3390\/ijms21020590","article-title":"TGF-beta\/Smad3 signalling modulates GABA neurotransmission: implications in parkinson's disease","volume":"21","author":"Munoz","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1681","DOI":"10.1007\/s10529-005-2730-9","article-title":"Expression of rice glutamate decarboxylase in Bifidobacterium longum enhances gamma-aminobutyric acid production","volume":"27","author":"Park","year":"2005","journal-title":"Biotechnol. Lett."},{"key":"B31","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.annepidem.2022.09.002","article-title":"Association of abnormal bowel health with major chronic diseases and risk of mortality","volume":"75","author":"Peng","year":"2022","journal-title":"Ann. Epidemiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"142452","DOI":"10.1016\/j.ijbiomac.2025.142452","article-title":"Polysaccharides from Cistanche deserticola mitigate inflammatory bowel disease via modulating intestinal microbiota and SRC\/EGFR\/PI3K\/AKT signaling pathways","volume":"308","author":"Qiao","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"778","DOI":"10.3390\/nu16060778","article-title":"Prebiotics and probiotics for gastrointestinal disorders","volume":"16","author":"Rau","year":"2024","journal-title":"Nutrients"},{"key":"B34","doi-asserted-by":"publisher","first-page":"10361","DOI":"10.1523\/JNEUROSCI.0441-14.2014","article-title":"Molecular and functional diversity of GABA-A receptors in the enteric nervous system of the mouse colon","volume":"34","author":"Seifi","year":"2014","journal-title":"J. Neurosci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1038\/s41564-018-0307-3","article-title":"GABA-modulating bacteria of the human gut microbiota","volume":"4","author":"Strandwitz","year":"2019","journal-title":"Nat. Microbiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"108","DOI":"10.3390\/medicina60010108","article-title":"Idiopathic slow transit constipation: pathophysiology, diagnosis, and management","volume":"60","author":"Vlismas","year":"2024","journal-title":"Medicina-Lithuania."},{"key":"B37","doi-asserted-by":"publisher","first-page":"127","DOI":"10.5582\/bst.2024.01036","article-title":"Considering traditional Chinese medicine as adjunct therapy in the management of chronic constipation by regulating intestinal flora","volume":"18","author":"Wang","year":"2024","journal-title":"Biosci. Trends"},{"key":"B38","doi-asserted-by":"publisher","first-page":"142048","DOI":"10.1016\/j.foodchem.2024.142048","article-title":"Theaflavin-3,3'-digallate (TF3) attenuated constipation by promoting gastrointestinal motility and modulating the gut microbiota: a comparative study of TF3 and the anti-constipation drug mosapride in mice","volume":"465","author":"Wu","year":"","journal-title":"Food Chem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"140808","DOI":"10.1016\/j.ijbiomac.2025.140808","article-title":"Gut microbiota: the pivotal conduit in the onset of constipation and its alleviation by tea flower polysaccharides (TFP) in a mouse model","volume":"304","author":"Wu","year":"","journal-title":"Int. J. Biol. Macromol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"100924","DOI":"10.1016\/j.crfs.2024.100924","article-title":"Lacticaseibacillus rhamnosus LRJ-1 alleviates constipation through promoting gut Bacteroides-derived \u03b3-aminobutyric acid production","volume":"9","author":"Xia","year":"2024","journal-title":"Curr. Res. Food Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"7476","DOI":"10.1002\/jsfa.13567","article-title":"Effects of garlic-derived fructan and oligofructose mixtures on intestinal health and constipation relief in mice","volume":"104","author":"Xie","year":"2024","journal-title":"J. Sci. Food Agric."},{"key":"B42","doi-asserted-by":"publisher","first-page":"117420","DOI":"10.1016\/j.jep.2023.117420","article-title":"Total alditols from Cistanche deserticola attenuate functional constipation by regulating bile acid metabolism","volume":"320","author":"Yin","year":"2024","journal-title":"J. Ethnopharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"5655","DOI":"10.2147\/DDDT.S481985","article-title":"Geraniol ameliorates pentylenetetrazol-induced epilepsy, neuroinflammation, and oxidative stress via modulating the GABAergic tract: in vitro and in vivo studies","volume":"18","author":"Younis","year":"2024","journal-title":"Drug Des. Dev. Ther."},{"key":"B44","doi-asserted-by":"publisher","first-page":"7036","DOI":"10.62347\/RQBJ2018","article-title":"Cistanche deserticola polysaccharide alleviates constipation by regulating intestinal barrier function and intestinal microbiota and their metabolites","volume":"16","author":"Yu","year":"2024","journal-title":"Am. J. Transl. Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"117218","DOI":"10.1016\/j.carbpol.2020.117218","article-title":"Chitosan oligosaccharides attenuate loperamide-induced constipation through regulation of gut microbiota in mice","volume":"253","author":"Zhang","year":"","journal-title":"Carbohyd Polym."},{"key":"B46","doi-asserted-by":"publisher","first-page":"105676","DOI":"10.1016\/j.ejps.2020.105676","article-title":"Modulation of gut microbiota and intestinal metabolites by lactulose improves loperamide-induced constipation in mice","volume":"158","author":"Zhang","year":"","journal-title":"Eur. J. Pharm. Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.3390\/foods13142220","article-title":"Soluble dietary fiber of hawthorn relieves constipation induced by loperamide hydrochloride by improving intestinal flora and inflammation, thereby regulating the aquaporin ion pathway in mice","volume":"13","author":"Zhang","year":"2024","journal-title":"Foods"},{"key":"B48","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1080\/10408398.2023.2278155","article-title":"Lactic acid bacteria in relieving constipation: mechanism, clinical application, challenge, and opportunity","volume":"65","author":"Zhang","year":"2025","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"B49","doi-asserted-by":"publisher","first-page":"4598","DOI":"10.7150\/thno.97096","article-title":"Exosome-like nanoparticles derived from fruits, vegetables, and herbs: innovative strategies of therapeutic and drug delivery","volume":"14","author":"Zhao","year":"2024","journal-title":"Theranostics"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1693366\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T05:21:02Z","timestamp":1762492862000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1693366\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,7]]},"references-count":49,"alternative-id":["10.3389\/fphar.2025.1693366"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1693366","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,7]]},"article-number":"1693366"}}