{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:02:41Z","timestamp":1785409361248,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","doi-asserted-by":"publisher","award":["25K11181"],"award-info":[{"award-number":["25K11181"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"award":["25K11181"],"award-info":[{"award-number":["25K11181"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020291","name":"Kitasato University School of Allied Health Sciences Research Grant","doi-asserted-by":"publisher","award":["2025-005"],"award-info":[{"award-number":["2025-005"]}],"id":[{"id":"10.13039\/501100020291","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2025-005"],"award-info":[{"award-number":["2025-005"]}],"id":[{"id":"https:\/\/ror.org\/00f2txz25","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Kitasato University Graduate School of Medical Sciences Research Grant","award":["2024-B22"],"award-info":[{"award-number":["2024-B22"]}]},{"name":"Kitasato University Graduate School of Medical Sciences Research Grant","award":["2025-B06"],"award-info":[{"award-number":["2025-B06"]}]},{"award":["2024-B22"],"award-info":[{"award-number":["2024-B22"]}],"id":[{"id":"https:\/\/ror.org\/00f2txz25","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2025-B06"],"award-info":[{"award-number":["2025-B06"]}],"id":[{"id":"https:\/\/ror.org\/00f2txz25","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Improvement of bowel function is accompanied by increased luminal flow and altered epithelial mechanical forces, yet the underlying epithelial mechanisms remain unclear. We investigated whether enhanced luminal stimulation is associated with epithelial mechanotransduction and junctional remodeling during changes in colonic motility. Sennoside was orally administered at 4.8 mg\/kg body weight to 5-week-old male BALB\/cAJcl mice for 21 days to model increased luminal stimulation. Stool characteristics, fecal water content, Bristol Stool Form Scale scores, and segmental colonic motility were assessed. Expression of Muc2, inflammatory cytokines, Trpv4, and E-cadherin was quantified across colonic regions. In CT26 monolayers, mechanical stress was applied to evaluate transient receptor potential channel induction, E-cadherin redistribution, and transepithelial electrical resistance, and the effect of Trpv4 knockdown. Sennoside softened stools, increased fecal water content (+18%) and Bristol scores (+57%), and enhanced distal colonic motility (+117%) without altering inflammatory cytokines. Trpv4 was selectively upregulated in the distal colon (3.3-fold). E-cadherin expression increased (2.5-fold) with junctional redistribution, whereas Muc2 decreased (\u221244%). In vitro, mechanical stress upregulated Trpv4 (2.5-fold), increased barrier resistance (+48%), and promoted E-cadherin assembly; these effects were augmented by sennoside and attenuated by Trpv4 silencing. These findings suggest that epithelial responses involving TRPV4-associated mechanotransduction and junctional remodeling are associated with altered barrier-related properties and distal colonic functional changes, providing insight into an epithelial component of stimulant laxative action.<\/jats:p>","DOI":"10.3390\/ijms27115057","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:46:48Z","timestamp":1780494408000},"page":"5057","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TRPV4-Dependent Epithelial Mechanoadaptation and Barrier Remodeling Mediate Sennoside-Induced Distal Colonic Motility"],"prefix":"10.3390","volume":"27","author":[{"given":"Yusuke","family":"Hara","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0374, Kanagawa, Japan"},{"name":"Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rei","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Biochemistry, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Regenerative Medicine and Cell Design Research Facility, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7722-5623","authenticated-orcid":false,"given":"Shun","family":"Tamaki","sequence":"additional","affiliation":[{"name":"Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Biochemistry, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Regenerative Medicine and Cell Design Research Facility, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsunori","family":"Maekawa","sequence":"additional","affiliation":[{"name":"Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Biochemistry, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Regenerative Medicine and Cell Design Research Facility, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki I.","family":"Kawamura","sequence":"additional","affiliation":[{"name":"National Institute of Global Health and Medicine, Japan Institute for Health Security, Shinjuku 162-8655, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taizo","family":"Tsujimoto","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0374, Kanagawa, Japan"},{"name":"Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chika","family":"Kusano","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0374, Kanagawa, Japan"},{"name":"Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Ichikawa","sequence":"additional","affiliation":[{"name":"Department of Regulation Biochemistry, Kitasato University Graduate School of Medical Sciences, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Department of Biochemistry, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Kanagawa, Japan"},{"name":"Regenerative Medicine and Cell Design Research Facility, Kitasato University School of Allied Health Sciences, Sagamihara 252-0373, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1053\/j.gastro.2023.03.214","article-title":"American Gastroenterological Association\u2013American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation","volume":"164","author":"Chang","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chen, Z., Peng, Y., Shi, Q., Chen, Y., Cao, L., Jia, J., Liu, C., and Zhang, J. (2022). Prevalence and Risk Factors of Functional Constipation According to the Rome Criteria in China: A Systematic Review and Meta-Analysis. Front. Med., 9.","DOI":"10.3389\/fmed.2022.815156"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00508-023-02156-w","article-title":"Global Prevalence of Constipation in Older Adults: A Systematic Review and Meta-Analysis","volume":"135","author":"Salari","year":"2023","journal-title":"Wien. Klin. Wochenschr."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Peng, X., Li, J., Wu, Y., Dai, H., Lynn, H.S., and Zhang, X. (2023). Association of Stool Frequency and Consistency with the Risk of All-Cause and Cause-Specific Mortality among U.S. Adults: Results from NHANES 2005\u20132010. Healthcare, 11.","DOI":"10.3390\/healthcare11010029"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Ohkusa, T., Koido, S., Nishikawa, Y., and Sato, N. (2019). Gut Microbiota and Chronic Constipation: A Review and Update. Front. Med., 6.","DOI":"10.3389\/fmed.2019.00019"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101982","DOI":"10.1016\/j.xcrm.2025.101982","article-title":"The Gut Microbiota\u2013Immune\u2013Brain Axis: Therapeutic Implications","volume":"6","author":"Moloney","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/j.1365-2982.2006.00835.x","article-title":"Chronic Constipation: Advances in Management","volume":"19","author":"Wald","year":"2007","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1136\/gut.11.12.1038","article-title":"The Action of Sennosides and Related Compounds on the Human Colon and Rectum","volume":"11","author":"Hardcastle","year":"1970","journal-title":"Gut"},{"key":"ref_9","first-page":"86","article-title":"Metabolism and Pharmacokinetics of Anthranoids","volume":"47","year":"1993","journal-title":"Pharmacology"},{"key":"ref_10","first-page":"783","article-title":"Colonoscopic resolution of melanosis coli after cessation of senna laxative use","volume":"17","author":"Chiba","year":"2024","journal-title":"Int. Med. Case Rep. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1179552218817321","DOI":"10.1177\/1179552218817321","article-title":"Melanosis Coli: A Helpful Contrast Effect or a Harmful Pigmentation?","volume":"11","author":"Mari","year":"2018","journal-title":"Clin. Med. Insights Gastroenterol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1007\/BF02234645","article-title":"Adverse Effects of Laxatives","volume":"44","author":"Xing","year":"2001","journal-title":"Dis. Colon Rectum"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.phymed.2003.10.008","article-title":"Senna and the Formation of Aberrant Crypt Foci and Tumors in Rats Treated with Azoxymethane","volume":"12","author":"Borrelli","year":"2005","journal-title":"Phytomedicine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"24","DOI":"10.2174\/138920111793937862","article-title":"TRP Channels in the Digestive System","volume":"12","author":"Holzer","year":"2011","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1126\/science.1193270","article-title":"Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels","volume":"330","author":"Coste","year":"2010","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.semcdb.2016.05.010","article-title":"Epithelial cell extrusion: Pathways and pathologies","volume":"67","author":"Gudipaty","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/ncb3136","article-title":"E-cadherin Junctions as Active Mechanical Integrators in Tissue Dynamics","volume":"17","author":"Lecuit","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrm3802","article-title":"Dynamic Contacts: Rearranging Adherens Junctions to Drive Epithelial Remodelling","volume":"15","author":"Takeichi","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mihara, H., Uchida, K., Watanabe, Y., Nanjo, S., Sakumura, M., Motoo, I., Ando, T., Minemura, M., Muhammad, J.S., and Yamamoto, H. (2023). Colonic TRPV4 Overexpression Is Related to Constipation Severity. BMC Gastroenterol., 23.","DOI":"10.1186\/s12876-023-02647-0"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.devcel.2020.12.018","article-title":"Cell Junction Mechanics beyond the Bounds of Adhesion and Tension","volume":"56","author":"Lenne","year":"2021","journal-title":"Dev. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"jcs264055","DOI":"10.1242\/jcs.264055","article-title":"Paths to Stability\u2014Actin Regulation of Adherens Junction Mechanics","volume":"138","author":"James","year":"2025","journal-title":"J. Cell Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1007\/978-3-319-05161-1_2","article-title":"TRPs in Mechanosensing and Volume Regulation","volume":"223","author":"Plant","year":"2014","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Jiao, R., Cui, D., Wang, S.C., Li, D., and Wang, Y.-F. (2017). Interactions of the Mechanosensitive Channels with Extracellular Matrix, Integrins, and Cytoskeletal Network in Osmosensation. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00096"},{"key":"ref_24","first-page":"85","article-title":"Prostaglandin-Mediated Action of Sennosides","volume":"36","author":"Beubler","year":"1988","journal-title":"Pharmacology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.jep.2013.12.055","article-title":"Rheinanthrone, a metabolite of sennoside A, triggers macrophage activation to decrease aquaporin-3 expression in the colon, causing the laxative effect of rhubarb extract","volume":"152","author":"Kon","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1146\/annurev.biochem.75.103004.142819","article-title":"TRP Channels","volume":"76","author":"Venkatachalam","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"18749","DOI":"10.1074\/jbc.M110.103606","article-title":"The TRPV4 Channel Contributes to Intercellular Junction Formation in Keratinocytes","volume":"285","author":"Sokabe","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.1111\/jgh.15596","article-title":"Mechanical Stimulation Activates Piezo1 to Promote Mucin2 Expression in Goblet Cells","volume":"36","author":"Xu","year":"2021","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e21074","DOI":"10.7554\/eLife.21074","article-title":"Direct Measurement of TRPV4 and PIEZO1 Activity Reveals Multiple Mechanotransduction Pathways in Chondrocytes","volume":"6","author":"Moroni","year":"2017","journal-title":"eLife"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/nri2653","article-title":"Intestinal Mucosal Barrier Function in Health and Disease","volume":"9","author":"Turner","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/nrm.2017.87","article-title":"Mechanobiology of YAP and TAZ in Physiology and Disease","volume":"18","author":"Panciera","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"17693","DOI":"10.1074\/jbc.REV119.007963","article-title":"Control of Cellular Responses to Mechanical Cues through YAP\/TAZ Regulation","volume":"294","author":"Dasgupta","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.1113\/JP271919","article-title":"Insights into the Mechanisms Underlying Colonic Motor Patterns","volume":"594","author":"Spencer","year":"2016","journal-title":"J. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1097\/MOG.0b013e32834d4f61","article-title":"Motility Disorders of the Colon and Rectum","volume":"28","author":"Wald","year":"2012","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0079-6468(05)43004-0","article-title":"Muscarinic Receptor Subtype Pharmacology and Physiology","volume":"43","author":"Eglen","year":"2005","journal-title":"Prog. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","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":"ref_37","doi-asserted-by":"crossref","first-page":"11934","DOI":"10.1039\/D4FO04444D","article-title":"Synergistic Effects of Ligilactobacillus salivarius Li01 and Psyllium Husk Prevent Mice from Developing Loperamide-Induced Constipation","volume":"15","author":"Xu","year":"2024","journal-title":"Food Funct."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"920","DOI":"10.3109\/00365529709011203","article-title":"Stool Form Scale as a Useful Guide to Intestinal Transit Time","volume":"32","author":"Lewis","year":"1997","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1089\/scd.2017.0242","article-title":"Tissue Engineering under Microgravity Conditions\u2014Use of Stem Cells and Specialized Cells","volume":"27","author":"Grimm","year":"2018","journal-title":"Stem Cells Dev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/5057\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:52:24Z","timestamp":1780494744000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/11\/5057"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,3]]},"references-count":39,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27115057"],"URL":"https:\/\/doi.org\/10.3390\/ijms27115057","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,3]]}}}