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Here we examined regulatory mechanisms of TRPV4 expression by co-culturing colon epithelial cell lines with intestinal bacteria and their derivatives. We also investigated TRPV4 expression in colon epithelium from patients with constipation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Colon epithelial cell lines were co-cultured with various enterobacteria (bacterial components and supernatant), folate, LPS, or short chain fatty acids. TRPV4 expression levels and promoter DNA methylation were assessed using pyrosequencing, and microarray network analysis. For human samples, correlation coefficients were calculated and multiple regression analyses were used to examine the association between clinical background, rectal TRPV4 expression level and mucosa-associated microbiota.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Co-culture of CCD841 cells with\n                      <jats:italic>P. acnes<\/jats:italic>\n                      ,\n                      <jats:italic>C. perfringens<\/jats:italic>\n                      , or\n                      <jats:italic>S. aureus<\/jats:italic>\n                      transiently decreased TRPV4 expression but did not induce methylation. Co-culture with clinical isolates and standard strains of\n                      <jats:italic>K. oxytoca<\/jats:italic>\n                      ,\n                      <jats:italic>E. faecalis<\/jats:italic>\n                      , or\n                      <jats:italic>E. coli<\/jats:italic>\n                      increased TRPV4 expression in CCD841 cells, and TRPV4 and TNF-alpha expression were increased by\n                      <jats:italic>E. coli<\/jats:italic>\n                      culture supernatants but not bacterial components. Although folate, LPS, IL-6, TNF-alpha, or SCFAs alone did not alter TRPV4 expression, TRPV4 expression following exposure to\n                      <jats:italic>E. coli<\/jats:italic>\n                      culture supernatants was inhibited by butyrate or TNF-alphaR1 inhibitor and increased by p38 inhibitor. Microarray network analysis showed activation of TNF-alpha, cytokines, and NOD signaling. TRPV4 expression was higher in constipated patients from the terminal ileum to the colorectum, and multiple regression analyses showed that low stool frequency, frequency of defecation aids, and duration were associated with TRPV4 expression. Meanwhile, incomplete defecation, time required to defecate, and number of defecation failures per 24\u00a0h were associated with increased\n                      <jats:italic>E. faecalis<\/jats:italic>\n                      frequency.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Colon epithelium cells had increased TRPV4 expression upon co-culture with\n                      <jats:italic>K. oxytoca<\/jats:italic>\n                      ,\n                      <jats:italic>E. faecalis<\/jats:italic>\n                      , or\n                      <jats:italic>E. coli<\/jats:italic>\n                      supernatants, as well as TNF\u03b1-stimulated TNF\u03b1R1 expression via a pathway other than p38. Butyrate treatment suppressed this increase. Epithelial TRPV4 expression was increased in constipated patients, suggesting that TRPV4 together with increased frequency of\n                      <jats:italic>E. faecalis<\/jats:italic>\n                      may be involved in the pathogenesis of various constipation symptoms.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12876-023-02647-0","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T05:04:01Z","timestamp":1673586241000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Colonic TRPV4 overexpression is related to constipation severity"],"prefix":"10.1186","volume":"23","author":[{"given":"Hiroshi","family":"Mihara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunitoshi","family":"Uchida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohachi","family":"Nanjo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Sakumura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iori","family":"Motoo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Ando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masami","family":"Minemura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jibran Sualeh","family":"Muhammad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumio","family":"Itoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Yasuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"issue":"2","key":"2647_CR1","doi-asserted-by":"publisher","first-page":"192","DOI":"10.5056\/jnm.2013.19.2.192","volume":"19","author":"JM Kwak","year":"2013","unstructured":"Kwak JM, Babygirija R, Gribovskaja-Rupp I, Takahashi T, Yamato S, Ludwig K. 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