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This study evaluated the effects of \u03b2\u2010sitosterol and sertraline on colonic motility, tight junction proteins and chloride channel (ClC\u20102) expression, intestinal inflammation and endotoxemia in water avoidance stress (WAS)\u2010induced rat model of IBS. Thirty\u2010five male Wistar rats were divided into five groups (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20097\/group): control, WAS+\u03b2\u2010sitosterol (25\u2009mg\/kg\/day in olive oil), WAS + sertraline (30\u2009mg\/kg\/day in saline), WAS + olive oil and WAS + saline groups. WAS (10 days) was used to induce IBS\u2010like symptoms in rats. Fecal pellet output (FPO), fecal water content (FWC), and intestinal transit were assessed to determine motility and diarrhea. QRT\u2010PCR quantified Claudin\u20101, Claudin\u20102, and ClC\u20102 mRNA expression. Endotoxemia and intestinal inflammation were assessed by measuring serum lipopolysaccharide (LPS) and colonic TNF\u2010\u03b1 level. WAS significantly increased FPO, FWC, and accelerated intestinal transit compared to control. Treatment with both \u03b2\u2010sitosterol and sertraline reduced FPO and FWC compared to untreated IBS rats. \u03b2\u2010sitosterol (but not sertraline) normalized intestinal transit. WAS significantly upregulated Claudin\u20102 and downregulated Claudin\u20101 compared to control. \u03b2\u2010sitosterol restored Claudin\u20101\/2 expression and upregulated ClC\u20102 above control levels. Sertraline increased Claudin\u20101 and ClC\u20102 but did not affect Claudin\u20102 compared to untreated IBS group. WAS caused significant colonic inflammation with a threefold TNF\u2010\u03b1 increase, confirming an IBS\u2010like state. Sertraline and \u03b2\u2010sitosterol significantly reduced TNF\u2010\u03b1 in colon tissue. \u03b2\u2010sitosterol significantly reduced serum LPS and preserved colonic crypt architecture, wall thickness, and mucosa compared to untreated IBS group. Sertraline reduced TNF\u2010\u03b1, LPS and improved wall thickness but did not affect crypt architecture or prevent erosion. \u03b2\u2010Sitosterol alleviated hypermotility, restored barrier integrity, reduced inflammation and prevented endotoxemia. ClC\u20102 modulation and mucosal healing of \u03b2\u2010sitosterol suggest its potential as a targeted IBS therapy.\n                  <\/jats:p>","DOI":"10.1002\/jbt.70789","type":"journal-article","created":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T21:00:34Z","timestamp":1777842034000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["\u03b2\u2010Sitosterol Restored Intestinal Barrier Integrity and Reduced Intestinal Hypermotility in Stress\u2010Induced IBS: Comparison With Sertraline"],"prefix":"10.1002","volume":"40","author":[{"given":"Sepideh","family":"Hajivand","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Medicine Isfahan University of Medical Sciences Isfahan Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1538-9034","authenticated-orcid":false,"given":"Mohammadreza","family":"Sharifi","sequence":"additional","affiliation":[{"name":"Department of Genetics and Molecular Biology, School of Medicine Isfahan University of Medical Sciences Isfahan Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7313-5086","authenticated-orcid":false,"given":"Ardeshir","family":"Talebi","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine Isfahan University of Medical Sciences Isfahan Iran"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5414-9594","authenticated-orcid":false,"given":"Maedeh","family":"Ghasemi","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine Isfahan University of Medical Sciences Isfahan Iran"},{"name":"Pharmaceutical Sciences Research Center Isfahan University of Medical Sciences Isfahan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,5,3]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2009.05.038"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph182312836"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2024.1380713"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.04.011"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2024.1465649"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21030972"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.14798"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2020.183503"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316906"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-024-01496-9"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.5217\/ir.2015.13.1.11"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/1756284821993586"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.5009\/gnl.2012.6.3.305"},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","unstructured":"A. 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