MaKayla L O'Guinn, David A Handler, Jonathan J Hsieh, Michael U Mallicote, Karina Feliciano, Christopher P Gayer
{"title":"FXR deletion attenuates intestinal barrier dysfunction in murine acute intestinal inflammation.","authors":"MaKayla L O'Guinn, David A Handler, Jonathan J Hsieh, Michael U Mallicote, Karina Feliciano, Christopher P Gayer","doi":"10.1152/ajpgi.00063.2024","DOIUrl":null,"url":null,"abstract":"<p><p>Accumulating literature suggests that the farnesoid-X receptor (FXR), a nuclear bile acid receptor best known for its role in bile acid homeostasis, is also a potent context-dependent regulator of inflammation. FXR may thus be relevant to several intestinal disease states including inflammatory bowel disease, necrotizing enterocolitis, and sepsis. In this study, we tested the effects of FXR deletion on acute murine intestinal inflammation. We found that FXR knockout (KO) mice were protected from intestinal injury and barrier dysfunction induced by lipopolysaccharide (LPS) injection, dithizone (DI)/<i>Klebsiella</i>, and cecal ligation/puncture models. In the LPS model, RNA sequencing and qPCR analysis showed that this protection correlated with substantial reduction in LPS-induced proinflammatory gene expression, including lower tissue levels of <i>Il1a</i>, <i>Il1b</i>, and <i>Tnf</i>. Examining functional effects on the epithelium, we found that LPS-induced tight junctional disruption as assessed by internalization of ZO-1 and occludin was ameliorated in FXR KO animals. Taken together, these data suggest a role for FXR in the intestinal barrier during inflammatory injury.<b>NEW & NOTEWORTHY</b> Intestinal barrier failure is a hallmark in gut-origin sepsis. We demonstrate that the intestinal barriers of farnesoid-X receptor (FXR) knockout (KO) animals are protected from inflammatory insult using multiple models of acute intestinal inflammation. This protection is due to decreased inflammatory cytokine production and maintenance of tight junctional architecture seen within the KO animals. This is the first report of FXR deletion being protective to the intestinal barrier.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":null,"pages":null},"PeriodicalIF":3.9000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427094/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Gastrointestinal and liver physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajpgi.00063.2024","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/11 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Accumulating literature suggests that the farnesoid-X receptor (FXR), a nuclear bile acid receptor best known for its role in bile acid homeostasis, is also a potent context-dependent regulator of inflammation. FXR may thus be relevant to several intestinal disease states including inflammatory bowel disease, necrotizing enterocolitis, and sepsis. In this study, we tested the effects of FXR deletion on acute murine intestinal inflammation. We found that FXR knockout (KO) mice were protected from intestinal injury and barrier dysfunction induced by lipopolysaccharide (LPS) injection, dithizone (DI)/Klebsiella, and cecal ligation/puncture models. In the LPS model, RNA sequencing and qPCR analysis showed that this protection correlated with substantial reduction in LPS-induced proinflammatory gene expression, including lower tissue levels of Il1a, Il1b, and Tnf. Examining functional effects on the epithelium, we found that LPS-induced tight junctional disruption as assessed by internalization of ZO-1 and occludin was ameliorated in FXR KO animals. Taken together, these data suggest a role for FXR in the intestinal barrier during inflammatory injury.NEW & NOTEWORTHY Intestinal barrier failure is a hallmark in gut-origin sepsis. We demonstrate that the intestinal barriers of farnesoid-X receptor (FXR) knockout (KO) animals are protected from inflammatory insult using multiple models of acute intestinal inflammation. This protection is due to decreased inflammatory cytokine production and maintenance of tight junctional architecture seen within the KO animals. This is the first report of FXR deletion being protective to the intestinal barrier.
期刊介绍:
The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.