1. Obeticholic acid attenuates the intestinal barrier disruption in a rat model of short bowel syndrome.
- Author
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Hou L, Wang H, Yan M, Cai Y, Zheng R, Ma Y, Tang W, and Jiang W
- Subjects
- Animals, Rats, Humans, Male, Gastrointestinal Microbiome drug effects, Female, Rats, Sprague-Dawley, Apoptosis drug effects, Middle Aged, Intestine, Small metabolism, Intestine, Small drug effects, Intestine, Small pathology, Adult, Tight Junction Proteins metabolism, Chenodeoxycholic Acid analogs & derivatives, Chenodeoxycholic Acid pharmacology, Short Bowel Syndrome metabolism, Short Bowel Syndrome drug therapy, Short Bowel Syndrome pathology, Receptors, Cytoplasmic and Nuclear metabolism, Receptors, Cytoplasmic and Nuclear agonists, Disease Models, Animal, Intestinal Mucosa metabolism, Intestinal Mucosa drug effects, Intestinal Mucosa pathology
- Abstract
Background: Short bowel syndrome (SBS) features nutrients malabsorption and impaired intestinal barrier. Patients with SBS are prone to sepsis, intestinal flora dysbiosis and intestinal failure associated liver disease. Protecting intestinal barrier and preventing complications are potential strategies for SBS treatment. This study aims to investigate the effects of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), have on intestinal barrier and ecological environment in SBS., Methods and Results: Through testing the small intestine and serum samples of patients with SBS, impaired intestinal barrier was verified, as evidenced by reduced expressions of intestinal tight junction proteins (TJPs), increased levels of apoptosis and epithelial cell damage. The intestinal expressions of FXR and related downstream molecules were decreased in SBS patients. Then, global FXR activator OCA was used to further dissect the potential role of the FXR in a rat model of SBS. Low expressions of FXR-related molecules were observed on the small intestine of SBS rats, along with increased proinflammatory factors and damaged barrier function. Furthermore, SBS rats possessed significantly decreased body weight and elevated death rate. Supplementation with OCA mitigated the damaged intestinal barrier and increased proinflammatory factors in SBS rats, accompanied by activated FXR-related molecules. Using 16S rDNA sequencing, the regulatory role of OCA on gut microbiota in SBS rats was witnessed. LPS stimulation to Caco-2 cells induced apoptosis and overexpression of proinflammatory factors in vitro. OCA incubation of LPS-pretreated Caco-2 cells activated FXR-related molecules, increased the expressions of TJPs, ameliorated apoptosis and inhibited overexpression of proinflammatory factors., Conclusions: OCA supplementation could effectively ameliorate the intestinal barrier disruption and inhibit overexpression of proinflammatory factors in a rat model of SBS and LPS-pretreated Caco-2 cells. As a selective activator of FXR, OCA might realize its protective function through FXR activation., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023. Published by Elsevier B.V.)
- Published
- 2024
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