Dataset Information

FXR Maintains the Intestinal Barrier and Stemness by Regulating CYP11A1-Mediated Corticosterone Synthesis in Biliary Obstruction Diseases.

ABSTRACT: Biliary obstruction diseases are often complicated by an impaired intestinal barrier, which aggravates liver injury. Treatment of the intestinal barrier is often neglected. To investigate the mechanism by which intestinal bile acid deficiency mediates intestinal barrier dysfunction after biliary obstruction and identify a potential therapeutic modality, we mainly used a bile duct ligation (BDL) mouse model to simulate biliary obstruction and determine the important role of the bile acid receptor FXR in maintaining intestinal barrier function and stemness. Through RNA-seq analysis of BDL and sham mouse crypts and qRT-PCR performed on intestinal epithelial-specific Fxr knockout (Fxr^ΔIEC) and wild-type mouse crypts, we found that FXR might maintain intestinal stemness by regulating CYP11A1 expression. Given the key role of CYP11A1 during glucocorticoid production, we also found that FXR activation could promote intestinal corticosterone (CORT) synthesis by ELISA. Intestinal organoid culture showed that an FXR agonist or corticosterone increased crypt formation and organoid growth. Further animal experiments showed that corticosterone gavage treatment could maintain intestinal barrier function and stemness, decrease LPS translocation, and attenuate liver injury in BDL mice. Our study hopefully provides a new theoretical basis for the prevention of intestinal complications and alleviation of liver injury after biliary obstruction.

SUBMITTER: Li Z

PROVIDER: S-EPMC10487515 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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FXR Maintains the Intestinal Barrier and Stemness by Regulating CYP11A1-Mediated Corticosterone Synthesis in Biliary Obstruction Diseases.

Li Zequn Z Dong Haijiang H Bian Suchen S Wu Hao H Song Wenfeng W Jia Xing X Chen Jian J Zhu Xingxin X Zhao Long L Xuan Zefeng Z Jin Cheng C Zhou Mengqiao M Zheng Shusen S Song Penghong P

International journal of molecular sciences 20230830 17

Biliary obstruction diseases are often complicated by an impaired intestinal barrier, which aggravates liver injury. Treatment of the intestinal barrier is often neglected. To investigate the mechanism by which intestinal bile acid deficiency mediates intestinal barrier dysfunction after biliary obstruction and identify a potential therapeutic modality, we mainly used a bile duct ligation (BDL) mouse model to simulate biliary obstruction and determine the important role of the bile acid receptor ...[more]

PMID: 37686300

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Project description:Background: The farnesoid X receptor (FXR) is a key factor regulating hepatic bile acid synthesis and enterohepatic circulation. Repression of bile acid synthesis by the FXR is a potential strategy for treating cholestatic liver disease. However, the role of intestinal FXR on the intestinal barrier and intestinal microbiota needs further investigation. Materials: Intestinal tissues were collected from patients with biliary atresia or without hepatobiliary disease. Then, intestinal mRNA levels of FXR-related molecules were determined. To investigate the effect of FXR activation, bile-duct-ligation rats were treated with obeticholic acid [OCA (5 mg/kg/day)] or vehicle (0.5% methyl cellulose) per oral gavage for 14 days. The mRNA levels of intestinal FXR, SHP, TNF-α, FGF15 and bile acid transporter levels were determined. In addition, the intestinal permeability, morphologic changes, and composition of the intestinal microbiota were evaluated. Gut Microbiome was determined by 16S rDNA MiSeq sequencing, and functional profiling of microbial communities was predicted with BugBase and PICRUSt2. Finally, the role of OCA in injured intestinal epithelial cell apoptosis and proliferation was examined by pretreatment with lipopolysaccharide (LPS) in Caco-2 cells. Results: The downstream of the FXR in ileum tissues was inhibited in biliary obstruction. Activation of the FXR signaling pathway by OCA significantly reduced liver fibrosis and intestinal inflammation, improved intestinal microbiota, and protected intestinal mucosa in BDL rats. OCA also altered the functional capacities of ileum microbiota in BDL rats. Significant differences existed between the controls and BDL rats, which were attenuated by OCA in the alpha diversity analysis. Principal coordinates analysis showed that microbial communities in BDL rats clustered separately from controls, and OCA treatment attenuated the distinction. Bugbase and PICRUSt2 analysis showed that OCA changed the composition and structure of the intestinal microbiota and improved the metabolic function of the intestinal microbiota by increasing the relative abundance of beneficial bacteria and reducing the relative abundance of harmful bacteria. Moreover, OCA reduced the apoptosis induced by LPS in Caco-2 cells. Conclusion: The FXR agonist, OCA, activates the intestinal FXR signaling pathway and improves the composition and structure of the intestinal microbiota and intestinal barrier in BDL rats.

Project description:BackgroundInflammatory bowel disease (IBD) presents a significant challenge due to its intricate pathogenesis. NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, is associated with transcriptional activation. NSD2 expression is decreased in both the intestinal epithelial cells (IECs) of IBD patients and the IBD mouse model. However, the precise role of NSD2 in IBD remains unexplored.MethodsColon tissues from IBD mice, SW620 cells and MC38 cells, were used as research subjects. Clinical databases of IBD patients were analysed to investigate whether NSD2 expression is reduced in the occurrence of IBD. NSD2-knockout mice were generated to further investigate the role of NSD2 in IBD. The IECs were isolated for RNA sequencing and chromatin immunoprecipitation sequencing to identify molecular signalling pathways and key molecules leading to IBD in mice. Molecular and cellular experiments were conducted to analyse and validate the role of NSD2 in the development of IBD. Finally, rescue experiments were performed to confirm the molecular mechanism of NSD2 in the development of IBD.ResultsDeficiency of NSD2 in mouse IECs aggravated epithelial barrier disruption and inflammatory response in IBD. Mechanistically, NSD2 loss led to downregulation of H3K36me2 and flavin-containing monooxygenase (FMO) (taurine-synthesis enzyme) mRNA, resulting in decreased taurine biosynthesis in IECs. Significantly, supplementation with taurine markedly alleviated the symptoms of NSD2 deficiency-induced IBD.ConclusionsThese data demonstrate that NSD2 plays a pivotal role in maintaining FMO-mediated taurine biosynthesis to prevent intestinal inflammation. Our findings also underscore the importance of NSD2-H3K36me2-mediated taurine biosynthesis in maintaining intestinal mucosal barrier homeostasis.Key pointsIn this study, we investigated the role of the histone methyltransferase NSD2 in preventing intestinal barrier disruption by sustaining taurine biosynthesis. NSD2 levels were reduced in both human specimens and mouse models of IBD. We demonstrate that NSD2 loss hinders the process of taurine synthesis in intestinal cells, leading to increased intestinal inflammation. Supplementation with taurine significantly relieved the symptoms caused by NSD2 deficiency. These data suggest that maintenance of NSD2-mediated taurine biosynthesis is vital for preserving the intestinal barrier and attenuating inflammation.

Dataset Information

FXR Maintains the Intestinal Barrier and Stemness by Regulating CYP11A1-Mediated Corticosterone Synthesis in Biliary Obstruction Diseases.

Publications

FXR Maintains the Intestinal Barrier and Stemness by Regulating CYP11A1-Mediated Corticosterone Synthesis in Biliary Obstruction Diseases.

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