Reversal of cholestatic liver disease by the inhibition of sphingosine 1-phosphate receptor 2 signaling
Huiling Cao,
Lin Chen,
Ziyang Zeng,
Xianfeng Wu,
Yuhao Lei,
Wen Jia,
Guang Yue,
Bin Yi,
Yu-jie Li,
Yuan Shi
Affiliations
Huiling Cao
Department of Neonatology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Childhood Nutrition and Health, Chongqing, China
Lin Chen
Southwest Hospital, Third Military Medical University, Chongqing, Chongqing, China
Ziyang Zeng
Southwest Hospital, Third Military Medical University, Chongqing, Chongqing, China
Xianfeng Wu
Southwest Hospital, Third Military Medical University, Chongqing, Chongqing, China
Yuhao Lei
Southwest Hospital, Third Military Medical University, Chongqing, Chongqing, China
Wen Jia
Department of Neonatology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Childhood Nutrition and Health, Chongqing, China
Guang Yue
Department of Neonatology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Childhood Nutrition and Health, Chongqing, China
Bin Yi
Southwest Hospital, Third Military Medical University, Chongqing, Chongqing, China
Yu-jie Li
Southwest Hospital, Third Military Medical University, Chongqing, Chongqing, China
Yuan Shi
Department of Neonatology, Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Childhood Nutrition and Health, Chongqing, China
Aims The objective of this study is to examine the impact of inhibiting Sphingosine 1-phosphate receptor 2 (S1PR2) on liver inflammation, fibrogenesis, and changes of gut microbiome in the context of cholestasis-induced conditions. Methods The cholestatic liver injury model was developed by common bile duct ligation (CBDL). Sprague-Dawley rats were randomly allocated to three groups, sham operation, CBDL group and JTE-013 treated CBDL group. Biochemical and histological assessments were conducted to investigate the influence of S1PR2 on the modulation of fibrogenic factors and inflammatory infiltration. We conducted an analysis of the fecal microbiome by using 16S rRNA sequencing. Serum bile acid composition was evaluated through the utilization of liquid chromatography-mass spectrometry techniques. Results In the BDL rat model, the study findings revealed a significant increase in serum levels of conjugated bile acids, accompanied by an overexpression of S1PR2. Treatment with the specific inhibitor of S1PR2, known as JTE-013, resulted in a range of specific effects on the BDL rats. These effects included the improvement of liver function, reduction of liver inflammation, inhibition of hepatocyte apoptosis, and suppression of NETosis. These effects are likely mediated through the TCA/S1PR2/NOX2/NLRP3 pathway. Furthermore, the administration of JTE-013 resulted in an augmentation of the diversity of the bacterial community’s diversity, facilitating the proliferation of advantageous species while concurrently inhibiting the prevalence of detrimental bacteria. Conclusions The results of our study suggest that the administration of JTE-013 may have a beneficial effect in alleviating cholestatic liver disease and restoring the balance of intestinal flora.
