Publications by authors named "Xinbei Tian"

6 Publications

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Fish oil-based lipid emulsion alleviates parenteral nutrition-associated liver diseases and intestinal injury in piglets.

JPEN J Parenter Enteral Nutr 2021 Jul 21. Epub 2021 Jul 21.

Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Background: Thisstudy aimed to investigate the impact of fish oil-based lipid emulsion (FO) on enterohepatic injuries and intestinal microbiota in piglets of parenteral nutrition (PN).

Methods: Newborn piglets were divided into three groups, including enteral diet (the controls), PN with 100% FO and PN with medium-chain triglyceride/long-chain triglyceride-based lipid emulsion (MCT/LCT) for 14 days. Serum biochemical indicators, hepatic and intestinal histology, and expression of genes associated with inflammation, oxidative stress, and lipid metabolism were measured. The bile acid (BA) profiles in serum and the taxonomic composition of the gut microbiome in different intestinal segments were analyzed.

Results: Compared with MCT/LCT-piglets, FO reduced inflammation, promoted fatty acid oxidation, and decreased oxidative stress in the liver. In the intestine, FO decreased intestinal inflammation and intestinal permeability, leading to reduced lipopolysaccharide entry into the blood circulation relative to MCT/LCT-piglets. PN groups have dominant contents of Proteobacteria and Bacteroides, whereas the control group have Firmicutes at the phylum level. FO altered the taxonomic compositions of the gut microbiome in different segments, increased the relative abundance of Bacteroidaceae in ileum, and Rikenellaceae and Ruminococcaceae in the colon. FO treatment shifted BA composition ratio in serum and had a lower ratio of secondary BAs to primary BAs.

Conclusion: FO alleviates PNLAD and intestinal injury by regulating the homeostasis of BAs' enterohepatic circulation and altering microbiota composition in different intestinal segments.
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http://dx.doi.org/10.1002/jpen.2229DOI Listing
July 2021

Loss function of Bcr mutation causes gastrointestinal dysmotility and brain developmental defects.

Neurogastroenterol Motil 2021 Jun 30:e14190. Epub 2021 Jun 30.

Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.

Background: The breakpoint cluster region (BCR) is a protein that originally forms a fusion protein with c-Abl tyrosine kinase and induces leukemia. Researchers have shown that BCR is enriched in the central nervous system and may contribute to neurological disorders. We aimed to investigate the physiological function of BCR in neural development in the gastrointestinal (GI) tract and brain.

Methods: Whole-exome sequencing was used to screen for mutations in the BCR. Bcr knockout mice (Bcr , ΔExon 2-22) were generated using the CRISPR/Cas9 system. Transit of carmine red dye and glass bead expulsion assays were used to record total and proximal GI transit and distal colonic transit.

Key Results: In an infant with pediatric intestinal pseudo-obstruction, we found a heterozygous de novo mutation (NM_004327.3:c.3072+1G>A) in BCR. Bcr deficiency mice (Bcr ) exhibited growth retardation and impaired gastrointestinal motility. Bcr mice had a prolonged average total GI transit time with increased distal colonic transit and proximal GI transit in isolation. Morphology analysis indicated that Bcr mice had a less number of neurons in the submucosal plexus and myenteric plexus. Bcr mice exhibited apparent structural defects in the brain, particularly in the cortex. Additionally, Bcr depletion in the mouse cortex altered the expression of Ras homologous (Rho) family small GTPases.

Conclusions And Inferences: BCR mutations are associated with intestinal obstruction in children. Loss of Bcr can cause intestinal dysmotility and brain developmental defects may via regulation of Rho GTPases.
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http://dx.doi.org/10.1111/nmo.14190DOI Listing
June 2021

Conditional depletion of macrophages ameliorates cholestatic liver injury and fibrosis via lncRNA-H19.

Cell Death Dis 2021 06 24;12(7):646. Epub 2021 Jun 24.

Division of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Although macrophages are recognized as important players in the pathogenesis of chronic liver diseases, their roles in cholestatic liver fibrosis remain incompletely understood. We previously reported that long noncoding RNA-H19 (lncRNA-H19) contributes to cholangiocyte proliferation and cholestatic liver fibrosis of biliary atresia (BA). We here show that monocyte/macrophage CD11B mRNA levels are increased significantly in livers of BA patients and positively correlated with the progression of liver inflammation and fibrosis. The macrophages increasingly infiltrate and accumulate in the fibrotic niche and peribiliary areas in livers of BA patients. Selective depletion of macrophages using the transgenic CD11b-diphtheria toxin receptor (CD11b-DTR) mice halts bile duct ligation (BDL)-induced progression of liver damage and fibrosis. Meanwhile, macrophage depletion significantly reduces the BDL-induced hepatic lncRNA-H19. Overexpression of H19 in livers using adeno-associated virus serotype 9 (AAV9) counteracts the effects of macrophage depletion on liver fibrosis and cholangiocyte proliferation. Additionally, both H19 knockout (H19) and conditional deletion of H19 in macrophage (H19) significantly depress the macrophage polarization and recruitment. lncRNA-H19 overexpressed in THP-1 macrophages enhance expression of Rho-GTPase CDC42 and RhoA. In conclusions, selectively depletion of macrophages suppresses cholestatic liver injuries and fibrosis via the lncRNA-H19 and represents a potential therapeutic strategy for rapid liver fibrosis in BA patients.
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http://dx.doi.org/10.1038/s41419-021-03931-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225916PMC
June 2021

A nonbile acid farnesoid X receptor agonist tropifexor potently inhibits cholestatic liver injury and fibrosis by modulating the gut-liver axis.

Liver Int 2021 09 18;41(9):2117-2131. Epub 2021 May 18.

Division of Pediatric Gastroenterology and Nutrition, Xin Hua hosiptal, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Background & Aims: Tropifexor (TXR) is a novel nonbile acid that acts as an agonist of farnesoid X receptor (FXR). TXR is currently in Phase 2 trials for the treatment of non-alcoholic steatohepatitis (NASH). Herein, we report the impact of TXR on in a piglet model in which cholestatic liver damage and fibrosis where induced by bile duct ligation (BDL).

Methods: The piglets received BDL and TXR for 2 wk. Hepatic, portal and colonic bile acid and amino acid profiles and gut microbiome were analysed. Portal fibroblast growth factor (FGF) 19 levels were measured using an enzyme-linked immunosorbent assay (ELISA).

Results: We first showed that bile acid metabolism and signalling are dysfunctional in patients with biliary atresia. Next, we observed that TXR potently suppresses BDL-induced liver injury, fibrosis and ductular reaction in piglets. Within the ileum, TXR enhances FGF19 expression and subsequently increases portal FGF19 levels. In the liver, TXR promotes the expression of small heterodimer partner (SHP) and inhibits cholesterol 7α-hydroxylase (CYP7A1). Additionally, TXR increases the abundance of bile acid-biotransforming bacteria in the distal ileum and alters the composition of amino acids in the colon. Lastly, TXR ameliorates intestinal barrier injury in piglets subjected to BDL.

Conclusion: TXR potently ameliorated cholestatic liver injury and fibrosis by modulating the gut-liver axis in piglets. It supports the clinical evaluation of TXR as a therapeutic strategy for cholestatic liver diseases, such as biliary atresia.
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http://dx.doi.org/10.1111/liv.14906DOI Listing
September 2021

The Farnesoid X Receptor Agonist Tropifexor Prevents Liver Damage in Parenteral Nutrition-fed Neonatal Piglets.

J Pediatr Gastroenterol Nutr 2021 07;73(1):e11-e19

Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University.

Objectives: Intestinal failure-associated liver disease (IFALD) is a life-threatening complication for patients with intestinal failure who receive long-term parenteral nutrition (PN). We evaluated the effects of the farnesoid X receptor agonist tropifexor on a neonatal piglet model of IFALD fed with PN.

Methods: The piglets received PN and tropifexor for 14 days, then levels of liver enzymes, bile acid metabolism, inflammation, and intestinal barrier markers were assessed using quantitative real-time PCR. Fibroblast growth factor (FGF) 19 serum levels were determined using enzyme-linked immunosorbent assays. Bile acids were determined in liver, serum, and intestinal contents, and the microbiome was sequenced in different intestinal segments.

Results: The PN model was established in newborn piglets. The levels of serum liver enzymes, pro-inflammatory factors, and oxidative stress increased in the livers of piglets fed with PN, but not in those fed with PN and tropifexor. Tropifexor stimulated FGF19 expression in ileal epithelial cells, increased portal FGF19 levels, then inhibited cholesterol 7α-hydroxylase expression in the liver. Tropifexor increased the relative abundance of bacteria associated with bile salt hydrolase and 7α-dehydrogenation in the contents of ileum and altered the composition of bile acids in serum, liver, and intestinal contents. Tropifexor also inhibited intestinal inflammation, alleviated intestinal mucosal atrophy, and improved the intestinal barrier.

Conclusions: Tropifexor might prevent liver damage in neonatal piglets receiving PN by altering the composition of intestinal microbiota and bile acids. Tropifexor also alleviates intestinal inflammation and preserves the intestinal barrier.
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http://dx.doi.org/10.1097/MPG.0000000000003135DOI Listing
July 2021

Long non-coding RNA H19 deficiency ameliorates bleomycin-induced pulmonary inflammation and fibrosis.

Respir Res 2020 Nov 2;21(1):290. Epub 2020 Nov 2.

Shanghai Institute for Pediatric Research, Shanghai, China.

Background: The poor understanding of pathogenesis in idiopathic pulmonary fibrosis (IPF) impaired development of effective therapeutic strategies. The aim of the current study is to investigate the roles of long non-coding RNA H19 (lncRNA H19) in the pulmonary inflammation and fibrosis of IPF.

Methods: Bleomycin was used to induce pulmonary inflammation and fibrosis in mice. The mRNAs and proteins expression in lung tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. H19 knockout (H19) mice were generated by CRISPR/Cas9.

Results: The expression of H19 mRNA was up-regulated in fibrotic lungs patients with IPF as well as in lungs tissues that obtained from bleomycin-treated mice. H19 mice suppressed bleomycin-mediated pulmonary inflammation and inhibited the Il6/Stat3 signaling. H19 deficiency ameliorated bleomycin-induced pulmonary fibrosis and repressed the activation of TGF-β/Smad and S1pr2/Sphk2 in the lungs of bleomycin-treated mice.

Conclusions: Our data suggests that H19 is a profibrotic lncRNA and a potential therapeutic target for IPF.
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http://dx.doi.org/10.1186/s12931-020-01534-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607673PMC
November 2020
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