Multi-omics Analysis of Biliary Organoids Reveals Metabolic and Fibro-inflammatory Dysregulation in Biliary Atresia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Xiaobin Wu
PROVIDER: PXD079366 | iProX | Sat Jun 06 00:00:00 BST 2026
REPOSITORIES: iProX
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Project description:<div><b>INTRODUCTION:</b> Neonatal cholestatic disorders are a group of hepatobiliary diseases occurring in the first 3 months of life. The most common causes of neonatal cholestasis are infantile hepatitis syndrome (IHS) and biliary atresia (BA). The clinical manifestations of the two diseases are too similar to distinguish them. However, early detection is very important in improving the clinical outcome of BA. Currently, a liver biopsy is the only proven and effective method used to differentially diagnose these two similar diseases in the clinic. However, this method is invasive. Therefore, sensitive and non-invasive biomarkers are needed to effectively differentiate between BA and IHS. We hypothesized that urinary metabolomics can produce unique metabolite profiles for BA and IHS.</div><div><b>OBJECTIVES:</b> The aim of this study was to characterize urinary metabolomic profiles in infants with BA and IHS, and to identify differences among infants with BA, IHS, and normal controls (NC).</div><div><b>METHODS:</b> Urine samples along with patient characteristics were obtained from 25 BA, 38 IHS, and 38 NC infants. A non-targeted gas chromatography-mass spectrometry (GC-MS) metabolomics method was used in conjunction with orthogonal partial least squares discriminant analysis (OPLS-DA) to explore the metabolomic profiles of BA, IHS, and NC infants.</div><div><b>RESULTS:</b> In total, 41 differentially expressed metabolites between BA vs. NC, IHS vs. NC, and BA vs. IHS were identified. N-acetyl-D-mannosamine and alpha-aminoadipic acid were found to be highly accurate at distinguishing between BA and IHS.</div><div><b>CONCLUSIONS:</b> BA and IHS infants have specific urinary metabolomic profiles. The results of our study underscore the clinical potential of metabolomic profiling to uncover metabolic changes that could be used to discriminate BA from IHS.</div>
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Project description:Biliary atresia (BA) is a rare cholestatic disease of unknown etiology that affects infants and shows an incidence of 1 out of 18,000 live births in Europe (1). The first therapeutic option is a timely performed portoenterostomy. However, the majority of patients suffer from a progressive inflammatory process, which leads to complete destruction of the extra- and intrahepatic biliary system followed by end-stage liver cirrhosis. Hence, BA is the leading indication for pediatric liver transplantation worldwide (2, 3). To understand the pathogenesis of the disease and improve theoutcome of BA patients, research has focused on the inflammatory process in liver and bile ducts, in which several factors are remarkably elevated, such as activated CD4 and CD8 T-cells, TNF alpha,IFN alpha and other proinflammatory TH1 cytokines (3-8). By the time of diagnosis, however, the disease has already reached an advanced state, characterized by the complete obstruction of the extrahepatic bile ducts with impaired bile flow and fibrosis or cirrhosis of the liver. Therefore, studies in humans focusing on the trigger mechanism of BA are limited due to the paucity of liver and availability of bile duct tissue for research. One infectious animal model has been developed, in which newborn Balb/c mice exclusively show the experimental BA phenotype after infection with rhesus rotavirus (RRV) (9, 10). This model allows the analysis of the inflammatory reactions in liver and bile ducts at early steps in the development of bile duct atresia (11-20). Furthermore, inbred mouse strains have been shown to have a different susceptibility for the development of experimental BA, suggesting that Balb/c mice have an immunological gap responsible for disease progression (10, 12). The aim of this study was to identify key genes responsible for the BA phenotype by comparing the transcriptomes at an early time point after virus infection, i.e. before bile duct atresia, between two mouse strains with different susceptibilities to BA. Differences in the virus titration and the clinical course of infected mice were analyzed, and variations in the hepatic gene response assessed by comparative microarray assays were correlated to variances in the hepatic inflammatory reaction. Balb/c mice and C57Black/6 (Black/6) mice were infected with RRV postpartum and signs of BA and survival were noted. Liver sections of diseased, healthy and control animals were assessed for T-cell expression, and the virus loads were determined. Second, mice were sacrificed after three days, and isolated hepatic RNA was subjected to gene expression analysis using Affymetrix Gene Chip MOE 430 2.0.We compared three individual expression profiles from RRV-infected Balb/c mice against 2 individual expression profiles from RRV-infected C57/BL6 control mice using the Affymetrix GeneChip MOE 430 2.0.
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Project description:Biliary atresia (BA) is a rare cholestatic disease of unknown etiology that affects infants and shows an incidence of 1 out of 18,000 live births in Europe (1). The first therapeutic option is a timely performed portoenterostomy. However, the majority of patients suffer from a progressive inflammatory process, which leads to complete destruction of the extra- and intrahepatic biliary system followed by end-stage liver cirrhosis. Hence, BA is the leading indication for pediatric liver transplantation worldwide (2, 3). To understand the pathogenesis of the disease and improve theoutcome of BA patients, research has focused on the inflammatory process in liver and bile ducts, in which several factors are remarkably elevated, such as activated CD4 and CD8 T-cells, TNF alpha,IFN alpha and other proinflammatory TH1 cytokines (3-8). By the time of diagnosis, however, the disease has already reached an advanced state, characterized by the complete obstruction of the extrahepatic bile ducts with impaired bile flow and fibrosis or cirrhosis of the liver. Therefore, studies in humans focusing on the trigger mechanism of BA are limited due to the paucity of liver and availability of bile duct tissue for research. One infectious animal model has been developed, in which newborn Balb/c mice exclusively show the experimental BA phenotype after infection with rhesus rotavirus (RRV) (9, 10). This model allows the analysis of the inflammatory reactions in liver and bile ducts at early steps in the development of bile duct atresia (11-20). Furthermore, inbred mouse strains have been shown to have a different susceptibility for the development of experimental BA, suggesting that Balb/c mice have an immunological gap responsible for disease progression (10, 12). The aim of this study was to identify key genes responsible for the BA phenotype by comparing the transcriptomes at an early time point after virus infection, i.e. before bile duct atresia, between two mouse strains with different susceptibilities to BA. Differences in the virus titration and the clinical course of infected mice were analyzed, and variations in the hepatic gene response assessed by comparative microarray assays were correlated to variances in the hepatic inflammatory reaction.
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