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Using next-generation sequencing of microRNAs to identify host and/or pathogen nucleic acid signatures in samples from children with biliary atresia - a pilot study.

ABSTRACT: Biliary atresia (BA) is a progressive disease affecting infants resulting in inflammatory obliteration and fibrosis of the extra- and intra-hepatic biliary tree. BA may be grouped into type 1 isolated; type 2 syndromic, where other congenital malformations may be present; type 3 cystic BA, where there is cyst formation within an otherwise obliterated biliary tree; and cytomegalovirus-associated BA. The cause of BA is unclear, with immune dysregulation, inflammation and infection, particularly with cytomegalovirus (CMV), all implicated. In this study a total of 50/67 samples were tested for CMV DNA using quantitative real-time PCR. Ten liver tissue and 8 bile samples from 10 patients representing the range of BA types were also analysed by next-generation sequencing. CMV DNA was found in 8/50 (16?%) patients and a total of 265 differentially expressed microRNAs were identified. No statistically significant differences between the various types of BA were found. However, differences were identified in the expression patterns of 110 microRNAs in bile and liver tissue samples (P<0.05). A small number of bacterial and viral sequences were found, although their relevance to BA remains to be determined. No direct evidence of viral causes of BA were found, although clear evidence of microRNAs associated with hepatocyte and cholangiocyte differentiation together with fibrosis and inflammation were identified. These include miR-30 and the miR-23 cluster (liver and bile duct development) and miR-29, miR-483, miR-181, miR-199 and miR-200 (inflammation and fibrosis).

SUBMITTER: Smith M

PROVIDER: S-EPMC7497833 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Using next-generation sequencing of microRNAs to identify host and/or pathogen nucleic acid signatures in samples from children with biliary atresia - a pilot study.

Smith Melvyn M Zuckerman Mark M Kandanearatchi Apsara A Thompson Richard R Davenport Mark M

Access microbiology 20200612 7

Biliary atresia (BA) is a progressive disease affecting infants resulting in inflammatory obliteration and fibrosis of the extra- and intra-hepatic biliary tree. BA may be grouped into type 1 isolated; type 2 syndromic, where other congenital malformations may be present; type 3 cystic BA, where there is cyst formation within an otherwise obliterated biliary tree; and cytomegalovirus-associated BA. The cause of BA is unclear, with immune dysregulation, inflammation and infection, particularly wi ...[more]

PMID: 32974591

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Project description:BACKGROUND & AIMS:Little is known about the factors that affect outcomes of patients with biliary atresia and there are no medical therapies that increase biliary drainage. METHODS:Liver biopsies and clinical data were obtained from infants with cholestasis and from children without liver disease (controls); messenger RNA (mRNA) was isolated, randomly assigned to discovery (n = 121) and validation sets (n = 50), and analyzed by RNA sequencing. Using the Superpc R package followed by Cox regression analysis, we sought to identify gene expression profiles that correlated with survival without liver transplantation at 24 months of age. We also searched for combinations of gene expression patterns, clinical factors, and laboratory results obtained at diagnosis and at 1 and 3 months after surgery that associated with transplant-free survival for 24 months of age. We induced biliary atresia in BALB/c mice by intraperitoneal administration of Rhesus rotavirus type A. Mice were given injections of the antioxidants N-acetyl-cysteine (NAC) or manganese (III) tetrakis-(4-benzoic acid)porphyrin. Blood and liver tissues were collected and analyzed by histology and immunohistochemistry. RESULTS:We identified a gene expression pattern of 14 mRNAs associated with shorter vs longer survival times in the discovery and validation sets (P < .001). This gene expression signature, combined with level of bilirubin 3 months after hepatoportoenterostomy, identified children who survived for 24 months with an area under the curve value of 0.948 in the discovery set and 0.813 in the validation set (P < .001). Computer models correlated a cirrhosis-associated transcriptome with decreased times of transplant-free survival; this transcriptome included activation of genes that regulate the extracellular matrix and numbers of activated stellate cells and portal fibroblasts. Many mRNAs expressed at high levels in liver tissues from patients with 2-year transplant-free survival had enriched scores for glutathione metabolism. Among mice with biliary atresia given injections of antioxidants, only NAC reduced histologic features of liver damage and serum levels of aminotransferase, gamma-glutamyl transferase, and bilirubin. NAC also reduced bile duct obstruction and liver fibrosis and increased survival times. CONCLUSIONS:In studies of liver tissues from infants with cholestasis, we identified a 14-gene expression pattern that associated with transplant-free survival for 2 years. mRNAs encoding proteins that regulate fibrosis genes were increased in liver tissues from infants who did not survive for 2 years, whereas mRNAs that encoded proteins that regulate glutathione metabolism were increased in infants who survived for 2 years. NAC reduced liver injury and fibrosis in mice with biliary atresia, and increased survival times. Agents such as NAC that promote glutathione metabolism might be developed for treatment of biliary atresia.

Dataset Information

Using next-generation sequencing of microRNAs to identify host and/or pathogen nucleic acid signatures in samples from children with biliary atresia - a pilot study.

Publications

Using next-generation sequencing of microRNAs to identify host and/or pathogen nucleic acid signatures in samples from children with biliary atresia - a pilot study.

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