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Serum Metabolomics Analysis Reveals a Distinct Metabolic Profile of Patients with Primary Biliary Cholangitis.

ABSTRACT: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease associated with profound metabolic changes. The purpose of this study was to identify a distinctive metabolic signature from the training set with 29 PBC patients, 30 hepatitis B virus (HBV)-caused cirrhosis (HBC) and 41 healthy controls, and to validate the applicability and stability of the distinctive model from the validation set with 21 PBC patients, 7 autoimmune hepatitis (AIH) and 9 HBC. The sera were investigated using high resolution nuclear magnetic resonance (NMR) and the datasets were analyzed pairwise using pattern recognition methods. 45 distinguishable metabolites were identified and 15 metabolic pathways were reprogrammed. The altered metabolic pathways were associated with glucose, fatty acid and amino acid metabolites. Logistic regression and ROC analysis were used to establish a diagnostic model with the equated (p)?=?-12.22-3.46*log(4-hydroxyproline)?+?6.62*log(3-hydroxyisovalerate)?-?2.44*log(citraconate)?-?3.80*log(pyruvate). The area under the curve (AUC) of the optimized model was 0.937 (95% confidence interval (CI): 0.868-0.976) in the training set and 0.890 (95% CI: 0.743-0.969) in the validation set. These results not only revealed the potential pathogenesis of PBC, but also provided a feasible diagnostic tool for PBC populations through detection of serum metabolites.

SUBMITTER: Hao J

PROVIDER: S-EPMC5429753 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Serum Metabolomics Analysis Reveals a Distinct Metabolic Profile of Patients with Primary Biliary Cholangitis.

Hao Juan J Yang Tao T Zhou Yang Y Gao Guo-Yuan GY Xing Feng F Peng Yuan Y Tao Yan-Yan YY Liu Cheng-Hai CH

Scientific reports 20170411 1

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease associated with profound metabolic changes. The purpose of this study was to identify a distinctive metabolic signature from the training set with 29 PBC patients, 30 hepatitis B virus (HBV)-caused cirrhosis (HBC) and 41 healthy controls, and to validate the applicability and stability of the distinctive model from the validation set with 21 PBC patients, 7 autoimmune hepatitis (AIH) and 9 HBC. The sera were investigated usi ...[more]

PMID: 28400566

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Project description:Purpose of reviewPrimary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO3- rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease.Recent findingsPBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses.SummaryPBC can be considered as a disorder of Cl-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.

Dataset Information

Serum Metabolomics Analysis Reveals a Distinct Metabolic Profile of Patients with Primary Biliary Cholangitis.

Publications

Serum Metabolomics Analysis Reveals a Distinct Metabolic Profile of Patients with Primary Biliary Cholangitis.

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