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Int. J. Mol. Sci. 2018, 19(10), 3188; https://doi.org/10.3390/ijms19103188

Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis

1
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
2
Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA
3
Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
4
Division of Surgical Research, Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
5
Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA 91342, USA
6
Division of Transplant Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
7
Seres Therapeutics, Cambridge, MA 02139, USA
*
Authors to whom correspondence should be addressed.
Received: 7 September 2018 / Revised: 11 October 2018 / Accepted: 13 October 2018 / Published: 16 October 2018
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Abstract

Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC (n = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, n = 19)) and to nondisease controls (NC, living donors, n = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann–Whitney U test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation. View Full-Text
Keywords: primary sclerosing cholangitis (PSC); portal venous blood; bile; metabolomics; enterohepatic circulation primary sclerosing cholangitis (PSC); portal venous blood; bile; metabolomics; enterohepatic circulation
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Tietz-Bogert, P.S.; Kim, M.; Cheung, A.; Tabibian, J.H.; Heimbach, J.K.; Rosen, C.B.; Nandakumar, M.; Lazaridis, K.N.; LaRusso, N.F.; Sung, J.; O’Hara, S.P. Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis. Int. J. Mol. Sci. 2018, 19, 3188.

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