Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, fibroinflammatory cholangiopathy. The role of the microbiota in PSC etiopathogenesis may be fundamentally important, yet remains obscure. We tested the hypothesis that germ‐free (GF) mutltidrug resistance 2 knockout (mdr2−/−) mice develo...

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Veröffentlicht in:Hepatology (Baltimore, Md.) Jg. 63; H. 1; S. 185 - 196
Hauptverfasser: Tabibian, James H., O'Hara, Steven P., Trussoni, Christy E., Tietz, Pamela S., Splinter, Patrick L., Mounajjed, Taofic, Hagey, Lee R., LaRusso, Nicholas F.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Wolters Kluwer Health, Inc 01.01.2016
Schlagworte:
Acids
Alkaline phosphatase
Animal models
Animals
Aspartate aminotransferase
Bile
Bile acids
Bilirubin
Cholangitis
Cholangitis, Sclerosing - etiology
Disease Models, Animal
Disease Progression
Embryo transfer
Female
Fibrosis
Gallbladder
Gastrointestinal Microbiome - physiology
Germfree
Hepatology
Hydroxyproline
Immunofluorescence
INK4a protein
Intestinal microflora
Intestine
Liver
Male
Metabolites
Mice
Mice, Knockout
Morphometry
p16 Protein
Rodents
Senescence
Therapeutic applications
Ursodeoxycholic acid
β-Galactosidase
ISSN:0270-9139, 1527-3350
Online-Zugang:Volltext
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Zusammenfassung:Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, fibroinflammatory cholangiopathy. The role of the microbiota in PSC etiopathogenesis may be fundamentally important, yet remains obscure. We tested the hypothesis that germ‐free (GF) mutltidrug resistance 2 knockout (mdr2−/−) mice develop a distinct PSC phenotype, compared to conventionally housed (CV) mdr2−/− mice. Mdr2−/− mice (n = 12) were rederived as GF by embryo transfer, maintained in isolators, and sacrificed at 60 days in parallel with age‐matched CV mdr2−/− mice. Serum biochemistries, gallbladder bile acids, and liver sections were examined. Histological findings were validated morphometrically, biochemically, and by immunofluorescence microscopy (IFM). Cholangiocyte senescence was assessed by p16INK4a in situ hybridization in liver tissue and by senescence‐associated β‐galactosidase staining in a culture‐based model of insult‐induced senescence. Serum biochemistries, including alkaline phosphatase, aspartate aminotransferase, and bilirubin, were significantly higher in GF mdr2−/− (P < 0.01). Primary bile acids were similar, whereas secondary bile acids were absent, in GF mdr2−/− mice. Fibrosis, ductular reaction, and ductopenia were significantly more severe histopathologically in GF mdr2−/− mice (P < 0.01) and were confirmed by hepatic morphometry, hydroxyproline assay, and IFM. Cholangiocyte senescence was significantly increased in GF mdr2−/− mice and abrogated in vitro by ursodeoxycholic acid (UDCA) treatment. Conclusions: GF mdr2−/− mice exhibit exacerbated biochemical and histological features of PSC and increased cholangiocyte senescence, a characteristic and potential mediator of progressive biliary disease. UDCA, a commensal microbial metabolite, abrogates senescence in vitro. These findings demonstrate the importance of the commensal microbiota and its metabolites in protecting against biliary injury and suggest avenues for future studies of biomarkers and therapeutic interventions in PSC. (Hepatology 2016;63:185–196)
Bibliographie:Joint first authors.
See Editorial on Page 26
Potential conflict of interest: Nothing to report.
This work was supported by National Institutes of Health grants AI089713 (to S.P.O.) and DK57993 (to N.F.L), the Mayo Foundation, PSC Partners Seeking a Cure, and the Clinical and Optical Microscopy Cores of the Mayo Clinic Center for Cell Signaling in Gastroenterology (P30DK084567).
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Joint first authors
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.27927