The DOI matches its Crossref record; 49 of the 50 references it cites were found in a registry or an index.
Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis
Open accessAbstract
UNLABELLED: 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 p16(INK4a) 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.
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“total elimination of intestinal microbiome in germ-free mice has been shown to aggravate liver injury in mouse models of liver fibrosis and PSC.64 65”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [65]
In the citing paper
“It has become apparent that the endogenous commensal microbiota provides hepatoprotective signals and that complete absence of the gut microbiota results in increased liver injury — probably owing to an absence of TLR4-mediated activation of anti-apoptotic NF-κB signalling — and a subsequent increase in liver fibrosis, as demonstrated in several models13,75,76.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [76]
In the citing paper
“However, recent studies have demonstrated an increase in liver fibrosis in germ-free mice75,76, which seemingly contradicts the decrease of liver fibrosis seen in gut-sterilized mice.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [76]
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Cites
Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis
Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S., & Medzhitov, R. (2004) · Cell · doi:10.1016/j.cell.2004.07.002 · Cited by 4,251
Interactions Between the Microbiota and the Immune System
Hooper, L. V., Littman, D. R., & Macpherson, A. J. (2012) · Science · doi:10.1126/science.1223490 · Cited by 4,173 · cited 1×
“Although still an active area of research, the protective effects of the commensal microbiota can be considered in two broad categories: (1) production of cytoprotective metabolites (or decreased production of injurious metabolites)(40-42) and (2) facilitation of normal immunological development.(42) Fig.”
BackgroundSenescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473 · cited 2×
“With this in mind, it is plausible that an alternative potential explanation for the increased degree of cholangiocyte senescence in GF mdr22/2 mice might be a relative immunological defect in GF mdr22/2 mice resulting in impaired clearance of senescent BECs.49,50 Senescent cell clearance has only recently been explor…”
BackgroundChemokine signaling via the CXCR2 receptor reinforces senescence
Acosta, J. C., O'Loghlen, A., Banito, A., Guijarro, M. V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., et al. (2008) · Cell · doi:10.1016/j.cell.2008.03.038 · Cited by 1,801 · cited 1×
“, induce senescence in neighboring cells), and initiate profibroinflammatory and protumorigenic cellular responses and outcomes.(43,45,46) Therefore, we propose that the high proportion of senescent cholangiocytes observed in GF mdr2 mice represents both a marker as well as a driver of more severe hepatobiliary diseas…”
BackgroundCellular senescence and the senescent secretory phenotype: therapeutic opportunities
Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., & Kirkland, J. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64098 · Cited by 1,774 · cited 2×
“Senescent cell clearance has only recently been explored, but may ultimately hold therapeutic promise in PSC (even in more advanced stages of disease) and other disorders.(44) In summary, by generating the first GF variant of the mdr2 murine model of PSC, we have demonstrated that the absence of the commensal microbio…”
BackgroundEASL Clinical Practice Guidelines: management of cholestatic liver diseases
European Association for the Study of the Liver (2009) · Journal of Hepatology · doi:10.1016/j.jhep.2009.04.009 · Cited by 1,729
Microbial Exposure During Early Life Has Persistent Effects on Natural Killer T Cell Function
Olszak, T., An, D., Zeissig, S., Vera, M. P., Richter, J., Franke, A., Glickman, J. N., Siebert, R., Baron, R. M., Kasper, D. L., et al. (2012) · Science · doi:10.1126/science.1219328 · Cited by 1,661
Senescence surveillance of pre-malignant hepatocytes limits liver cancer development
Kang, T.-W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., et al. (2011) · Nature · doi:10.1038/nature10599 · Cited by 1,621 · cited 2×
“With this in mind, it is plausible that an alternative potential explanation for the increased degree of cholangiocyte senescence in GF mdr22/2 mice might be a relative immunological defect in GF mdr22/2 mice resulting in impaired clearance of senescent BECs.49,50 Senescent cell clearance has only recently been explor…”
BackgroundSmit, J., Schinkel, A. H., Elferink, R. P. J. O., Groen, A. K., Wagenaar, E., van Deemter, L., Mol, C. A. A. M., Ottenhoff, R., van der Lugt, N. M. T., van ROON, M. A., et al. (1993) · Cell · doi:10.1016/0092-8674(93)90380-9 · Cited by 1,456
Diagnosis and Management of Primary Sclerosing Cholangitis
Chapman, R. W., Fevery, J., Kalloo, A. N., Nagorney, D. M., Boberg, K. M., Shneider, B. L., & Gores, G. J. (2009) · Hepatology · doi:10.1002/hep.23294 · Cited by 1,230
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Tilg, H., Adolph, T. E., & Trauner, M. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.09.017 · Cited by 843
The gut microbiome and liver cancer: mechanisms and clinical translation
Yu, L.-X., & Schwabe, R. F. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.72 · Cited by 634
Bernardi, M., Moreau, R., Angeli, P., Schnabl, B., & Arroyo, V. (2015) · Journal of Hepatology · doi:10.1016/j.jhep.2015.07.004 · Cited by 645
Gut microbiome and liver diseases
Tilg, H., Cani, P. D., & Mayer, E. A. (2016) · Gut · doi:10.1136/gutjnl-2016-312729 · Cited by 525
Interactions between gut bacteria and bile in health and disease
Long, S. L., Gahan, C. G. M., & Joyce, S. A. (2017) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2017.06.002 · Cited by 495
Metadata
- Authors
- Tabibian, J. H., O'Hara, S. P., Trussoni, C. E., Tietz, P. S., Splinter, P. L., Mounajjed, T., Hagey, L. R., & LaRusso, N. F.
- Affiliations
- Mayo Clinic (US)
- Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN
- University of California San Diego (US)
- Corresponding author
- LaRusso, Nicholas F.
- Venue
- Hepatology
- Published
- 2015-08-10
- Volume
- 63
- Issue
- 1
- Pages
- 185-196
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC4670294
- OpenAlex
- W1945590693
- Cited by
- 223
- References
- 50
- Citations by year
- 2026: 14 · 2025: 7 · 2024: 17 · 2023: 18 · 2022: 17 · 2021: 24 · 2020: 20 · 2019: 25 · 2018: 27 · 2017: 28 · 2016: 19 · 2015: 5
- FWCI
- 15.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Mayo Clinic (P30 DK084567)
- Mayo Foundation for Medical Education and Research
- PSC Partners Seeking a Cure
- National Institutes of Health
- University of California, San Diego
- Center for Cell Signaling in Gastroenterology, Mayo Clinic (P30 DK084567)
- National Institute of Allergy and Infectious Diseases (R01AI089713, AI089713)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK57993, P30DK084567, R01DK057993)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- primary sclerosing cholangitis, gut microbiota, germ-free mice, Mdr2 knockout mice, bile acid metabolism, secondary bile acids, ursodeoxycholic acid, liver fibrosis, ductopenia, biliary injury
- MeSH terms
- Gastrointestinal Microbiome, Animals, Disease Models, Animal, Female, Male, Cholangitis, Sclerosing, Mice, Knockout, Disease Progression, Mice
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