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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]
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“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]
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“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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“Barrier disruption can also aggravate fibrosis, as shown in Mdr2−/− [284], but not in heterozygous Mdr2+/− mice [285].”
BackgroundResultInfluentialPrimary Sclerosing Cholangitis and Inflammatory Bowel Disease: A Review
Cunha, T. D., Vaziri, H., & Wu, G. Y. (2022) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2021.00344 · Cited by 43
Cellular senescence in liver diseases: From molecular drivers to therapeutic targeting
Du, K., Umbaugh, D. S., Ren, N., & Diehl, A. M. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.08.021 · Cited by 42
The intestinal microbiome and paediatric liver disease
Leung, D. H., & Yimlamai, D. (2017) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(16)30241-2 · Cited by 40
Han, W., Huang, C., Zhang, Q., Tao, S., Hu, X., Xu, J., Jiang, R., Xu, B., Liu, Y., & Hou, J. (2021) · European Journal of Clinical Investigation · doi:10.1111/eci.13714 · Cited by 40
Crosstalk between Gut Microbiota and Bile Acids in Cholestatic Liver Disease
Shi, Q., Yuan, X., Zeng, Y., Wang, J., Zhang, Y., Chen, X., & Li, L. (2023) · Nutrients · doi:10.3390/nu15102411 · Cited by 41
Peng, Z., Rothweiler, S., Wei, G., Ikenaga, N., Liu, S. B., Sverdlov, D., Vaid, K. A., Longhi, M. S., Kuang, M., Robson, S. C., et al. (2017) · Hepatology Communications · doi:10.1002/hep4.1084 · Cited by 40
“(30) This is in direct contradiction to our data derived from specific-pathogen-free Mdr2–/– mice, which clearly show improvement in their liver disease with antibiotic-mediated gut decontamination (and worsening on induction of experimental colitis).”
ResultAlsuraih, M., Trussoni, C. E., Splinter, P. L., LaRusso, N. F., & O’Hara, S. P. (2020) · Liver International · doi:10.1111/liv.14569 · Cited by 40
Self-citationThe microbiota of the bilio-pancreatic system: a cohort, STROBE-compliant study
Carlo, P. D., Serra, N., D’Arpa, F., Agrusa, A., Gulotta, G., Fasciana, T., Rodolico, V., Giammanco, A., & Sergi, C. M. (2019) · Infection and Drug Resistance · doi:10.2147/idr.s200378 · Cited by 38
Research Progress of Fecal Microbiota Transplantation in Liver Diseases
Zhao, Y., Chen, G., Xu, J., Chen, D., Yang, B., Chen, Z., & Wei, L. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12041683 · Cited by 38
“The protective role of gut microbiota in PSC has been demonstrated using germ-free multidrug resistance 2 knockout (mdr2−/−) mouse models [86].”
BackgroundTietz-Bogert, P. S., Kim, M., Cheung, A., Tabibian, J. H., Heimbach, J. K., Rosen, C. B. B., Nandakumar, M., Lazaridis, K. N., LaRusso, N. F., Sung, J., et al. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103188 · Cited by 38
“, Abcb4−/− mouse) leads to more severe disease [19].”
BackgroundSelf-citationKriss, M. S., Verna, E. C., Rosen, H. R., & Lozupone, C. (2018) · Transplantation · doi:10.1097/tp.0000000000002568 · Cited by 37
“Mouse models of PSC have established the importance of dysbiosis in disease progression, in part through alterations in microbial-mediated BA metabolism.(102,103) Alterations in BA composition and gut microbial composition have also been noted in patients with both PSC and PBC.”
Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology
Maroni, L., Ninfole, E., Pinto, C., Benedetti, A., & Marzioni, M. (2020) · Cells · doi:10.3390/cells9030736 · Cited by 37
“As expected, secondary bile acids were absent in GF Mdr2 knockout mice, while cholangiocyte senescence was significantly increased in vitro and could be reduced by treatment with the secondary bile acid ursodeoxycholic acid [82].”
BackgroundAlsuraih, M., O’Hara, S. P., Woodrum, J. E., Pirius, N., & LaRusso, N. F. (2021) · JHEP Reports · doi:10.1016/j.jhepr.2021.100250 · Cited by 38
“Cholangiocytes in the bile ducts from patients with PSC and the multidrug-resistance 2 (Mdr2) mouse, a well-accepted murine model of PSC, exhibit an abundance of various markers of cellular senescence.(4,7,8) Cellular senescence is a cellular response to chronic injury that initially involves cell cycle arrest and the…”
BackgroundSelf-citationBiliary Epithelial Senescence in Liver Disease: There Will Be SASP
Meadows, V., Baiocchi, L., Kundu, D., Sato, K., Fuentes, Y., Wu, C., Chakraborty, S., Glaser, S. S., Alpini, G. D., Kennedy, L. L., et al. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.803098 · Cited by 36
“mice housed in a germ-free facility had exacerbated biliary senescence/SASP, associated DR and liver fibrosis (Tabibian et al., 2016).”
BackgroundOutside the liver box: The gut microbiota as pivotal modulator of liver diseases
Wahlstrom, A. M. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.07.004 · Cited by 35
Philips, C. A., Augustine, P., & Phadke, N. D. (2018) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2018.00033 · Cited by 36
Czaja, A. J. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i45.6579 · Cited by 35
Gut-Liver Immune Traffic: Deciphering Immune-Pathogenesis to Underpin Translational Therapy
Bozward, A. G., Ronca, V., Osei‐Bordom, D., & Oo, Y. H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.711217 · Cited by 36
“Commensal microbiota and its metabolites protect against biliary injury (134).”
BackgroundRole of microbiome in autoimmune liver diseases
Schneider, K. M., Kummen, M., Trivedi, P. J., & Hov, J. R. (2023) · Hepatology · doi:10.1097/hep.0000000000000506 · Cited by 38
Chen, W.-L., Zhang, P., Zhang, X., Xiao, T., Zeng, J., Guo, K., Qiu, H., Cheng, G., Wang, Z., Zhou, W., et al. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2388805 · Cited by 35
“10 According to related research, downregulating Bifidobacterium species, including B. adolescentis , B. bifidum , and B. longum , was linked to higher serum TBIL levels.”
BackgroundThe enteric microbiome in hepatobiliary health and disease
Tabibian, J. H., Varghese, C., LaRusso, N. F., & O’Hara, S. P. (2015) · Liver International · doi:10.1111/liv.13009 · Cited by 33
“microbial metabolite ursodeoxycholic acid (which was absent in GF mice) abrogates human cholangiocyte senescence in an in vitro model of LPS- or H202-induced cellular senescence (62).”
Self-citationTherapy of Primary Sclerosing Cholangitis - Today and Tomorrow
Halilbasic, E., Fuchs, C. D., Hofer, H., Paumgartner, G., & Trauner, M. (2015) · Digestive Diseases · doi:10.1159/000440827 · Cited by 33
The emerging role of AMP-activated protein kinase in cholestatic liver diseases
Li, X., Liu, R., Zhang, L., & Jiang, Z. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.09.002 · Cited by 34
Intestinal microbiota drives cholestasis-induced specific hepatic gene expression patterns
Juanola, O., Hassan, M., Kumar, P., Yılmaz, B., Keller, I., Simillion, C., Engelmann, C., Tacke, F., Dufour, J., Gottardi, A. D., et al. (2021) · Gut Microbes · doi:10.1080/19490976.2021.1911534 · Cited by 33
Shriki, A., Lanton, T., Sonnenblick, A., Levkovitch-Siany, O., Eidelshtein, D., Abramovitch, R., Rosenberg, N., Pappo, O., Elgavish, S., Nevo, Y., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0321 · Cited by 34
“IL6 deficiency–enhanced tumorigenesis in Mdr2 / mice is associated with disruption of senescence and the SASP Previous findings by our lab and confirmed by others demonstrate that cellular senescence is an inherent feature of the Mdr2 / hepatic microenvironment manifest by upregulation of senescence markers including…”
BackgroundBile Acid Receptor Therapeutics Effects on Chronic Liver Diseases
Meadows, V., Kennedy, L. L., Kundu, D., Alpini, G. D., & Francis, H. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00015 · Cited by 31
“The multidrug resistance cassette 2 knock-out mouse (MDR2) is a mouse model utilized to mimic the PSC phenotype including increased cholestasis, intrahepatic bile duct mass and hepatic inflammation due to hepatic BA build up (36, 37).”
BackgroundAnimal Models of Autoimmune Liver Diseases: a Comprehensive Review
Liu, S.-P., Bian, Z.-H., Zhao, Z.-B., Wang, J., Zhang, W., Leung, P. S. C., Li, L., & Lian, Z. (2020) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-020-08778-6 · Cited by 33
The Microbiome and Immune Regulation After Transplantation
Tabibian, J. H., & Kenderian, S. S. (2016) · Transplantation · doi:10.1097/tp.0000000000001444 · Cited by 32
“With respect to the microbiome and the underlying disease (eg, indication for liver transplantation), a recent report described successful treatment of recurrent primary sclerosing cholangitis, an idiopathic disease with emerging links to microbial dysbiosis.(5,54,55) Variation of gut microbiota was found to predict e…”
BackgroundSelf-citationJain, V., Alexander, E. C., Burford, C., Verma, A., & Dhawan, A. K. (2020) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0000000000002973 · Cited by 31
“Experimental models, in particular germ-free (microbial-free) mouse models for biliary disease, have highlighted an association between the gut microbiota and cholestasis (13,14).”
New Therapeutic Targets in Autoimmune Cholangiopathies
Gerussi, A., Luca, M. D., Cristoferi, L., Ronca, V., Mancuso, C., Milani, C., D’Amato, D., O'Donnell, S. E., Carbone, M., & Invernizzi, P. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00117 · Cited by 30
“Germ-free Mdr2-/- mice show increased hepatitis and cholestatic injury compared to conventionally-housed Mdr2-/mice (82).”
BackgroundThe Microbiome in Autoimmune Liver Diseases: Metagenomic and Metabolomic Changes
Zheng, Y., Ran, Y., Zhang, H., Wang, B., & Zhou, L. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.715852 · Cited by 29
Intestinal microbiota in primary sclerosing cholangitis
Hov, J. R., & Kummen, M. (2016) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000334 · Cited by 29
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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