Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis
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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 aggravates liver injury in mouse models of liver fibrosis and PSC.
“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]
The endogenous commensal microbiota provides hepatoprotective signals; complete absence of the gut microbiota increases liver injury, probably through lack of TLR4-mediated anti-apoptotic NF-κB signalling, and increases liver fibrosis.
“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]
Germ-free mice show increased liver fibrosis, which seemingly contradicts the decreased fibrosis seen in gut-sterilized mice.
“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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Novel therapeutic targets for cholestatic and fatty liver disease
Trauner, M., & Fuchs, C. D. (2022) · Gut · doi:10.1136/gutjnl-2021-324305 · Cited by 204 · see citing works
Palmela, C., Peerani, F., Castañeda, D., Torres, J., & Itzkowitz, S. H. (2017) · Gut and Liver · doi:10.5009/gnl16510 · Cited by 176 · see citing works
“Tabibian et al.30 used MDR2 knockout mice (a widely utilized animal model of PSC) to assess the role of the commensal microbiota in the pathogenesis of biliary injury.”
BackgroundMethodInfluentialLiao, L., Schneider, K. M., Gálvez, E. J. C., Frissen, M., Marschall, H., Su, H., Hatting, M., Wahlstrom, A. M., Haybaeck, J., Puchas, P., et al. (2019) · Gut · doi:10.1136/gutjnl-2018-316670 · Cited by 175 · see citing works
Paracrine cellular senescence exacerbates biliary injury and impairs regeneration
Ferreira-Gonzalez, S., Lu, W.-Y., Raven, A., Dwyer, B., Man, T. Y., O’Duibhir, E., Lewis, P. J. S., Campana, L., Kendall, T. J., Bird, T. G., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03299-5 · Cited by 161 · see citing works
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Liver–Microbiome Axis in Health and Disease
Adolph, T. E., Grander, C., Moschen, A. R., & Tilg, H. (2018) · Trends in Immunology · doi:10.1016/j.it.2018.05.002 · Cited by 152 · see citing works
Bile Salt Hydrolases: At the Crossroads of Microbiota and Human Health
Bourgin, M., Kriaa, A., Mkaouar, H., Mariaule, V., Jablaoui, A., Maguin, E., & Rhimi, M. (2021) · Microorganisms · doi:10.3390/microorganisms9061122 · Cited by 147 · see citing works
“In this context, the gut microbiota and bile acid composition were analyzed in a mice model and demonstrated that the illness severity was increased in germ-free mice [126].”
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The gut ecosystem and immune tolerance
Shao, T., Hsu, R., Rafizadeh, D. L., Wang, L., Bowlus, C. L., Kumar, N., Mishra, J., Timilsina, S., Ridgway, W. M., Gershwin, M. E., et al. (2023) · Journal of Autoimmunity · doi:10.1016/j.jaut.2023.103114 · Cited by 136 · see citing works
Altered gut microbial metabolism of essential nutrients in primary sclerosing cholangitis
Kummen, M., Thingholm, L. B., Rühlemann, M. C., Holm, K., Hansen, S. H., Moitinho-Silva, L., Liwinski, T., Zenouzi, R., Storm-Larsen, C., Midttun, Ø., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.12.058 · Cited by 129 · see citing works
Gut microbiota depletion exacerbates cholestatic liver injury via loss of FXR signalling
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Gut microbiome in primary sclerosing cholangitis: A review
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The microbiota and the gut–liver axis in primary sclerosing cholangitis
Hov, J. R., & Karlsen, T. H. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-022-00690-y · Cited by 121 · see citing works
Bile Acids and Cancer: Direct and Environmental-Dependent Effects
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“We confirmed the overall protection of resident microbiota in GF mdr2 −/− mice 14 26 27 in a more aggressive genetic background (C57BL/6).”
Cabrera, D., Arab, J. P., & Arrese, M. A. (2019) · Handbook of experimental pharmacology · doi:10.1007/164_2019_241 · Cited by 100 · see citing works
The Role of Gut Microbiome-Derived Short-Chain Fatty Acid Butyrate in Hepatobiliary Diseases
Pant, K., Venugopal, S. K., Pisarello, M. J. L., & Gradilone, S. A. (2023) · American Journal Of Pathology · doi:10.1016/j.ajpath.2023.06.007 · Cited by 96 · see citing works
The IBD and PSC phenotypes of PSC-IBD
Ricciuto, A., Kamath, B. M., & Griffiths, A. M. (2018) · Current Gastroenterology Reports · doi:10.1007/s11894-018-0620-2 · Cited by 94 · see citing works
Trivedi, P. J., Hirschfield, G. M., Adams, D., & Vierling, J. M. (2024) · Gastroenterology · doi:10.1053/j.gastro.2024.01.049 · Cited by 98 · see citing works
The Role of Gut Microbiota in Some Liver Diseases: From an Immunological Perspective
Wang, L., Cao, Z.-M., Zhang, L., Li, J.-M., & Lv, W. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.923599 · Cited by 87 · see citing works
“The study (103) showed that Germ-free mdr2−/−mice exhibited worsening biochemical and histological features of PSCs due to lack of secondary BAs, and increased senescence of cholangiocytes, and another study (83) uncovered that after 8 weeks of treatment with Colesevelam, the level of secondary BAs in Mdr2−/− mice was…”
BackgroundABCB4 gene aberrations in human liver disease: an evolving spectrum
Reichert, M., & Lammert, F. (2018) · Seminars in Liver Disease · doi:10.1055/s-0038-1667299 · Cited by 81 · see citing works
Isaacs‐Ten, A., Echeandia, M., Moreno‐Gonzalez, M., Brion, A., Goldson, A. J., Philo, M. R., Patterson, A. M., Parker, A., Galduroz, M., Baker, D., et al. (2020) · Hepatology · doi:10.1002/hep.31228 · Cited by 80 · see citing works
The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation
Schrumpf, E., Kummen, M., Valestrand, L., Greiner, T. U., Holm, K., Arulampalam, V., Reims, H. M., Baines, J. F., Bäckhed, F., Karlsen, T. H., et al. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.09.020 · Cited by 78 · see citing works
“A recent study demonstrated that germ free (GF) multidrug resistance knock out (Mdr2) mice developed more severe liver disease compared with conventionally raised (CONV-R) Mdr2 mice [16].”
Kim, Y. S., Hurley, E., Park, Y., & Ko, S. (2023) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01042-9 · Cited by 78 · see citing works
Gut microbiota in liver disease: too much is harmful, nothing at all is not helpful either
Hartmann, P., Chu, H., Duan, Y., & Schnabl, B. (2019) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00370.2018 · Cited by 73 · see citing works
The gut microbial influence on cholestatic liver disease
Kummen, M., & Hov, J. R. (2019) · Liver International · doi:10.1111/liv.14153 · Cited by 74 · see citing works
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Arab, J. P., Arrese, M. A., & Shah, V. H. (2019) · Hepatology Research · doi:10.1111/hepr.13473 · Cited by 72 · see citing works
The Microbiome in Primary Sclerosing Cholangitis: Current Evidence and Potential Concepts
Hov, J., & Karlsen, T. (2017) · Seminars in Liver Disease · doi:10.1055/s-0037-1608801 · Cited by 65 · see citing works
Bile acid homeostasis paradigm and its connotation with cholestatic liver diseases
Yang, T., Khan, G. J., Wu, Z., Wang, X., Zhang, L., & Jiang, Z. (2018) · Drug Discovery Today · doi:10.1016/j.drudis.2018.09.007 · Cited by 64 · see citing works
Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis
Czaja, A. J. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i42.9257 · Cited by 62 · see citing works
The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis
Guicciardi, M. E., Trussoni, C. E., LaRusso, N. F., & Gores, G. J. (2019) · Hepatology · doi:10.1002/hep.31067 · Cited by 62 · see citing works
Self-citationThe Role of Microbiota in Primary Sclerosing Cholangitis and Related Biliary Malignancies
Özdirik, B., Müller, T., Wree, A., Tacke, F., & Sigal, M. J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136975 · Cited by 61 · see citing works
“Further, they revealed an elevation in cholangiocyte senescence, which is a characteristic of progressive biliary disease [55].”
BackgroundInfluentialPrimary sclerosing cholangitis
Manns, M. P., Bergquist, A. M., Karlsen, T. H., Levy, C., Muir, A. J., Ponsioen, C. Y., Trauner, M., Wong, G. L., & Younossi, Z. M. (2025) · Nature Reviews Disease Primers · doi:10.1038/s41572-025-00600-x · Cited by 71 · see citing works
“Notably, microbiota may not trigger liver injury but may also have protective actions since total elimination of intestinal micro-biome in germ-free mice aggravates fibrosis and bile duct injury 277 .”
Association of serum bilirubin in newborns affected by jaundice with gut microbiota dysbiosis
Zhou, S., Wang, Z., He, F., Qiu, H., Wang, Y., Wang, H., Zhou, J., Zhou, J., Cheng, G., Zhou, W., et al. (2018) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2018.09.016 · Cited by 61 · see citing works
Cellular Senescence in Liver Disease and Regeneration
Ferreira-González, S., Rodrigo‐Torres, D., Gadd, V. L., & Forbes, S. J. (2021) · Seminars in Liver Disease · doi:10.1055/s-0040-1722262 · Cited by 58 · see citing works
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The intestinal and biliary microbiome in autoimmune liver disease—current evidence and concepts
Liwinski, T., Heinemann, M., & Schramm, C. (2022) · Seminars in Immunopathology · doi:10.1007/s00281-022-00936-6 · Cited by 59 · see citing works
Cholangiocytes and the environment in primary sclerosing cholangitis: where is the link?
O’Hara, S. P., Karlsen, T. H., & LaRusso, N. F. (2017) · Gut · doi:10.1136/gutjnl-2017-314249 · Cited by 56 · see citing works
Self-citationSong, W., Park, H., Ha, J. M., Shin, S. G., Park, H.-G., Kim, J., Zhang, T., Ahn, D., Kim, S., Yang, Y., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-29445-z · Cited by 56 · see citing works
Animal models of cholestasis: An update on inflammatory cholangiopathies
Mariotti, V., Cadamuro, M., Spirlı̀, C., Fiorotto, R., Strazzabosco, M., & Fabris, L. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.07.025 · Cited by 56 · see citing works
Tabibian, J. H., Ali, A. H., & Lindor, K. D. (2018) · Europe PMC (PubMed Central) · Cited by 55 · see citing works
Self-citationRemote Sensing Between Liver and Intestine: Importance of Microbial Metabolites
Fu, Z. D., & Cui, J. Y. (2017) · Current Pharmacology Reports · doi:10.1007/s40495-017-0087-0 · Cited by 54 · see citing works
Primary sclerosing cholangitis: A review and update
Tabibian, J. H., & Bowlus, C. L. (2017) · Liver Research · doi:10.1016/j.livres.2017.12.002 · Cited by 57 · see citing works
Self-citationGut-liver axis: Pathophysiological concepts and medical perspective in chronic liver diseases
Rodrigues, S. G., der Merwe, V., Krag, A. A., & Wiest, R. (2024) · Seminars in Immunology · doi:10.1016/j.smim.2023.101859 · Cited by 51 · see citing works
Binda, C., Gibiino, G., Coluccio, C., Sbrancia, M., Dajti, E., Sinagra, E., Capurso, G., Sambri, V., Cucchetti, A., Ercolani, G., et al. (2022) · Microorganisms · doi:10.3390/microorganisms10020312 · Cited by 52 · see citing works
Nevens, F., Trauner, M. A., & Manns, M. P. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.10.007 · Cited by 51 · see citing works
Primary sclerosing cholangitis: 50 years of a gut–liver relationship and still no love?
Karlsen, T. H. (2016) · Gut · doi:10.1136/gutjnl-2016-312137 · Cited by 47 · see citing works
Mattner, J. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17111864 · Cited by 46 · see citing works
“In this context, it has been recently shown that fibrosis, ductular reaction, and ductopenia are significantly more severe in germ-free (GF) mutltidrug resistant 2 knockout (mdr2−/−) mice than in conventionally housed animals [103].”
BackgroundInflammation and the Gut-Liver Axis in the Pathophysiology of Cholangiopathies
Giordano, D. M., Pinto, C., Maroni, L., Benedetti, A., & Marzioni, M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103003 · Cited by 46 · see citing works
“In line with these findings, decreased levels of secondary bile acids, which are commensal flora metabolites exerting anti-inflammatory functions in vitro, have been found in PSC and IBD patients compared to healthy controls [116].”
BackgroundResultInfluentialRajapaksha, I. G., Gunarathne, L. S., Asadi, K., Cunningham, S. C., Sharland, A. F., Alexander, I. E., Angus, P., & Herath, C. B. (2019) · Hepatology Communications · doi:10.1002/hep4.1434 · Cited by 45 · see citing works
The Gut–Liver Axis in Chronic Liver Disease: A Macrophage Perspective
Muynck, K. D., Vanderborght, B., Vlierberghe, H. V., & Devisscher, L. (2021) · Cells · doi:10.3390/cells10112959 · Cited by 47 · see citing works
“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 41 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“(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 · see citing works
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 · see citing works
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 · see citing works
“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 37 · see citing works
“, 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 · see citing works
“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 · see citing works
“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 37 · see citing works
“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 · see citing works
“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 · see citing works
Philips, C. A., Augustine, P., & Phadke, N. D. (2018) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2018.00033 · Cited by 36 · see citing works
Czaja, A. J. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i45.6579 · Cited by 35 · see citing works
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 · see citing works
“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 35 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 32 · see citing works
The Microbiome and Immune Regulation After Transplantation
Tabibian, J. H., & Kenderian, S. S. (2016) · Transplantation · doi:10.1097/tp.0000000000001444 · Cited by 31 · see citing works
“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 · see citing works
“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 · see citing works
“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 28 · see citing works
Intestinal microbiota in primary sclerosing cholangitis
Hov, J. R., & Kummen, M. (2016) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000334 · Cited by 27 · see citing works
- 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 · 2012: 1
- 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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