Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with underlying inflammatory bowel disease (IBD). This study investigates how PSC predisposes individuals to altered inflammatory immune responses compared with IBD alone. A case-control study was conducted with a cohort of 75 patients, including 16 with PSC (14 with concomitant IBD), 39 with IBD alone, and 20 controls. Serum bile acid profile, proteomic analysis, and immune-related gene expression in the colon tissue were examined. Colonic tissue from PSC patients exhibited up-regulation of immune regulation and inflammatory signaling mRNA markers, including LGR5, IL-8, CCL2, COX2, TWIST1, and SNAIL. Additionally, PSC patients displayed a distinct proinflammatory serum proteomic signature and moderate elevation of some bile acids, such as glycochenodeoxycholic acid (GCDCA). Co-incubation of human-derived monocytes with GCDCA partially replicated the inflammatory profile observed in PSC. These findings suggest that circulating bile acids modulate the peripheral immune system proinflammatory response, contributing to the unique PSC phenotype.

Center for the Study of Liver and Gastrointestinal Diseases Carlos 3 National Institute of Health Madrid Spain

CIIS Centro de Investigação Interdisciplinar em Saúde Faculdade de Medicina Universidade Católica Portuguesa Lisboa Portugal

Department of Biochemistry and Genetics School of Sciences University of Navarra Pamplona Spain

Department of Liver and Gastrointestinal Diseases Biogipuzkoa Health Research Institute Donostia University Hospital University of the Basque Country San Sebastian Spain

Division of Gastroenterology Hospital Beatriz Ângelo Loures Portugal

Division of Gastroenterology Hospital da Luz Lisboa Portugal

Division of Gastroenterology Hospital Lusíadas Lisboa Portugal

Division of Gastroenterology ULS Santa Maria Lisboa Portugal

Experimental Hepatology and Drug Targeting University of Salamanca Salamanca Spain

Ikerbasque Basque Foundation for Science Bilbao Spain

Mendel Centre of Plant Genomics and Proteomics Central European Institute of Technology Masaryk University Brno Czech Republic

Research Institute for Medicines Faculty of Pharmacy Universidade de Lisboa Lisboa Portugal

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Chazouilleres O., Beuers U., Bergquist A., Karlsen T.H., Levy C., Samyn M., et al. EASL Clinical Practice guidelines on sclerosing cholangitis. J. Hepatol. 2022;77:761–806. doi: 10.1016/j.jhep.2022.05.011. PubMed DOI

Emek E., Serin A., Sahin T., Yazici P., Yuzer Y., Tokat Y., et al. Experience in liver transplantation due to primary sclerosing cholangitis: a single center experience. Transplant. Proc. 2019;51:2439–2441. doi: 10.1016/j.transproceed.2019.01.156. PubMed DOI

Tabibian J.H.and Bowlus C.L Primary sclerosing cholangitis: a review and update. Liver Res. 2017;1:221–230. doi: 10.1016/j.livres.2017.12.002. PubMed DOI PMC

Mousa O.Y., Juran B.D., McCauley B.M., Vesterhus M.N., Folseraas T., Turgeon C.T., et al. Bile acid profiles in primary sclerosing cholangitis and their ability to predict hepatic decompensation. Hepatology. 2021;74:281–295. doi: 10.1002/hep.31652. PubMed DOI PMC

Fuchs C.D., Simbrunner B., Baumgartner M., Campbell C., Reiberger T.and Trauner M Bile acid metabolism and signalling in liver disease. J. Hepatol. 2025;82:134–153. doi: 10.1016/j.jhep.2024.09.032. PubMed DOI

Fleishman J.S.and Kumar S Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct. Target. Ther. 2024;9:97.:97. doi: 10.1038/s41392-024-01811-6. PubMed DOI PMC

Ananthakrishnan A.N., Bernstein C.N., Iliopoulos D., Macpherson A., Neurath M.F., Ali R.A.R., et al. Environmental triggers in IBD: a review of progress and evidence. Nat. Rev. Gastroenterol. Hepatol. 2018;15:39–49. doi: 10.1038/nrgastro.2017.136. PubMed DOI

Bergquist A.and Ponsioen C.Y Inflammatory bowel disease and primary sclerosing cholangitis: One disease or two? J. Hepatol. 2024;80:155–168. doi: 10.1016/j.jhep.2023.09.031. PubMed DOI

Qiu P., Ishimoto T., Fu L., Zhang J., Zhang Z.and Liu Y The gut microbiota in inflammatory bowel disease. Front. Cell. Infect. Microbiol. 2022;12:733992. doi: 10.3389/fcimb.2022.733992. PubMed DOI PMC

Torres J., Bao X., Goel A., Colombel J.-F., Pekow J., Jabri B., et al. The features of mucosa-associated microbiota in primary sclerosing cholangitis. Aliment. Pharmacol. Ther. 2016;43:790–801. doi: 10.1111/apt.13552. PubMed DOI PMC

Torres J., Palmela C., Brito H., Bao X., Ruiqi H., Moura-Santos P., et al. The gut microbiota, bile acids and their correlation in primary sclerosing cholangitis associated with inflammatory bowel disease. United European Gastroenterol. J. 2018;6:112–122. doi: 10.1177/2050640617708953. PubMed DOI PMC

Shaw D.G., Aguirre-Gamboa R., Vieira M.C., Gona S., DiNardi N., Wang A., et al. Antigen-driven colonic inflammation is associated with development of dysplasia in primary sclerosing cholangitis. Nat. Med. 2023;29:1520–1529. doi: 10.1038/s41591-023-02372-x. PubMed DOI PMC

LeníĿek M., Vecka M., Žížalová K.and Vítek L Comparison of simple extraction procedures in liquid chromatography⿿mass spectrometry based determination of serum 7α-hydroxy-4-cholesten-3-one, a surrogate marker of bile acid synthesis. Journal of Chromatography B. 2016;1033–1034:317–320. doi: 10.1016/j.jchromb.2016.08.046. PubMed DOI

Dyer R.G., Hetherington C.S., Alberti K.G.M.M.and Laker M.F Simultaneous measurement of phytosterols (campesterol and β-sitosterol) and 7-ketocholesterol in human lipoproteins by capillary column gas chromatography. Journal of Chromatography B: Biomedical Sciences and Applications. 1995;663:1–7. doi: 10.1016/0378-4347(94)00410-7. PubMed DOI

Nytofte N.S., Serrano M.A., Monte M.J., Gonzalez-Sanchez E., Tumer Z., Ladefoged K., et al. A homozygous nonsense mutation (c.214C->A) in the biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis. J. Med. Genet. 2011;48:219–225. doi: 10.1136/jmg.2009.074567. PubMed DOI

Steiner C.,, von Eckardstein A.,, Rentsch K.M Quantification of the 15 major human bile acids and their precursor 7α-hydroxy-4-cholesten-3-one in serum by liquid chromatography–tandem mass spectrometry. Journal of Chromatography B. 2010;878:2870–2880. doi: 10.1016/j.jchromb.2010.08.045. PubMed DOI

Pires D., Calado M., Velez T., Mandal M., Catalão M.J., Neyrolles O., et al. Modulation of cystatin C in human macrophages improves anti-mycobacterial immune responses to Mycobacterium tuberculosis infection and coinfection with HIV. Front. Immunol. 2021;12:742822. doi: 10.3389/fimmu.2021.742822. PubMed DOI PMC

Wiśniewski J.R., Zougman A., Nagaraj N.and Mann M Universal sample preparation method for proteome analysis. Nat. Methods. 2009;6:359–362. doi: 10.1038/nmeth.1322. PubMed DOI

Stejskal K., Potěšil D.and Zdráhal Z Suppression of peptide sample losses in autosampler vials. J. Proteome Res. 2013;12:3057–3062. doi: 10.1021/pr400183v. PubMed DOI

Demichev V., Messner C.B., Vernardis S.I., Lilley K.S.and Ralser M DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput. Nat. Methods. 2020;17:41–44. doi: 10.1038/s41592-019-0638-x. PubMed DOI PMC

Perez-Riverol Y., Csordas A., Bai J., Bernal-Llinares M., Hewapathirana S., Kundu D.J., et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 2019;47:D442–D450. doi: 10.1093/nar/gky1106. PubMed DOI PMC

Szklarczyk D., Kirsch R., Koutrouli M., Nastou K., Mehryary F., Hachilif R., et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51:D638–D646. doi: 10.1093/nar/gkac1000. PubMed DOI PMC

Woolbright B.L.and Jaeschke H Novel insight into mechanisms of cholestatic liver injury. World J. Gastroenterol. 2012;18:4985–4993. doi: 10.3748/wjg.v18.i36.4985. PubMed DOI PMC

Lozano E., Sanchez-Vicente L., Monte M.J., Herraez E., Briz O., Banales J.M., et al. Cocarcinogenic effects of intrahepatic bile acid accumulation in cholangiocarcinoma development. Mol. Cancer Res. 2014;12:91–100. doi: 10.1158/1541-7786.MCR-13-0503. PubMed DOI

Gonzalez B., Fisher C.and Rosser B.G Glycochenodeoxycholic acid (GCDC) induced hepatocyte apoptosis is associated with early modulation of intracellular PKC activity. Mol. Cell. Biochem. 2000;207:19–27. doi: 10.1023/a:1007021710825. PubMed DOI

Mosser D.M.and Edwards J.P Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008;8:958–969. doi: 10.1038/nri2448. PubMed DOI PMC

Shapouri-Moghaddam A., Mohammadian S., Vazini H., Taghadosi M., Esmaeili S.A., Mardani F., et al. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol. 2018;233:6425–6440. doi: 10.1002/jcp.26429. PubMed DOI

Aras S.and Zaidi M.R TAMeless traitors: macrophages in cancer progression and metastasis. Br. J. Cancer. 2017;117:1583–1591. doi: 10.1038/bjc.2017.356. PubMed DOI PMC

Mantovani A., Marchesi F., Malesci A., Laghi L.and Allavena P Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 2017;14:399–416. doi: 10.1038/nrclinonc.2016.217. PubMed DOI PMC

Prenen H.and Mazzone M Tumor-associated macrophages: a short compendium. Cell. Mol. Life Sci. 2019;76:1447–1458. doi: 10.1007/s00018-018-2997-3. PubMed DOI PMC

Torres J., Pineton de Chambrun G., Itzkowitz S., Sachar D.B.and Colombel J.F Review article: colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease. Aliment. Pharmacol. Ther. 2011;34:497–508. doi: 10.1111/j.1365-2036.2011.04753.x. PubMed DOI

Loftus E.V. Jr, Harewood G.C., Loftus C.G., Tremaine W.J., Harmsen W.S., Zinsmeister A.R., et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut. 2005;54:91–96. doi: 10.1136/gut.2004.046615. PubMed DOI PMC

Leung K.K., Li W., Hansen B., Gulamhusein A., Lapointe-Shaw L., Shaheen A.A., et al. Primary sclerosing cholangitis-inflammatory bowel disease: Epidemiology, mortality, and impact of diagnostic sequence. JHEP Rep. 2025;7:101272. doi: 10.1016/j.jhepr.2024.101272. PubMed DOI PMC

Boonstra K., Drenth J.P.H., Poen A.C., Witteman B.J.M, et al. Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease. Inflamm. Bowel Dis. 2012;18:2270–2276. doi: 10.1002/ibd.22938. PubMed DOI

Zhang R., Lauwers G.Y.and Choi W.T Increased risk of non-conventional and invisible dysplasias in patients with primary sclerosing cholangitis and inflammatory bowel disease. Journal of Crohn’s and Colitis. 2022;16:1825–1834. doi: 10.1093/ecco-jcc/jjac090. PubMed DOI

Leibovitzh H., Nayeri S., Borowski K., Hernandez-Rocha C., Lee S.H., Turpin W., et al. Inflammatory bowel disease associated with primary sclerosing cholangitis is associated with an altered gut microbiome and bile acid profile. J. Crohns. Colitis. 2024;18:1957–1966. doi: 10.1093/ecco-jcc/jjae096. PubMed DOI PMC

Cai S.Y., Ouyang X., Chen Y., Soroka C.J., Wang J., Mennone A., et al. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight. 2017;2:e90780. doi: 10.1172/jci.insight.90780. PubMed DOI PMC

Kühn T., Stepien M., López-Nogueroles M., Damms-Machado A., Sookthai D., Johnson T., et al. Prediagnostic Plasma Bile Acid Levels and Colon Cancer Risk: A Prospective Study. J. Natl. Cancer Inst. 2020;112:516–524. doi: 10.1093/jnci/djz166. PubMed DOI PMC

Cayrol C.and Girard J.P Interleukin-33 (IL-33): a critical review of its biology and the mechanisms involved in its release as a potent extracellular cytokine. Cytokine. 2022;156:155891. doi: 10.1016/j.cyto.2022.155891. PubMed DOI

Meniailo M.E., Malashchenko V.V., Shmarov V.A., Gazatova N.D., Melashchenko O.B., Goncharov A.G, et al. Interleukin-8 favors pro-inflammatory activity of human monocytes/macrophages. Int. Immunopharmacol. 2018;56:217–221. doi: 10.1016/j.intimp.2018.01.036. PubMed DOI

Nagaoka S., Yamada D., Eguchi H., Yokota Y., Iwagami Y., Asaoka T., et al. The blockade of interleukin-33 released by hepatectomy would be a promising treatment option for cholangiocarcinoma. Cancer Sci. 2021;112:347–358. doi: 10.1111/cas.14709. PubMed DOI PMC

Zhang Z.Y., Guo X., Liu J.T.Y., Gu Y.J., Ji X.W., Zhu S., et al. Conjugated bile acids alleviate acute pancreatitis through inhibition of TGR5 and NLRP3 mediated inflammation. J. Transl. Med. 2024;22:1124. doi: 10.1186/s12967-024-05922-0. PubMed DOI PMC

Donkers J.M.and Roscam Abbing R.L.P Developments in bile salt based therapies: a critical overview. Biochem. Pharmacol. 2019;161:1–13. doi: 10.1016/j.bcp.2018.12.018. PubMed DOI

Trauner M., Gulamhusein A., Hameed B., Caldwell S., Shiffman M.L., Landis C., et al. The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis. Hepatology. 2019;70:788–801. doi: 10.1002/hep.30509. PubMed DOI PMC

Sanyal A.J., Ling L., Beuers U., DePaoli A.M., Lieu H.D., Harrison S.A., et al. Potent suppression of hydrophobic bile acids by aldafermin, an FGF19 analogue, across metabolic and cholestatic liver diseases. JHEP Rep. 2021;3:100255. doi: 10.1016/j.jhepr.2021.100255. PubMed DOI PMC

Kowdley K.V., Vuppalanchi R., Levy C., Floreani A., Andreone P., LaRusso N.F., et al. A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis. J. Hepatol. 2020;73:94–101. doi: 10.1016/j.jhep.2020.02.033. PubMed DOI PMC