Gut microbiota-derived imidazole propionate promotes primary sclerosing cholangitis via p38 signalling
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts that can lead to biliary cancer and end-stage liver disease. PSC is associated with inflammatory bowel disease and an altered gut microbiota. However, the molecular mechanisms underlying gut-liver interactions in PSC remain poorly characterized. Here we show that the gut microbiota-derived metabolite imidazole propionate (ImP) is a disease driver in PSC. Individuals with PSC have higher circulating ImP levels than individuals with related conditions, and high ImP levels predict reduced survival in PSC. Cholangiocytes exposed to ImP show activated mammalian target of rapamycin complex 1 (mTORC1) signalling and secrete pro-inflammatory and pro-fibrogenic factors. Chronic administration of ImP to mice induces liver inflammation and fibrosis through a p38-dependent mechanism, upstream of mTORC1. We propose that chronic exposure to ImP induces cholangiocyte injury, which alone or in concert with other factors causes clinical worsening of PSC. Therefore, targeting ImP production or signalling may represent therapeutic avenues in PSC.
Authors
- Ida Björk
- Ahmad H. Ali (ORCID: https://orcid.org/0000-0001-8553-7744)
- Konstantinos N. Lazaridis (ORCID: https://orcid.org/0000-0002-0437-681X)
- Hólmfríður Helgadóttir (ORCID: https://orcid.org/0000-0001-8688-449X)
- Henrik M. Reims
- Peder R. Braadland (ORCID: https://orcid.org/0000-0002-0794-7737)
- Guido Carpino (ORCID: https://orcid.org/0000-0001-8570-2519)
- Martin Cornillet (ORCID: https://orcid.org/0000-0001-7981-0927)
- Diletta Overi (ORCID: https://orcid.org/0000-0003-3561-8903)
- Marte Lie Høivik (ORCID: https://orcid.org/0000-0002-0104-465X)
- Tom H. Karlsen (ORCID: https://orcid.org/0000-0002-8289-9931)
- Trine Folseraas (ORCID: https://orcid.org/0000-0003-2011-1923)
- Espen Melum (ORCID: https://orcid.org/0000-0001-6903-6878)
- Krzysztof Grzyb (ORCID: https://orcid.org/0000-0002-2718-8125)
- Enya Amundsen-Isaksen (ORCID: https://orcid.org/0000-0001-6926-7131)
- Annika Lundqvist (ORCID: https://orcid.org/0000-0002-4736-0244)
- Marios Nikolaidis (ORCID: https://orcid.org/0000-0002-3902-9367)
- Andreas Abildgaard (ORCID: https://orcid.org/0000-0002-5501-259X)
- Lise Katrine Engesæter
- Johannes R. Hov (ORCID: https://orcid.org/0000-0002-5900-8096)
- Antonio Molinaro (ORCID: https://orcid.org/0000-0003-3432-2238)
- Brian D. Juran
- Alba Carreras (ORCID: https://orcid.org/0000-0001-8787-8833)
- Petra Hanzely
- Adrian McCann
- P M Ueland
- Sara K.V. Tjønnfjord (ORCID: https://orcid.org/0000-0003-1887-9255)
- Mette Vesterhus
- Lars Bossen
- Bryan M. McCauley
- Katharina R. Beck
- Fredrik Bäckhed
- Anna Frank
- Vincenzo Cardinale
- Marco Carbone
- Lei Geng
- Eugenio Gaudio
- Laura Cristoferi
- Henning Grønbæk
- Annika Bergquist
Institutions
- Oslo University Hospital (NO)
- Karolinska University Hospital (SE)
- University of Oslo (NO)
- Aarhus University (DK)
- Sahlgrenska University Hospital (SE)
- Novo Nordisk Foundation (DK)
- Aarhus University Hospital (DK)
- Karolinska Institutet (SE)
- Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT)
- Region Västra Götaland (SE)
- Azienda Ospedaliera San Gerardo (IT)
- Mayo Clinic in Arizona (US)
- Haraldsplass Diakonale Sykehus (NO)
- Bevital (Norway) (NO)
- University of Bergen (NO)
- University of Milano-Bicocca (IT)
- University of Missouri (US)
- Sapienza University of Rome (IT)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Metabolism
- Published
- 2026-09-04
- DOI
- https://doi.org/10.1038/s42255-026-01600-1
- Primary Topic
- Liver Diseases and Immunity
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Knut och Alice Wallenbergs Stiftelse
- Sapienza Università di Roma
- Norges Forskningsråd
- United European Gastroenterology
- National Institutes of Health
- Wallenberg Centre for Molecular and Translational Medicine