Antonio Molinaro, Peder Rustøen Braadland, Guido Carpino, Alba Carreras, Marios Nikolaidis, Petra Hanzely, Katharina R Beck, Ahmad H Ali, Lars Bossen, Anna Frank, Annika Lundqvist, Brian D Juran, Diletta Overi, Lei Geng, Enya Amundsen-Isaksen, Henrik Mikael Reims, Ida Björk, Krzysztof Grzyb, Andreas Abildgaard, Trine Folseraas, Martin Cornillet, Hólmfríður Helgadóttir, Bryan M McCauley, Laura Cristoferi, Marco Carbone, Vincenzo Cardinale, Marte L Høivik, Lise Katrine Engesæter, Sara K V Tjønnfjord, Adrian McCann, Per M Ueland, Mette Vesterhus, Tom H Karlsen, Henning Grønbæk, Eugenio Gaudio, Konstantinos N Lazaridis, Annika Bergquist, Espen Melum, Fredrik Bäckhed, Johannes Roksund Hov
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.