Gut-Liver Axis Metabolomics Link Microbial Imidazole Propionate to Reduced Survival in PSC

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Data Quality: STRONG
Summary of  Nature Metabolism https://doi.org/10.1038/s42255-026-01600-1 
Dr. Antonio Molinaro et al.

Points

Oslo University Hospital researchers identified the gut bacterial metabolite imidazole propionate as an active driver of inflammation and fibrosis in primary sclerosing cholangitis.
Circulating imidazole propionate levels were significantly higher in affected patients and strongly predicted reduced overall transplant-free clinical survival.
In vitro exposure of human cholangiocytes to imidazole propionate activated mammalian target of rapamycin complex one signaling and induced pro-fibrogenic factor secretion.
Chronic animal model administration proved that imidazole propionate triggers liver inflammation and tissue fibrosis through a p38-dependent signaling pathway upstream of mTORC1.
Pharmacological blockade of p38 or mTOR signaling negated harmful inflammatory responses, offering an immediate strategy to evaluate existing immunosuppressive drugs in clinical trials.

Summary

This study evaluated the role of gut microbiota-derived metabolites in driving pathological progression in primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease often leading to cirrhosis, biliary cancer, and liver transplantation within 10 to 20 years. Led by Johannes E. Roksund Hov and Peder Braadland at the University of Oslo and Oslo University Hospital, in collaboration with the University of Gothenburg, the research was published in Nature Metabolism. The investigation aimed to map the gut-liver axis mechanisms through advanced blood metabolomics profiling of over 1,000 small molecules in patient cohorts to identify specific bacterial metabolites capable of triggering biliary inflammation and fibrosis.

Metabolomic screening identified imidazole propionate (ImP), a molecule exclusively generated by gut flora, as significantly elevated in circulating blood samples from PSC patients compared to individuals with related hepatic conditions. Elevated ImP concentrations directly predicted reduced transplant-free survival. Mechanistic evaluations in cultured human cholangiocytes demonstrated that ImP exposure triggers secretion of pro-inflammatory and pro-fibrogenic factors via activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Chronic administration of ImP in mouse models successfully induced systemic liver inflammation and biliary fibrosis through a p38-dependent pathway operating upstream of mTORC1.

Pharmacological or genetic inhibition of the p38-mTORC1 pathway effectively abolished ImP-induced tissue injury and fibrotic remodeling. Given that approved mTOR inhibitor medications are currently utilized as post-transplantation immunosuppressants, these agents represent an immediate candidate class for repurposed clinical trials aimed at slowing PSC disease progression and preventing post-transplant recurrence. The authors conclude that gut-derived ImP acts as an active driver of PSC pathology, highlighting targeting ImP synthesis or its downstream p38-mTORC1 signaling axis as a promising chronotherapeutic strategy.

Link to the article: https://www.nature.com/articles/s42255-026-01600-1

References

Molinaro, A., Braadland, P. R., Carpino, G., Carreras, A., Nikolaidis, M., Hanzely, P., Beck, K. R., Ali, A. H., Bossen, L., Frank, A., Lundqvist, A., Juran, B. D., Overi, D., Geng, L., Amundsen‑Isaksen, E., Reims, H. M., Björk, I., Grzyb, K., Abildgaard, A., … Hov, J. R. (2026). Gut microbiota-derived imidazole propionate promotes primary sclerosing cholangitis via p38 signalling. Nature Metabolism, 1–16. https://doi.org/10.1038/s42255-026-01600-1