Primary sclerosing cholangitis (PSC) is a rare but serious disease that affects both the liver and the bile ducts, the tiny tubes that carry bile out of the liver.
"In PSC, the bile ducts become inflamed and gradually narrow and scar. As they tighten, bile can't flow properly, a bit like a drainpipe under a sink that slowly gets blocked," says Professor Johannes E. Roksund Hov at the University of Oslo. He is also a senior consultant at Oslo University Hospital, and group leader at the Norwegian PSC Research Centre and Research Institute of Internal Medicine.
When bile and waste products build up, the liver is damaged over time. Many people with PSC develop cirrhosis and liver failure, and a large proportion will need a liver transplant within 10-20 years of being diagnosed.
PSC also increases the risk of cancer.
"PSC is now the most common reason for liver transplantation in Norway. It is difficult to treat, and many patients become seriously ill," says Hov.
"We see young adults with small children who suddenly face a very uncertain future. At present we don't have a medicine that clearly slows the disease."
The new study, published in Nature Metabolism, strengthens the evidence for a connection between signals from the gut and the progression of PSC and point to existing medicines that could be tested as new treatments.
A close connection between gut and liver
Researchers have long suspected that PSC is linked to the gut. Most people with PSC also have an inflammatory bowel disease (IBD).
"All the blood from the gut goes straight to the liver," Hov explains. "So, it's not surprising that the gut and liver are closely connected."
"But when we see long term disease in both the gut and liver at the same time, it suggests there may be common causes. Something from the gut may be helping to trigger or worsen the liver disease."
A different gut flora in PSC
Over the last few years, Hov and his colleagues have studied the gut flora, the community of bacteria living in the intestine, in people with PSC.
They have shown that the gut flora in PSC is clearly different from that in healthy people.
"In PSC, we find a different mix of bacteria, and less variety overall. The gut flora looks more 'unhealthy'," says Hov.
Another important observation is that PSC often returns after a liver transplant.
"Even when the diseased liver is removed and replaced with a healthy one, PSC can reappear in the new liver," says Peder Rustøen Braadland, first author and postdoctoral researcher at NoPSC and Research Institute of Internal Medicine.
"That strongly suggests that something outside the liver is involved, and we've long suspected the gut. Our new results support that idea much more strongly than before."
One bacterial molecule stands out
To pinpoint what it is about the gut flora that affects PSC, the researchers used advanced blood analyses to measure over 1,000 different small molecules. One particular molecule stood out very clearly from all the others.
This molecule is produced only by gut bacteria but is absorbed from the intestine into the bloodstream and carried to the liver.
"When we looked at patients' blood samples over time, we saw that those with high levels of this molecule tended to do worse," Hov says.
"People who had a lot of it in their blood were more likely to develop severe disease and to need a liver transplant. That suggests this bacterial molecule is linked to a more aggressive form of PSC."
Testing the theory in mice
To test whether the molecule actually contributes to disease, the team carried out experiments in mice. Healthy mice were given drinking water containing the bacterial molecule.
"We saw changes developing in their bile ducts that looked like early disease," says Braadland. "And in mice that already had bile duct disease, it clearly got worse when they received the molecule."
When the researchers switched off the genes that the molecule acts on in the bile ducts, the effect disappeared.
"When we blocked this response, the harmful effect of the molecule disappeared," Braadland explains. "That tells us that the molecule is not just a bystander, but it can actively drive disease in the bile ducts."
Activating system related to stress and inflammation
The bacterial molecule activates a cellular system called mTOR, which helps control how cells grow and respond to stress and inflammation. In PSC, the molecule makes this system more active in bile duct cells, promoting inflammation and scarring.
"The interesting thing is that we already have medicines that can dampen mTOR activity," says Hov.
"These medicines are used today to suppress the immune system after organ transplantation. We now want to see whether they can also slow down PSC."
Planning clinical trials with existing medicines
Because mTOR-inhibiting drugs are already approved, the team hopes to move relatively quickly into clinical studies. They plan to test the medicines both before and after liver transplant.
"In the first studies, we will test different doses and look for signs that the disease is progressing more slowly in those who receive the medicine," Hov says.
"Before transplant, we want to see if the drugs can stabilise the disease and possibly delay the need for a new liver. After transplant, we will investigate whether they can reduce the risk that PSC comes back in the new liver and improve treatment if it does."
Could diet and gut health also matter?
The study has also given new insight into how PSC develops. Because the key molecule is produced only by gut bacteria, it may be possible in future to influence its levels by changing the gut environment.
"In principle, we can imagine that changes in diet, or other ways of altering the gut flora, could have a positive effect on PSC in the long term," says Hov.
"Future treatment may therefore involve a combination of approaches with medicines that block harmful signals in the bile ducts, together with lifestyle measures that improve the balance of bacteria in the gut."
Hopes for progress within five years
The researchers expect that it will take several years to know whether this new approach will work.
"It will probably be at least five years before we know whether these medicines really look promising in PSC, and longer before we have firm answers," says Hov. "But in the world of drug development, that is still quite a short time."
For people with the liver disease, even a small step could make a difference.
"PSC is a disease where we essentially have no effective treatment apart from liver transplantation," says Braadland.
"These results give us a concrete treatment strategy to test. Moving from no options to a realistic plan is an important step, both for research and, we hope, for patients."
About the study
The study is based on close collaboration with researchers at the University of Gothenburg, with contributions from several other countries, and published in the journal Nature Metabolism.
The project forms part of Johannes E. Roksund Hov's ERC Consolidator Grant.
Reference
Molinaro, A & Braadland, P. et al. Gut microbiota-derived imidazole propionate promotes primary sclerosing cholangitis via p38 signalling. Nature Metabolism. https://www.nature.com/articles/s42255-026-01600-1
