Researchers at the University of Oslo and Oslo University Hospital have, together with international collaborators, discovered that a small molecule made exclusively by gut bacteria can actively drive disease in the bile ducts and worsen primary sclerosing cholangitis (PSC), a serious liver and bile duct disease. The findings, published in Nature Metabolism, strengthen 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.
PSC is a chronic condition and the leading reason for liver transplantation in Norway. There is currently no proven drug treatment that alters the course of the disease.
“We now have strong indications that a specific molecule from gut bacteria helps drive PSC,” says Professor Johannes E. Roksund Hov, University of Oslo and Oslo University Hospital, and principal investigator at the Norwegian PSC Research Centre (NoPSC) and Research Institute of Internal Medicine. “Identifying a specific gut‑derived molecule that drives disease gives us a clear target and a strategy to test.”
A rare disease and a leading reason for liver transplantation
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. The bile ducts become inflamed and gradually narrow and scar. As they tighten, bile can’t flow properly, like a drainpipe under a sink that slowly gets blocked. When bile and waste products build up, the liver is progressively damaged. Many patients develop cirrhosis and liver failure, and a large proportion need liver transplantation within 10–20 years of being diagnosed. PSC also increases the risk of cancer.
“We see young adults with small children who suddenly face a very uncertain future,” says Hov. “At present we don’t have a medicine that clearly slows the disease.”
Strengthening the gut–liver connection
Researchers at NoPSC have long suspected that PSC is closely linked to the gut. Most patients with PSC also have inflammatory bowel disease (IBD). Over recent years, Hov and colleagues have mapped the gut flora in people with PSC, showing that it is clearly different from that of healthy individuals.
Another important observation is that PSC often returns after liver transplantation. “Even when the diseased liver is removed and replaced with a healthy one, PSC can reappear in the new liver,” says Peder Braadland, first author and postdoctoral researcher at the NoPSC. “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 – and existing drugs
Using advanced blood analyses, the team measured over 1,000 small molecules and identified one that is made only by gut bacteria. Patients with higher levels of this molecule had more severe disease and were more likely to need liver transplantation. Experiments in mice showed that the molecule could trigger disease and worsen bile duct damage, and that blocking this response removed the harmful effect.
The molecule activates a cellular system called mTOR, which regulates inflammation and scarring. Medicines that inhibit mTOR are already approved and used as immunosuppressants after organ transplantation.
“Because mTOR‑targeting drugs already exist, we can move relatively quickly into clinical studies, studying them both before and after transplant. Our goal is to see whether these medicines can slow disease progression in PSC and possibly reduce the risk of the disease returning after liver transplantation,” Hov explains.
Hope for progress within a few years
The researchers expect first answers from clinical trials in about five years.
“For people with PSC, even a small step forward matters. Moving from no real medical options to a realistic treatment strategy is an important change, both for research and, we hope, for patients,” Braadland says.”
About the research
The study is the result of close collaboration between the Norwegian PSC Research Centre (NoPSC) at University of Oslo and Oslo University Hospital, and researchers at the University of Gothenburg, with contributions from several international partners. The work forms part of Professor Johannes E. Roksund Hov’s ERC Consolidator Grant on PSC and the gut–liver axis.