Gut bacterial metabolite linked to inflammation in liver disease

Researchers have identified a link between specific activities in gut bacteria and the liver disease PSC. The finding could explain a long-suspected connection between gut bacteria and PSC. It also opens up new treatment options.

PSC stands for primary sclerosing cholangitis, a rare chronic liver disease that primarily affects young adults and causes inflammation and scarring of the liver’s bile ducts. Over time, PSC can lead to severe liver damage, an increased risk of bile duct and liver cancer, and the need for a liver transplant. 

Sweden is one of the countries where relatively many people live with PSC, which reflects the higher incidence in Scandinavia compared to other parts of the world. There are currently no effective medical treatments that can stop or reverse the course of the disease in PSC. 

The disease is associated with inflammatory bowel disease and an altered composition of bacteria in the intestine. Researchers have long suspected that the gut microbiota plays a role in PSC, but it has been unclear exactly how gut bacteria contribute to damage to the bile ducts.

Potential missing link identified

In the current study, researchers at the University of Gothenburg and colleagues identified what may potentially be a missing link: the metabolite ImP (imidazole propionate), a molecule formed when certain gut bacteria break down dietary components.

The study shows that individuals with PSC had elevated levels of ImP, and that high ImP levels could predict poorer survival outcomes in PSC. In experiments on mice, the researchers were able to induce liver inflammation through chronic administration of ImP.

When ImP encounters the protective cells lining the bile ducts, these cells exhibit activated signaling that drives inflammation and fibrosis. Fibrosis involves the formation of excess, hard scar tissue, causing the organ to stiffen and struggle to function.

A combination of causes

The study suggests that PSC may arise when metabolites produced by an altered gut microbiota continuously reach and damage the bile ducts. The results thus provide a potential biological explanation for the long-suspected link between gut bacteria and PSC. Importantly, we also identified the molecular pathway underlying these effects.”

Antonio Molinaro, researcher, University of Gothenburg and senior consultant hepatologist at Sahlgrenska University Hospital

“This opens up several possible future avenues for treatment: reducing the bacterial production of ImP, inhibiting the bacterial enzymes responsible for its production, or blocking the signaling pathway through which ImP appears to cause damage,” he says.

The study does not suggest that ImP is the sole cause of PSC. The disease is likely caused by a complex combination of genetic, immunological, and environmental factors, as well as changes in the gut microbiota. However, the results indicate that ImP may contribute significantly to the onset and progression of the disease and help explain a substantial part of the clinical picture of PSC.

The study is published in the journal Nature Metabolism.