Gut bacterial molecule may be biomarker of rare disease of liver and bile duct

Researchers have identified imidazole propionate, a metabolite produced by gut bacteria, as a possible driver of inflammation and fibrosis in primary sclerosing cholangitis. The discovery could help to explain the gut–liver connection associated with the rare disease and provide several potential targets for treatment

Researchers have identified a gut bacterial metabolite that may contribute directly to primary sclerosing cholangitis (PSC), a rare chronic liver disease in which the disorder develops without another identifiable disease or injury that directly causes damage to the bile-duct and where no effective disease-modifying treatment is available.

The international study, led by researchers at the University of Gothenburg in Sweden, has provided a possible biological explanation for the long-suspected relationship between changes in the gut microbiota and damage to the bile ducts. The findings could also support the development of therapies that reduce production of the metabolite or block the molecular signals through which it causes harm.

PSC causes chronic inflammation and scarring within the ducts that carry bile from the liver to the digestive system. As scar tissue accumulates, the ducts can narrow or become obstructed. This can prevent bile from draining properly and progressively damage the liver.

The disease often affects young and middle-aged adults and is particularly prevalent in northern Europe. Sweden and other Scandinavian countries have reported a comparatively high incidence. PSC can eventually lead to cirrhosis, liver failure and the need for a liver transplant. It also increases the risk of cholangiocarcinoma – a cancer of the bile ducts – as well as some other hepatobiliary cancers.

Although treatments can help to manage certain symptoms and complications, no medicine has been shown to stop or reverse the underlying course of PSC reliably. Liver transplantation therefore remains the only potentially curative option for people with advanced disease, although PSC can recur in a transplanted liver.

PSC has a particularly strong association with inflammatory bowel disease, especially ulcerative colitis. People with the condition also tend to have an altered intestinal microbial community. These observations have led researchers to suspect that communication between the gut and liver contributes to the disease but the mechanisms responsible have remained uncertain.

The gut and liver have a close anatomical and biochemical relationship. Blood from the intestine passes directly to the liver through the portal vein exposing the organ to nutrients, microbial products and other compounds absorbed from the digestive tract. Bile travels in the opposite direction, from the liver through the bile ducts and into the intestine.

The researchers focused on imidazole propionate (ImP), a small molecule that certain gut bacteria produce through the metabolism of histidine, an amino acid found in dietary protein. ImP has previously been associated with metabolic disorders and cardiovascular disease but its potential role in PSC had not been established.

The study found that people with PSC had higher circulating concentrations of ImP than people with related conditions. Higher concentrations were also associated with reduced survival among those with PSC which suggested that the metabolite might have value as a marker of disease severity or prognosis. Further work will be necessary before clinicians can use ImP as a routine biomarker.

Laboratory experiments indicated that ImP acted upon cholangiocytes, the specialised epithelial cells that line the bile ducts. Exposure to the metabolite activated mechanistic target of rapamycin complex 1, a molecular signalling system that helps cells to regulate growth, metabolism and responses to nutrients.

The exposed cholangiocytes released factors that promoted inflammation and fibrosis. Fibrosis occurs when excessive connective tissue accumulates in response to persistent injury. Although scar formation initially forms part of the body’s repair process, continued fibrosis can distort tissue structure, stiffen the affected organ and impair its function.

The researchers also administered ImP chronically to mice. This exposure caused liver inflammation and fibrosis through a mechanism dependent upon p38 signalling. The p38 proteins form part of a family of enzymes that controls cellular responses to stress and inflammatory stimuli. The results placed p38 activity upstream of mechanistic target of rapamycin complex 1 in the pathway through which ImP appeared to injure bile duct cells.

“The study suggests that PSC may arise when metabolites produced by an altered gut microbiota continuously reach and damage the bile ducts.

“The results therefore 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,” said Dr. Antonio Molinaro, a researcher at the University of Gothenburg and senior consultant hepatologist at Sahlgrenska University Hospital, also in Gothenburg.

“This opens several possible avenues for future treatment by reducing bacterial production of ImP and inhibiting the bacterial enzymes responsible for its production or block the signalling pathway through which ImP appears to cause damage,” Molinaro said.

However, the research has identified biological targets but it has not demonstrated that a treatment directed against ImP can prevent or reverse PSC in people.

The findings also do not indicate that ImP is the sole cause of PSC. The disease probably results from a complex interaction between genetic susceptibility, immune dysfunction, environmental exposures and changes within the gut microbiota. ImP may act alongside these factors to initiate or intensify bile duct injury rather than cause the condition independently.

Nevertheless, the combination of patient data, experiments with bile duct cells and studies in mouse models has strengthened the evidence that this bacterial metabolite contributes to the disease process. It has also provided a defined molecular pathway that researchers can investigate as a potential source of therapeutic targets.

For further reading please visit: 10.1038/s42255-026-01600-1