Gut Bacteria Byproduct Linked to Liver-Destroying Disease, Study Finds

For people living with primary sclerosing cholangitis, a rare and often fatal disease that scars the bile ducts, treatment options have long stalled at "wait for a transplant." A new study in Nature Metabolism identifies a specific molecule made by gut bacteria, imidazole propionate (ImP), as a driver of that damage rather than just a bystander. Across more than 1,000 patients in Norway, Sweden and the United States, higher blood levels of ImP tracked with worse disease and shorter survival without a transplant, and in mice the compound alone was enough to trigger liver inflammation and scarring through a signaling pathway that existing drugs already target.

Imidazole Propionate Tracks With PSC Severity

Researchers first screened blood from 132 people with primary sclerosing cholangitis (PSC) and 32 people without it, and found broad shifts in the blood chemistry of PSC patients, with 261 of 1,108 tested molecules linked to the disease. After narrowing that list down by testing which molecules also predicted survival and which stayed elevated even years after a liver transplant (ruling out changes that were just a side effect of failing liver function), one metabolite kept showing up: imidazole propionate, a byproduct that certain gut bacteria produce when they break down the amino acid histidine (an essential building block of protein). The compound had previously been linked to type 2 diabetes, heart failure, and wound healing in other research, and it was selected in 71% of resampled test runs here, more than any other candidate.

The team then confirmed the finding in four separate validation groups covering more than 1,000 additional patients across Norway, Sweden, and the United States. In every one of those groups, people with higher ImP had shorter transplant-free survival, and the association held up even in patients tracked for years after their transplant. Doubling a patient's blood ImP level was linked to an 18% higher risk of the disease recurring after a transplant.

PSC Overlaps Heavily With Bowel Disease

Primary sclerosing cholangitis is closely tied to the gut. Up to 80% of people with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis, and the disease mostly strikes young adults. There is currently no approved drug that slows PSC down, and a liver transplant is the only real treatment. Left untreated, the median time from diagnosis to transplant or death is 13 to 21 years. Even a transplant is not a permanent fix: PSC can recur in the new liver in some patients, a complication doctors call recurrent PSC (rPSC).

One clue points at the colon specifically: patients with PSC who had undergone a proctocolectomy (surgical removal of the colon) had lower ImP levels than patients with other types of bowel surgery or no colon surgery at all, matching earlier evidence that colon removal can improve liver outcomes in PSC.

Organoids And Mice Confirm The Mechanism

To test whether ImP actually causes liver injury rather than just marking it, the researchers grew cholangiocyte organoids (miniature, lab-grown clusters of the cells that line the bile ducts) from PSC patients and exposed them to the compound. Within days, the organoids released more inflammatory and scar-forming proteins (including TNF and IL-6) and lost their normal shape.

In live mice, drinking water dosed with ImP for eight weeks produced the same pattern: more immune cells in the liver's portal areas, more fibrosis (scarring), and more proliferating bile duct cells, all despite normal body weight and normal results on standard liver blood tests, meaning the damage would not necessarily show up on routine bloodwork. Germ-free mice colonized with a single ImP-producing bacterium developed similar injury, directly linking one gut microbe to liver damage. Mechanistically, ImP works by switching on a signaling protein called p38, which in turn activates mTORC1 (mechanistic target of rapamycin complex 1, a master regulator of cell growth). Mice genetically engineered to lack the p38 genes were protected from ImP's effects entirely, even when dosed with the compound, pinning down the pathway responsible.

What This Means For Gut Health Now

This research does not point to a diet, supplement, or probiotic that treats or prevents PSC, and nothing here should be read that way. What it does offer is a specific, druggable pathway. The mTOR-blocking drug sirolimus, already used in some transplant patients for unrelated reasons, was linked to lower rates of disease recurrence: among 182 people who received a liver transplant for PSC, sirolimus use was less common among those who later developed recurrent disease (6%) than among those who didn't (16%). For someone managing PSC or IBD-related liver concerns, this is a research lead worth being aware of, and a reasonable question to raise with a hepatologist as trials develop, not a reason to change current treatment.

Key Limitations Of The New Findings

The human data here is correlational: elevated ImP tracks with worse PSC outcomes, but that is not the same as proving it causes the disease in people the way the mouse experiments demonstrate causation in mice. The sirolimus signal came from a small retrospective comparison, not a controlled trial. The authors also note that the liver damage seen in mice was modest in scale, and that a p38-blocking drug called pirfenidone, tested separately in a small human PSC pilot study, showed a trend toward less scarring but was poorly tolerated by patients, a reminder that targeting this pathway safely is not yet solved.

Existing Drugs Could Be Repurposed Next

Because ImP already has a documented role in type 2 diabetes and other metabolic disease, tools and drugs developed for those conditions could plausibly be repurposed for PSC. The study's authors point to two broad strategies worth testing: reducing ImP production at its source, either by limiting the compound's dietary building blocks or by blocking the bacterial enzyme that makes it, and blocking its downstream signaling with existing mTOR-pathway drugs. Both remain untested in a real PSC clinical trial.

Common Questions

What is imidazole propionate? It's a small molecule that certain gut bacteria produce when they break down the amino acid histidine. It has separately been linked to type 2 diabetes and heart failure risk in prior research.

Does this mean gut bacteria cause PSC? Not on their own. PSC is thought to involve a mix of genetics, immune dysfunction, and environmental factors; this study adds gut-derived ImP as one contributing driver rather than a single cause.

Can changing my diet or gut bacteria treat PSC? No diet, supplement, or probiotic was tested in this study, and none should be assumed to work based on these findings. The research points toward drug targets, not lifestyle fixes.

Is there a treatment available now based on this study? No. Sirolimus's association with lower recurrence came from existing transplant patients already on the drug for other reasons, not a clinical trial designed to test it for PSC, so it isn't an established treatment for the disease yet.

Key Takeaways

• Blood levels of the gut bacterial byproduct imidazole propionate (ImP) were consistently elevated in primary sclerosing cholangitis across more than 1,000 patients in three countries, and higher levels predicted shorter transplant-free survival.
• In mice and lab-grown bile duct cells, ImP alone triggered the same inflammation and scarring seen in PSC, working through a p38-to-mTORC1 signaling pathway; genetically blocking that pathway prevented the damage.
• An existing transplant drug, sirolimus, was linked to lower rates of disease recurrence in one retrospective group, a lead that researchers say is worth testing directly.
• This is early-stage research: human data is correlational, no diet or supplement has been shown to help, and any drug approach still needs a real clinical trial.

References

1. Antonio Molinaro, Peder Rustøen Braadland, Guido Carpino, et al. (2026). Gut microbiota-derived imidazole propionate promotes primary sclerosing cholangitis via p38 signalling. Nature Metabolism. https://doi.org/10.1038/s42255-026-01600-1
2. Treatment for Primary Sclerosing Cholangitis (NIDDK). NIH. https://www.niddk.nih.gov/health-information/liver-disease/primary-sclerosing-cholangitis/treatment
3. Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology (Nature Communications, 2020). Nature. https://www.nature.com/articles/s41467-020-19589-w