A gut-restricted drug protects the liver after bowel surgery in mice

Up to 15% of patients who undergo radical small bowel resection develop liver damage that can progress to organ failure. There are no approved drugs to prevent this complication. The surgery, often lifesaving for conditions like necrotizing enterocolitis in premature infants, leaves patients with shortened intestines that struggle to absorb nutrients. The liver, already under metabolic stress, takes additional hits from toxic substances that gut bacteria produce and that a compromised intestinal barrier can no longer contain.

A team at Washington University School of Medicine in St. Louis has now synthesized and tested a compound that addresses this problem with a targeted approach: it works only in the gut, never reaching the rest of the body. The drug, called WUSTL0717, protected mice from liver fibrosis and improved their ability to absorb nutrients after bowel surgery. The study was published March 6, 2026, in Gastroenterology.

Good cholesterol as a liver shield

The intellectual foundation for this work was laid in 2021, when senior author Gwendalyn Randolph and the late Brad Warner, a pediatric surgeon at WashU Medicine, discovered that harmful substances produced by gut bacteria travel to the liver after small bowel resection. But they also found a natural defense: high-density lipoprotein (HDL), commonly known as good cholesterol, acts as a shield that prevents these bacterial products from damaging liver tissue.

That finding pointed toward a drug class called liver X receptor (LXR) agonists, which boost HDL production. The problem was that earlier LXR agonists that acted throughout the body caused severe side effects, including dangerous lipid accumulation in the liver. The drug class had been largely abandoned.

Keeping the drug where it belongs

The WashU team took a different approach. Bahaa Elgendy, an associate professor of anesthesiology with expertise in medicinal chemistry, synthesized a gut-restricted version of an LXR agonist. The original compound had been identified by a pharmaceutical company but never developed commercially. Elgendy redesigned it so that, when taken orally, it would remain in the intestinal tract rather than entering systemic circulation.

Testing confirmed that WUSTL0717 stayed in the intestines when administered to mice. It activated the LXR pathway locally, boosting HDL production in intestinal tissue, without triggering the systemic effects that had made whole-body LXR agonists problematic.

Better weight, less scarring

The researchers tested WUSTL0717 in mice that had undergone small bowel resection. When the drug was administered starting three weeks after surgery, treated mice showed improved nutrient absorption and gained weight compared to untreated controls. This addressed one of the most immediate clinical problems of short bowel syndrome: progressive, often irreversible weight loss.

The liver results were equally striking. Mice treated with WUSTL0717 had significantly less collagen, the protein that forms scar tissue, in their livers compared with untreated mice. Gene expression analysis revealed decreased activity of fibrosis-associated genes, including those responsible for collagen accumulation. In other words, the drug was not just reducing a marker of damage but suppressing the molecular machinery of scarring.

The children most affected

Short bowel syndrome disproportionately affects premature infants who survive necrotizing enterocolitis, a devastating intestinal disease. These children often depend on parenteral nutrition, receiving nutrients through a vein via a feeding pump, sometimes for years. That feeding method itself causes liver damage over time, compounding the injury from the bowel surgery. Many of these children eventually need liver transplants.

The next study from the WashU team will examine whether WUSTL0717 still protects the liver when combined with parenteral nutrition, testing whether the drug can defend against both sources of liver injury simultaneously.

Mouse study, human aspirations

This is preclinical research. WUSTL0717 has not been tested in humans, and the path from a mouse study to an approved therapy typically spans many years and frequently fails. Mouse models of short bowel syndrome do not fully replicate the human condition, particularly the prolonged dependence on intravenous nutrition and the complex immune responses in human patients.

The researchers have filed a patent for the use of WUSTL0717 to treat short bowel syndrome through WashU's Office of Technology Management. Several of the study's authors have intellectual property interests in the compound, which they have disclosed.

Still, the absence of any approved therapy for this complication gives the work clinical urgency. As Colin Martin, a pediatric surgeon and co-author on the study, noted, the lack of treatment options has profound implications for the long-term health of patients with short bowel syndrome.