A modern compound, developed by researchers at Washington University School of Medicine in St. Louis, offers a potential breakthrough in preventing liver damage following a radical small bowel resection – a life-saving surgery that can often lead to serious long-term complications. The research, published March 6 in Gastroenterology, demonstrates promising results in mice, suggesting a path toward mitigating the need for liver transplants in patients undergoing this procedure. This new approach focuses on a “gut-restricted” therapy, aiming to minimize side effects by targeting only the gastrointestinal tract.
Small bowel resection, although essential for treating diseased or dying portions of the small intestine, carries a significant risk of long-term liver damage, affecting up to 15% of patients. Currently, there are no medications specifically designed to prevent or manage this complication. The surgery often leads to short bowel syndrome, a condition where the shortened intestine struggles to absorb sufficient nutrients, particularly impacting premature infants with necrotizing enterocolitis, a severe gastrointestinal illness. These patients frequently require long-term intravenous feeding, which further increases their risk of liver disease and potential need for transplantation.
A Targeted Approach to Liver Protection
The research builds upon earlier work by the late Brad Warner, MD, a pediatric surgeon at WashU Medicine and Gwendalyn Randolph, PhD, the Emil R. Unanue Distinguished Professor of Immunology in the WashU Medicine Department of Pathology &. Immunology. A 2021 study, published in 2021, revealed that harmful substances produced by gut bacteria contribute to liver damage after bowel resection. However, the study also identified high-density lipoprotein (HDL), often referred to as “good” cholesterol, as a protective factor against this damage.
Inspired by these findings, the researchers focused on liver X receptor (LXR) agonists – a class of drugs known to increase HDL production. Previous attempts with systemic LXR agonists, which affect the entire body, were hampered by severe side effects. To overcome this challenge, the team, led by Randolph and Bahaa Elgendy, PhD, an associate professor of anesthesiology at WashU Medicine specializing in medicinal chemistry, sought to develop a “gut-restricted” LXR agonist. They utilized a compound initially identified by a pharmaceutical company but never commercially developed, synthesizing it specifically for this study.
The resulting compound, named WUSTL0717, demonstrated a targeted effect, remaining within the intestines when administered orally to mice. This localized action is crucial for minimizing systemic side effects, a major hurdle in previous LXR agonist research.
Promising Results in Preclinical Trials
Testing on mice revealed that WUSTL0717 significantly improved nutrient absorption and aided in weight gain three weeks after small bowel resection, compared to untreated mice. More importantly, the compound protected the liver from fibrosis – the accumulation of scar tissue that impairs liver function. Mice treated with WUSTL0717 exhibited reduced collagen levels in their livers, a key indicator of fibrosis, and a decrease in the activity of genes associated with scar tissue formation.
“Our future goal is to create the next generation of tissue-specific therapies that preserve therapeutic benefit while reducing unintended systemic effects,” said Elgendy. “This precision-based strategy allows us to revisit important biological targets that were previously considered too challenging to develop safely.”
The researchers have filed a patent for the utilize of WUSTL0717 to treat short bowel syndrome through WashU’s Office of Technology Management (OTM). Their next study will investigate whether the compound maintains its protective effects even with the added stress of intravenous nutrition, a common long-term treatment for short bowel syndrome that can itself contribute to liver damage.
Colin A. Martin, MD, the Brad and Barbara Warner Endowed Professor of Surgery at WashU Medicine, emphasized the potential impact of these findings. “The absence of therapies for patients with short bowel syndrome has profound implications for their long-term health,” said Martin. “These preclinical findings represent a crucial leap forward in our goal of developing a treatment that safeguards liver function and improves nutrient absorption, enhancing the quality of life for patients affected by short bowel syndrome.”
Reference: Kim A, Alligood DM, Maram L, et al. A gut-restricted liver X receptor agonist ameliorates liver injury in experimental short bowel syndrome. Gastroenterology. 2026:S0016508525066569. Doi: 10.1053/j.gastro.2025.12.015
The researchers are continuing to refine and test WUSTL0717, with the next phase of research focused on evaluating its efficacy alongside intravenous nutrition. This ongoing work represents a significant step toward developing a much-needed therapy for patients facing the challenges of short bowel syndrome and the risk of debilitating liver complications.
Have thoughts on this story? Share your comments below.
