If part of the small intestine becomes diseased or dies, treatment may include surgically removing the affected tissue. Although this surgery, called radical small bowel resection, is lifesaving, it can lead to long-term liver damage and liver failure, requiring a liver transplant. There are no medications to prevent or manage this serious complication, which is reported to affect up to 15% of patients after small bowel resection.
Now, researchers at Washington University School of Medicine in St. Louis have synthesized and tested in mice a new compound that may protect the liver from damage and improve nutrient absorption after small intestine resection. They also found that the drug only acts on the gastrointestinal tract, helping to avoid side effects in other parts of the body.
The study will be published March 6 in the journal Gastroenterology.
Our goal is to develop treatments that can preserve liver function and reduce the need for liver transplantation in people who have undergone small intestine surgery. This study provides a promising path to developing such treatments. ”
Dr. Gwendalyn Randolph, senior author of the study, Emil R. Unanyu Distinguished Professor of Immunology, Department of Pathology and Immunology, Washington University School of Medicine
Protects the liver through the intestines
People treated with small bowel resection include premature infants with necrotizing enterocolitis. Necrotizing enterocolitis is a serious gastrointestinal disease that requires surgery to remove dying intestinal tissue. However, this surgery causes short bowel syndrome, which is characterized by a shortened intestine and difficulty absorbing nutrients. Children with this condition often require long-term use of a feeding pump to deliver nutrients directly into their veins. They also have a higher risk of liver disease, and in some cases may need a liver transplant later in life.
The late Dr. Brad Warner, a pediatric surgeon and researcher at WashU Medicine specializing in pediatric gastrointestinal surgery, dedicated his research to improving outcomes for short bowel syndrome. A joint study with Randolph published in 2021 found that after small bowl resection, harmful substances produced by intestinal bacteria migrate to the liver and cause liver damage. But they also observed that high-density lipoproteins (HDL), often referred to as “good” cholesterol, may act as a protective shield that prevents gut-derived substances from harming the liver.
In the new study, co-authored by Warner, the researchers focused on a class of drugs called liver X receptor agonists that increase HDL production in the liver and intestines. Previous studies of this class of drugs found that drugs that act systemically (systemic liver X receptor agonists) cause severe side effects. So the research team set out to test “gut-only” liver X receptor agonists, which affect only the intestines and not other parts of the body. They used a compound that was originally identified by a pharmaceutical company but never developed commercially. For this study, it was synthesized by Dr. Bahaa Elgendy, an associate professor of anesthesiology at WashU Medicine and co-author of the study, with expertise in medicinal chemistry.
Researchers found that the new compound, named WUSTL0717, reached and remained in the intestines when administered orally to mice.
We next tested whether WUSTL0717 could prevent the irreversible weight loss that commonly occurs after small bowel resection. They found that administering the drug to mice three weeks after small intestine resection improved nutrient absorption and promoted weight gain compared to untreated mice.
Researchers also found that the drug protects the liver from fibrosis, a buildup of scar tissue that impairs liver function. Intestine-resected mice treated with WUSTL0717 had less collagen in their livers, a key component of scar tissue, compared to untreated mice or mice that underwent sham surgery, in which the small intestine was severed and quickly reattached without removing any tissue. Genetic analysis also revealed reduced activity of genes associated with fibrosis, including genes involved in collagen accumulation, in the livers of treated mice.
“Our future goal is to develop next-generation tissue-specific treatments that maintain therapeutic efficacy while reducing unintended systemic effects,” said Ergendy, whose research aims to develop treatments that specifically activate LXR receptors only in the tissues where they are needed, in order to improve the efficacy of current LXR-based treatments and reduce side effects. “This precision-based strategy allows us to re-address important biological targets that were previously considered too difficult to develop safely.”
The researchers, in collaboration with WashU’s Office of Technology Management (OTM), have filed a patent for the use of WUSTL0717 in the treatment of short bowel syndrome. Their next study will examine whether the compound protects the liver despite the added stress of parenteral nutrition, since long-term use of parenteral nutrition has negative effects on the liver.
“The lack of a treatment for patients with short bowel syndrome has serious implications for their long-term health,” said study co-author Colin A. Martin, MD, the Brad and Barbara Warner Endowed Professor of Surgery at Wash U School of Medicine, a pediatric surgeon who treats children with the gastrointestinal disease. “These preclinical findings represent an important step forward in our goal of developing treatments that protect liver function, improve nutrient absorption, and improve the quality of life for patients affected by short bowel syndrome.”
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Reference magazines:
Kim, A. others. (2026). Intestinal-restricted liver X receptor agonists ameliorate liver damage in experimental short bowel syndrome. Gastroenterology. DOI: 10.1053/j.gastro.2025.12.015. https://www.gastrojournal.org/article/S0016-5085(25)06656-9/fulltext
