Researchers at Washington University School of Medicine in St. Louis have developed a new compound that could help protect the liver from damage after radical small bowel resection surgery, according to findings published March 6 in Gastroenterology.
Small bowel resection, which involves removing diseased or dead sections of the small intestine, is sometimes necessary to save lives but can result in long-term liver complications for up to 15% of patients. These complications may require a liver transplant and there are currently no approved medications to prevent or manage them.
The new study focused on a group of drugs called liver X receptor agonists, which are known to increase production of high-density lipoprotein (HDL), often referred to as "good" cholesterol. Previous research by WashU scientists showed that HDL could protect the liver from harmful substances produced by gut bacteria following bowel surgery.
Earlier attempts with systemic versions of these drugs led to severe side effects throughout the body. The WashU team instead tested a "gut-restricted" version—meaning it works only within the intestines—to avoid such issues. The compound, named WUSTL0717, was synthesized by Bahaa Elgendy, PhD, an associate professor of anesthesiology at WashU Medicine and co-author on the study.
Testing in mice showed that WUSTL0717 remained in the intestines when given orally and improved nutrient absorption and weight gain three weeks after surgery compared with untreated mice. It also reduced signs of fibrosis—the build-up of scar tissue—in the livers of treated animals.
Genetic analysis found decreased activity in genes linked to fibrosis and collagen accumulation among treated mice compared with those who received no treatment or underwent sham surgeries.
"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 research team has filed a patent for using WUSTL0717 to treat short bowel syndrome through Washington University's Office of Technology Management. They plan further studies to determine if the compound remains effective when combined with intravenous nutrition—a common intervention for children who have undergone this type of surgery but one that itself can cause liver damage over time.
"The absence of therapies for patients with short bowel syndrome has profound implications for their long-term health," said Colin A. Martin, MD, Brad and Barbara Warner Endowed Professor of Surgery at WashU Medicine and pediatric surgeon. "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."
