When part of the small intestine becomes diseased or dies, surgeons often have to remove the damaged tissue. This surgery, known as radical small bowel resection, can save lives. However, this has a major drawback. Many patients subsequently develop serious liver problems, including liver failure that requires long-term damage and transplantation. Currently, no drugs exist to prevent or treat this complication, which affects up to 15% of patients after surgery.
Researchers at Washington University School of Medicine in St. Louis developed a new compound and tested it in mice. Their findings suggest that the drug may protect the liver while improving the body’s ability to absorb nutrients after surgery. Importantly, this compound only acts within the gastrointestinal tract, so it may help avoid unwanted side effects elsewhere in the body.
The study was published on March 6th. Gastroenterology.
“Our goal is to advance therapeutics that can preserve liver function and reduce the need for liver transplantation in people who have undergone small intestine surgery,” said Gwendalyn Randolph, Ph.D., lead author of the study and the Emil R. Unanue Distinguished Professor of Immunology in the Department of Pathology and Immunology at WashU School of Medicine. “This study provides a promising path to developing such treatments.”
Short bowel syndrome and long-term risks
Patients undergoing small bowel resections also include premature infants with necrotizing enterocolitis, a severe intestinal disease that requires removal of damaged tissue. After surgery, many people develop short bowel syndrome. This is a condition in which the shortened intestines struggle to absorb nutrients effectively.
Children with this condition often rely on long-term parenteral nutrition through a pump. Although necessary, this approach can place additional stress on the liver. As a result, these patients face a higher risk of liver disease and may ultimately require transplantation.
Gut bacteria, “good” cholesterol, and liver protection
The late Dr. Brad Warner, a pediatric surgeon and researcher at WashU Medicine, has focused much of his research on improving outcomes for children with short bowel syndrome. In a 2021 study conducted in collaboration with Randolph, researchers found that substances produced by gut bacteria can migrate to the liver after surgery and cause damage.
They also discovered that high-density lipoprotein (HDL), often referred to as “good” cholesterol, helps protect the liver by blocking these harmful substances.
Targets the gut without side effects throughout the body
Based on these findings, the research team turned to a class of drugs known as liver X receptor agonists, which increase HDL production in the liver and intestines. Previous versions of these drugs affected the entire body and caused severe side effects.
To address this issue, scientists tested “gut-restricted” versions designed to work only in the intestines. The compound, originally identified by a pharmaceutical company but never brought to market, was synthesized for this study by co-author Dr. Bahaa Elgendy, an associate professor of anesthesiology at WashU Medicine and with expertise in medicinal chemistry.
When the compound, called WUSTL0717, was given orally to mice, it remained in the intestines instead of spreading throughout the body.
Improved nutrient absorption and reduced weight loss
Researchers evaluated whether WUSTL0717 could reduce the severe weight loss that often occurs after small bowel resection. Mice treated with the drug three weeks after surgery showed improved nutrient absorption and increased body weight compared to untreated mice.
Reduced liver scarring and healthier liver function
The research team also found that the compound protects the liver from fibrosis, the buildup of scar tissue that interferes with normal function. Treated mice had lower levels of collagen, a key component of scar tissue, than untreated mice or mice that received a sham procedure in which the intestines were cut and reattached without removing any tissue.
Further analysis showed that the livers of treated mice had reduced activity of genes associated with fibrosis, including genes involved in collagen production.
“Our future goal is to develop next-generation tissue-specific treatments that maintain therapeutic efficacy while reducing unintended systemic effects,” said Ergendy. “This precision-based strategy allows us to re-address important biological targets that were previously considered too difficult to develop safely.”
Next steps towards potential treatments
The researchers filed a patent application through WashU’s Office of Technology Management (OTM) for the use of WUSTL0717 in the treatment of short bowel syndrome. Future studies will test whether the compound’s effects last longer when patients are also receiving parenteral nutrition, which can put additional stress on the liver.
“The lack of a treatment for patients with short bowel syndrome has serious implications for their long-term health,” said Colin A. Martin, MD, Brad and Barbara Warner Endowed Professor of Surgery at WashU Medicine and co-author of the study. “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.”
This research was supported by the National Institutes of Health. Grant number R01DK119147, R01AI168044, U01AI63064, T32AI007163, T32AR007279, DK077653, R01NS134932, S10OD030332, P30 DK020579, P30 DK052574, P30 AR074992, P30 CA91842, P30 CA091842, UL1 TR002345, UL1 TR002345 and P30 DK020579; Children’s Discovery Institute, grant numbers CDI-CORE-2015-505 and CDI-CORE-2019-813. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Conflict of interest: Authors Kim A, Werner B, Ergendy B, and Randolph G are part of the intellectual property claim for the use of intestinal LXR agonists to treat SBS, US patent application Ser.
