New drug protects liver after intestinal surgery and boosts nutrient absorption

Researchers at Washington University School of Medicine in St. Louis have developed a new compound and tested it in mice. Their findings suggest the drug may protect the liver while also improving the body's ability to absorb nutrients after surgery. Importantly, the compound works only within the gastrointestinal tract, which may help avoid unwanted side effects elsewhere in the body.

The study is published March 6 in Gastroenterology.

"Our goal is to advance a therapeutic drug capable of preserving liver function and mitigating the necessity for liver transplants in people who've undergone small bowel surgery," said Gwendalyn Randolph, PhD, the study's senior author and the Emil R. Unanue Distinguished Professor of Immunology in the WashU Medicine Department of Pathology & Immunology. "This study offers a promising pathway for developing such a treatment."

Short Bowel Syndrome and Long-Term Risks

Patients who undergo small bowel resection include premature infants with necrotizing enterocolitis, a severe intestinal disease that requires removal of damaged tissue. After surgery, many develop short bowel syndrome, a condition in which the shortened intestine struggles to absorb nutrients effectively.

Children with this condition often depend on long-term intravenous feeding through a pump. While necessary, this approach can further strain the liver. As a result, these patients face a high risk of liver disease and may eventually need a transplant.

Gut Bacteria, "Good" Cholesterol, and Liver Protection

The late Brad Warner, MD, a pediatric surgeon and researcher at WashU Medicine, focused much of his work on improving outcomes for children with short bowel syndrome. In a 2021 study conducted with Randolph, researchers discovered that substances produced by gut bacteria can travel to the liver after surgery and cause damage.

They also found that high-density lipoprotein, or HDL, often called "good" cholesterol, can help protect the liver by blocking these harmful substances.

Targeting the Gut Without Whole-Body Side Effects

Building 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. Earlier versions of these drugs affected the entire body and caused serious side effects.

To address this issue, the scientists tested a "gut-restricted" version designed to act only in the intestines. The compound, originally identified by a pharmaceutical company but never brought to market, was synthesized for this study by Bahaa Elgendy, PhD, an associate professor of anesthesiology at WashU Medicine and a co-author with expertise in medicinal chemistry.

When given orally to mice, the compound, called WUSTL0717, remained in the intestines rather than spreading throughout the body.

Improved Nutrient Absorption and Reduced Weight Loss

The researchers evaluated whether WUSTL0717 could counteract the severe weight loss that often follows small bowel resection. Mice treated with the drug three weeks after surgery showed improved nutrient absorption and gained more weight compared to untreated mice.

Reduced Liver Scarring and Healthier Liver Function

The team also found that the compound protected the liver from fibrosis, a buildup of scar tissue that interferes with normal function. Treated mice had lower levels of collagen, a major component of scar tissue, than untreated mice or those that underwent a sham procedure in which the intestine was cut and reconnected without removing tissue.

Further analysis showed reduced activity in genes linked to fibrosis, including those involved in collagen production, in the livers of treated mice.

"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."

Next Steps Toward a Potential Treatment

The researchers have filed a patent through WashU's Office of Technology Management (OTM) for the use of WUSTL0717 in treating short bowel syndrome. Future studies will test whether the compound remains effective when patients are also receiving intravenous nutrition, which can place additional stress on the liver.

"The absence of therapies for patients with short bowel syndrome has profound implications for their long-term health," said Colin A. Martin, MD, the Brad and Barbara Warner Endowed Professor of Surgery at WashU Medicine and a co-author of the study. "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."

This work was supported by the National Institutes of Health, grant numbers 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; the Children's Discovery Institute, grant numbers CDI-CORE-2015-505 and CDI-CORE-2019-813; the Foundation for Barnes-Jewish Hospital, grant numbers 3770 and 4642. 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, Warner B, Elgendy B, and Randolph G are part of an intellectual property claim for the use of intestinal LXR agonists to treat SBS, US Patent Application No. 18/997, 728 entitled "Compositions for the Treatment of Intestinal Failure and Use Thereof."