New Drug Shows Promise in Preventing Liver Damage After Small Bowel Surgery | Short Bowel Syndrome Treatment

A new compound, tested in mice, shows promise in protecting the liver and improving nutrient absorption following radical small bowel resection – a surgical procedure to remove diseased or damaged sections of the small intestine. This development offers a potential pathway to reduce the need for liver transplants in patients who undergo this life-saving, yet often complicated, surgery. Currently, up to 15% of patients experience long-term liver complications after small bowel resection, and We find no existing medications specifically designed to prevent or treat this issue.

Short Bowel Syndrome and the Liver’s Vulnerability

Radical small bowel resection is often necessary for premature infants with necrotizing enterocolitis, a severe intestinal disease, and for adults facing conditions like Crohn’s disease or cancer. But, removing significant portions of the small intestine can lead to short bowel syndrome (SBS), where the remaining intestine struggles to adequately absorb nutrients. Patients with SBS frequently require long-term intravenous (IV) feeding, which, while life-sustaining, can place a considerable burden on the liver. This increased stress elevates the risk of liver disease and, liver failure requiring transplantation.

Researchers at Washington University School of Medicine in St. Louis have been investigating the underlying mechanisms linking intestinal surgery to liver damage. A 2021 study, conducted in collaboration with the late Brad Warner, MD, a pediatric surgeon at WashU Medicine, revealed that substances produced by gut bacteria can travel to the liver after surgery and contribute to damage. Conversely, the study as well found that high-density lipoprotein (HDL), often referred to as “good” cholesterol, can offer protection by blocking these harmful substances. American Journal of Transplantation details the evolving understanding of visceral transplantation in patients with intestinal failure associated liver disease.

A Gut-Restricted Approach to Liver Protection

Building on these findings, the research team focused on liver X receptor (LXR) agonists – a class of drugs known to increase HDL production in both the liver and intestines. Previous iterations of these drugs had systemic effects, causing unwanted side effects throughout the body. To overcome this challenge, the team developed a “gut-restricted” version of an LXR agonist, designed to act solely within the intestines. This compound, originally identified by a pharmaceutical company but never brought to market, was synthesized for the study by Bahaa Elgendy, PhD, an associate professor of anesthesiology at WashU Medicine.

The compound, named WUSTL0717, demonstrated a remarkable ability to remain localized within the intestines when administered orally to mice, minimizing the risk of systemic side effects. This targeted approach is a significant step forward in developing safer and more effective therapies.

Improved Outcomes in Mouse Models

The researchers evaluated WUSTL0717’s effectiveness in counteracting the weight loss commonly observed after small bowel resection. Mice treated with the drug three weeks post-surgery exhibited improved nutrient absorption and gained more weight compared to untreated control groups. Importantly, the study, published March 6 in Gastroenterology, also revealed a protective effect on the liver.

Treated mice showed reduced liver fibrosis – the buildup of scar tissue that impairs liver function. Analysis revealed lower levels of collagen, a key component of scar tissue, and decreased activity in genes associated with fibrosis, including those involved in collagen production. This suggests that WUSTL0717 can actively mitigate the development of liver damage following intestinal surgery.

Beyond the Mouse Model: Next Steps and Potential Applications

The research team has filed a patent application for the utilize of WUSTL0717 in treating short bowel syndrome through WashU’s Office of Technology Management. Future studies will investigate the compound’s efficacy in patients receiving concurrent IV nutrition, a common scenario that can further stress the liver.

“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.”

Colin A. Martin, MD, the Brad and Barbara Warner Endowed Professor of Surgery at WashU Medicine, emphasized the profound implications of this research. “The absence of therapies for patients with short bowel syndrome has profound implications for their long-term health,” he stated. “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.”

Combined small bowel and reduced auxiliary liver transplantation is an established therapy for liver disease and intestinal failure. World J Gastroenterol details this process.

While this research is still in its early stages, the development of WUSTL0717 represents a promising advancement in the treatment of short bowel syndrome and a potential strategy to reduce the need for liver transplantation in vulnerable patients. Further research and clinical trials will be crucial to determine the compound’s safety and efficacy in humans. A related study published in Drug Target Review highlights a similar approach to protecting liver health after small bowel surgery, though focusing on a different compound and mechanism.