Longitudinal study reveals how GLP-2 analog therapy transforms the intestinal environment

Researchers from Japan discover that glucagon-like peptide-2 (GLP-2) analogs can deeply and beneficially reshape the intestinal environment.

Short bowel syndrome (SBS) represents one of the most challenging conditions in gastroenterology, affecting patients who have lost significant portions of their small intestine due to surgery, disease, or congenital abnormalities. Patients with SBS often struggle with chronic malnutrition and depend heavily on parenteral (intravenous) nutrition, which can severely impact their quality of life and impose a substantial burden on healthcare systems. Although the prognosis of SBS has improved in recent years, life-threatening complications such as catheter-related bloodstream infections and liver failure due to parenteral nutrition remain major concerns.

Glucagon-like peptide-2 (GLP-2) analogs, particularly teduglutide, have emerged as a significant breakthrough in treating SBS. These compounds help patients improve nutrient absorption and reduce their dependence on parenteral nutrition by mimicking the effect of GLP-2, an intestinal hormone responsible for maintaining gut health. Unfortunately, while their clinical effectiveness is well-established, the precise way in which these treatments work at the cellular level within the human body remain unclear. More specifically, the way in which these molecules affect the gut's epithelial cells and immune cells, as well as how they influence the gut microbiome, are largely unknown. Understanding these mechanisms is crucial for optimizing current SBS therapies.

To address this knowledge gap, a research team led by Assistant Professor Yumi Kudo from the Department of Pediatric Surgery, School of Medicine at Keio University, Japan, conducted the first comprehensive longitudinal study examining how GLP-2 analog therapy transforms the intestinal environment at the cellular level. The study, co-authored by Associate Professor Tomohisa Sujino, Professor Akihiro Fujino, and Senior Assistant Professor Yohei Yamada from Keio University, will be published in the journal JCI Insight on September 23, 2025.

The researchers tracked five male patients with SBS over a period of one year of teduglutide treatment. They collected intestinal tissue biopsies, blood samples, and gut microbiome samples from the patients at three time points: before the start of treatment, at six months into the treatment, and at 12 months into the treatment. Using the technique of single-cell RNA sequencing, the researchers were able to examine individual cells and identify how different cell populations changed over time. In addition, they used ribosomal RNA sequencing to monitor shifts in the gut microbiome composition and cell population over time. This longitudinal approach provided detailed insights into the progressive transformations in the intestinal environment during the treatment phase.

Their findings revealed a vast post-treatment remodeling of the intestinal ecosystem. Patients showed significant clinical improvements, including weight gain, a reduced need for intravenous nutrition, and increased levels of serum biomarkers that indicate better nutrient absorption. At the cellular level, the researchers discovered that treatment with GLP-2 analog promoted the expansion of the villi (nutrient-absorbing structures) and intestinal crypts. Moreover, the population of regulatory T cells, which help control inflammation, increased substantially, while that of inflammatory Th2 cells decreased. The gut microbiome also became more diverse, with higher alpha diversity and increased bacterial production of short-chain fatty acids, compounds that support intestinal barrier function and regulate immune responses.

Through careful analysis, the team found that cells that expressed immune-related genes (MCH I/II-expressing Top1 cluster) decreased, while cells specialized for nutrient absorption (enterocyte-Top2 and middle clusters) expanded. This shift suggested that GLP-2 analog therapy leads to beneficial adaptations for patients struggling with malabsorption. "Our findings indicate that GLP-2 analogs reshape intestinal immunity and microbiota, fostering a less inflammatory environment while promoting nutrient uptake efficiency," explains Dr. Kudo. "These insights offer a deeper understanding of the role of GLP-2 analogs in gut adaptation and provide a foundation for refining clinical strategies for SBS treatment."

Notably, these results have important implications beyond SBS. GLP-2 analogs could potentially benefit patients requiring immunosuppression, such as those who have undergone bone marrow or organ transplantation. By promoting a less inflammatory intestinal environment and enhancing nutrient absorption, these therapies could also help address malabsorption issues common in immunocompromised patients. "To our knowledge, this is the first study to provide human-based evidence supporting the efficacy of GLP-2 analogs. It also represents a rare example of reverse translational research, wherein clinical findings precede and inform subsequent basic research," concludes Dr. Sujino.

Further research efforts in this direction can help clarify the various effects of GLP-2 analogs, solidifying their potential for providing effective treatments for gastrointestinal and possibly immune-related disorders.