How Short Bowel Syndrome Treatments Induce Cellular Changes in the Intestine: Insights from a Longitudinal Study

Short bowel syndrome (SBS) remains a complex challenge in gastroenterology, affecting individuals who have lost substantial parts of their small intestine due to surgery, disease, or congenital disorders. Patients often face ongoing malnutrition and rely heavily on parenteral nutrition, which can diminish their quality of life and place significant pressure on healthcare resources.

While recent advances have improved prognosis, serious complications like bloodstream infections and liver failure caused by long-term intravenous feeding continue to pose serious risks. The advent of glucagon-like peptide-2 (GLP-2) analogs, especially teduglutide, has represented a breakthrough in SBS management. These drugs enhance nutrient absorption and reduce parenteral nutrition dependence by simulating the presence of natural GLP-2, a hormone vital for maintaining gut integrity.

Despite proven clinical benefits, the underlying cellular mechanisms through which GLP-2 analogs exert their effects have not been fully understood. Key questions remain about how they influence gut epithelial and immune cells, as well as the gut microbiome. Gaining clarity on these mechanisms is essential to refining and optimizing SBS treatments.

A pioneering longitudinal study led by Assistant Professor Yumi Kudo from Keio University’s Department of Pediatric Surgery aimed to fill this knowledge gap. The study, co-authored with colleagues including Associate Professor Tomohisa Sujino, involved tracking changes at the cellular level in patients undergoing teduglutide therapy. Over the course of a year, five male SBS patients provided intestinal biopsies, blood, and gut microbiome samples at three different points: before treatment, at six months, and at twelve months.

Utilizing advanced techniques such as single-cell RNA sequencing and ribosomal RNA sequencing, researchers observed dynamic transformations within the gut environment. The treatment promoted significant structural remodeling, notably an increase in the size of villi and crypts, which are essential for nutrient absorption. Immunologically, regulatory T cells that control inflammation increased, while inflammatory Th2 cells decreased, fostering a less reactive gut environment. The microbiome itself grew more diverse, with enhanced bacterial production of short-chain fatty acids, molecules known to support gut barrier function and immune regulation.

Cell analysis revealed a reduction in immune-related cells expressing MHC I/II genes and a corresponding rise in cells specialized for nutrient uptake, such as enterocytes. These data suggest that GLP-2 analog therapy facilitates an adaptive process in the intestine—enhancing nutrient absorption capacity while mitigating inflammation.

Dr. Kudo highlighted that these findings demonstrate how GLP-2 analogs reconfigure the immune system and microbiota, creating a more favorable environment for gut healing and function. This research provides vital insights into the molecular basis of SBS treatment and could inform future therapies, including applications for patients needing immunosuppression after transplants, owing to the therapy’s immune-modulating effects.

The study is the first to present concrete human-based evidence of the cellular adaptations driven by GLP-2 analogs. It exemplifies reverse translational research where clinical observations help to elucidate underlying biological processes, paving the way for improved clinical strategies and targeted therapies. Continued research will help clarify additional effects of these drugs and expand their potential for treating gastrointestinal and immune-related disorders.