A longitudinal single cell analysis of GLP-2 treatment in the patients with short bowel syndrome

A glucagon-like peptide-2 (GLP-2) analog is clinically used to enhance nutrient absorption in patients with short bowel syndrome (SBS); however, its precise mechanism remains unclear. To address this, we conducted longitudinal single-cell RNA sequencing (scRNA-seq) of intestinal tissue from patients with SBS over a year, integrating microbiome composition analysis. Post-treatment, the beta diversity of the gut microbiome increased, indicating a more varied microbial environment. scRNA-seq analysis revealed a decrease in TCRγδ cells and an increase in regulatory T (Treg) cells, suggesting a shift towards an immunoregulatory intestinal environment. Additionally, nutrient-absorbing enterocyte-top2 and middle clusters expanded, enhancing the absorption capacity, whereas MHC class I/II-expressing enterocyte-top1 cells declined, potentially modulating immune responses. Our study employed a cutting-edge longitudinal single-cell approach to track cellular dynamics in response to GLP-2 analog treatment. These findings indicate that GLP-2 analogs reshape intestinal immunity and microbiota, fostering a less inflammatory environment, while promoting nutrient uptake efficiency. These insights offer a deeper understanding of GLP-2’s role in gut adaptation and provide a foundation for refining the clinical strategies for SBS treatment.