Longitudinal single-cell analysis of glucagon-like peptide-2 treatment in patients with short bowel syndrome
Yumi Kudo, Kentaro Miyamoto, Shohei Suzuki, Akihiko Chida, Anna Tojo, Mai Hasegawa, Arina Shigehara, Ikuko Koya, Yoshinari Ando, Masayasu Sato, Aya Kondo, Tomoko Kumagai, Harunori Deguchi, Yoshiki Sugiyama, Yoko Ito, Koji Shirosaki, Satoko Yamagishi, Yutaro Maeda, Hiroki Kanamori, Motohiro Kano, Mototoshi Kato, Hanako Tsujikawa, Yusuke Yoshimatsu, Kaoru Takabayashi, Koji Okabayashi, Takanori Kanai, Naoki Hosoe, Motohiko Kato, Jonathan Moody, Chung-Chau Hon, Tatsuo Kuroda, Yohei Yamada, Akihiro Fujino, Tomohisa Sujino
Yumi Kudo, Kentaro Miyamoto, Shohei Suzuki, Akihiko Chida, Anna Tojo, Mai Hasegawa, Arina Shigehara, Ikuko Koya, Yoshinari Ando, Masayasu Sato, Aya Kondo, Tomoko Kumagai, Harunori Deguchi, Yoshiki Sugiyama, Yoko Ito, Koji Shirosaki, Satoko Yamagishi, Yutaro Maeda, Hiroki Kanamori, Motohiro Kano, Mototoshi Kato, Hanako Tsujikawa, Yusuke Yoshimatsu, Kaoru Takabayashi, Koji Okabayashi, Takanori Kanai, Naoki Hosoe, Motohiko Kato, Jonathan Moody, Chung-Chau Hon, Tatsuo Kuroda, Yohei Yamada, Akihiro Fujino, Tomohisa Sujino
View: Text | PDF
Clinical Research and Public Health Clinical Research Gastroenterology

Longitudinal single-cell analysis of glucagon-like peptide-2 treatment in patients with short bowel syndrome

Abstract

BACKGROUND Glucagon-like peptide-2 (GLP-2) analogs are used clinically to enhance nutrient absorption in patients with short bowel syndrome (SBS); however, the precise mechanism remains unclear. To address this, the study aimed to clarify the dynamics of intestinal epithelial cells and immune cells in patients with SBS treated with GLP-2 analogs.METHODS Five male patients diagnosed with SBS, all of whom received treatment with the GLP-2 analog teduglutide, were included in the study. We conducted longitudinal single-cell RNA sequencing (scRNA-Seq) analysis of intestinal tissue from patients with SBS over a year, integrating microbiome composition analysis.RESULTS After treatment, the α-diversity of the gut microbiome increased, indicating a more varied microbial environment. ScRNA-Seq analysis revealed a reduction of T helper 2 cells and an increase in regulatory T cells, suggesting a shift toward an immunoregulatory intestinal environment. Additionally, nutrient-absorbing enterocyte-Top2 and middle clusters expanded, enhancing the absorption capacity, whereas major histocompatibility complex class I/II–expressing enterocyte-Top1 cells declined, potentially modulating immune responses.CONCLUSION The study 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 the role of GLP-2 analogs in gut adaptation and provide a foundation for refining clinical strategies for SBS treatment.FUNDING This work was supported by Sakaguchi Memorial Foundation, Grants-in-Aid from the Japanese Society for the Promotion of Science (JSPS) (21K18272, 23H03665, 23H02899, 23K27590, 25K22627, 23K08037), JST FOREST(21457195), and the Takeda Japan Medical Office Funded Research Grant 2022.

Authors

Yumi Kudo, Kentaro Miyamoto, Shohei Suzuki, Akihiko Chida, Anna Tojo, Mai Hasegawa, Arina Shigehara, Ikuko Koya, Yoshinari Ando, Masayasu Sato, Aya Kondo, Tomoko Kumagai, Harunori Deguchi, Yoshiki Sugiyama, Yoko Ito, Koji Shirosaki, Satoko Yamagishi, Yutaro Maeda, Hiroki Kanamori, Motohiro Kano, Mototoshi Kato, Hanako Tsujikawa, Yusuke Yoshimatsu, Kaoru Takabayashi, Koji Okabayashi, Takanori Kanai, Naoki Hosoe, Motohiko Kato, Jonathan Moody, Chung-Chau Hon, Tatsuo Kuroda, Yohei Yamada, Akihiro Fujino, Tomohisa Sujino

×

Figure 1

GLP-2 analog is effective for patients with SBS.

Options: View larger image (or click on image) Download as PowerPoint
GLP-2 analog is effective for patients with SBS. (A) Study design: Five ...
(A) Study design: Five male patients with short bowel syndrome (SBS) were enrolled and treated with the glucagon-like peptide-2 (GLP-2) analog teduglutide. Serum samples, intestinal tissue biopsies, luminal microbiome samples, and clinical records were collected at 3 time points: before treatment (0 months, 0M), 6 months after initiation (6M), and 12 months after initiation (12M). Intestinal microbiomes were analyzed using 16S ribosomal RNA (16S rRNA) sequencing, and intestinal tissue samples underwent histological examination and single-cell RNA sequencing (scRNA-Seq). (B and D) Body weight (B) and stool output (D): Each line represents changes in body weight or stool weight for an individual patient across the 3 time points. (C) Parenteral fluid volume: Each dot represents the volume of parenteral fluid administered to an individual patient across the 3 time points; bars indicate the mean ± SD. (E) The eicosatrienoic acid/arachidonic acid (T/T) ratio in blood: The left panel shows changes in the T/T ratio at the 3 time points. The right panel compares the T/T ratio before treatment (0M) with posttreatment (either 6M or 12M, with the later time point selected). Each dot represents an individual sample; bars indicate the mean ± SD. Values are log-transformed. (F) Blood biomarkers: Changes in blood levels of lipase and citrulline at the 3 time points. (G) Intestinal villi length: Changes in the total villus length (sum of villus height and crypt depth) at the 3 time points based on histological analysis. Each dot represents an individual sample; bars indicate the mean ± SD. Due to missing crypt depth data for case 4 at 6M, this data point was excluded. Statistical analyses included the 1-tailed paired t tests (B–F) and the Mann-Whitney test (G). IE, intestinal epithelium; LP, lamina propria; N/A, not available due to missing crypt depth data.