Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans

Johana Norona, Petya Apostolova, Dominik Schmidt, Rebekka Ihlemann, Nadine Reischmann, Gregory Taylor, Natalie Köhler, Jocelyn de Heer, Steffen Heeg, Geoffroy Andrieux, Benjamin A. Siranosian, Annette Schmitt-Graeff, Dietmar Pfeifer, Antonella Catalano, Ian J. Frew, Michele Proietti, Bodo Grimbacher, Alla Bulashevska, Ami S. Bhatt, Tilman BrummerTill Clauditz, Tatjana Zabelina, Nicolaus Kroeger, Bruce R. Blazar, Melanie Boerries, Francis Ayuk, Robert Zeiser

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagonlike- peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2-based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.

Original languageEnglish (US)
Pages (from-to)1442-1455
Number of pages14
Issue number12
StatePublished - Sep 17 2020

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