Glucose-dependent insulinotropic polypeptide receptor signaling alleviates gut inflammation in mice
Rola Hammoud, Kiran Deep Kaur, Jacqueline A. Koehler, Laurie L. Baggio, Chi Kin Wong, Katie E. Advani, Bernardo Yusta, Irina Efimova, Fiona M. Gribble, Frank Reimann, Sigal Fishman, Chen Varol, Daniel J. Drucker
Rola Hammoud, Kiran Deep Kaur, Jacqueline A. Koehler, Laurie L. Baggio, Chi Kin Wong, Katie E. Advani, Bernardo Yusta, Irina Efimova, Fiona M. Gribble, Frank Reimann, Sigal Fishman, Chen Varol, Daniel J. Drucker
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Research Article Endocrinology

Glucose-dependent insulinotropic polypeptide receptor signaling alleviates gut inflammation in mice

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are gut-derived peptide hormones that potentiate glucose-dependent insulin secretion. The clinical development of GIP receptor–GLP-1 receptor (GIPR–GLP-1R) multiagonists exemplified by tirzepatide and emerging GIPR antagonist–GLP-1R agonist therapeutics such as maritide is increasing interest in the extrapancreatic actions of incretin therapies. Both GLP-1 and GIP modulate inflammation, with GLP-1 also acting locally to alleviate gut inflammation in part through antiinflammatory actions on GLP-1R+ intestinal intraepithelial lymphocytes. In contrast, whether GIP modulates gut inflammation is not known. Here, using gain- and loss-of-function studies, we show that GIP alleviates 5-fluorouracil–induced (5FU-induced) gut inflammation, whereas genetic deletion of Gipr exacerbates the proinflammatory response to 5FU in the murine small bowel (SB). Bone marrow (BM) transplant studies demonstrated that BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation in the context of global Gipr deficiency. Within the gut, Gipr was localized to nonimmune cells, specifically stromal CD146+ cells. Hence, the extrapancreatic actions of GIPR signaling extend to the attenuation of gut inflammation, findings with potential translational relevance for clinical strategies modulating GIPR action in people with type 2 diabetes or obesity.

Authors

Rola Hammoud, Kiran Deep Kaur, Jacqueline A. Koehler, Laurie L. Baggio, Chi Kin Wong, Katie E. Advani, Bernardo Yusta, Irina Efimova, Fiona M. Gribble, Frank Reimann, Sigal Fishman, Chen Varol, Daniel J. Drucker

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Figure 2

GIPR agonism protects against high-dose 5FU–induced gut damage and inflammation.

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GIPR agonism protects against high-dose 5FU–induced gut damage and infla...
(A) Schematic representation of the experimental protocol. (B–D) Body weight, small bowel weight and length adjusted for tibia length as well as SB weight/length ratio (n = 10), and gut permeability measured as the concentration of plasma ovalbumin 3 hours after oral ovalbumin gavage (n = 5). (E) Representative images for ileum stained with H&E, anti-Ki67, anti-neutrophil elastase (anti-NE), and anti-CD68 antibody (magnification, 20×). Scale bar: 50 μm. (F) Quantification of villus height, crypt depth, and crypt density (n = 8–9). (G) Average number of Ki67+ cells per ring (n = 9–10). (H) Average number of NE+ cells per ring (n = 7–10). (I) Average positive area of CD68+ signal per ring (n = 8–10). (J) Ileal gene expression relative to Ppia of inflammatory markers in response to 5FU and [DAla2 ]-GIP coadministration (n = 9–10). (K and L) Representative images (magnification, 20×). Scale bar: 50 μm. Quantification of anti-NE staining within the ileum of mice treated with either Veh, 5FU, 5FU and semaglutide (Sema, 10 nmol/kg/day), or 5FU and tirzepatide (TZP, 3 nmol/kg/day) (n = 8–10). Data are presented as mean ± SD of samples pooled from 2 independent mouse cohorts. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001 by 2-way ANOVA followed by Tukey post hoc tests (B–D, F–J) and by 1-way ANOVA followed by Dunnett’s test with 5FU as the control (L).