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 6

BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation in the context of global Gipr deficiency.

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BM-derived Gipr-expressing cells suppress 5FU-induced gut inflammation i...
(A) Percentage of sorted CD45.1+ and CD45.2+ cells out of total CD45+ cells in the peripheral blood of Gipr–/– and Gipr+/+ CD45.2 recipient mice transplanted with BM from WT CD45.1 mice (i.e., Gipr+/+BM-WT versus Gipr–/–BM-WT) (n = 10–16) as depicted in Supplemental Figure 8A. (B and C) BM Gipr expression relative to Rpl32 (n = 4–11) and ileal Gipr and Gip expression relative to Tbp in Gipr+/+BM-WT and Gipr–/–BM-WT mice with or without 5FU exposure (n = 5–12). (D) Total plasma GIP concentration (n = 5–12). (E and F) Ileal gene expression (E) relative to Tbp and protein expression (F) of cytokines (n = 5–12). (G) Plasma cytokine concentrations (n = 5–12). Data are presented as mean ± SD of samples pooled from 3 independent mouse cohorts. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001 by 2-way ANOVA followed by Tukey post hoc tests.