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

doi:10.1172/jci.insight.174825

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

Rola Hammoud,¹ Kiran Deep Kaur,¹ Jacqueline A. Koehler,¹ Laurie L. Baggio,¹ Chi Kin Wong,¹ Katie E. Advani,¹ Bernardo Yusta,¹ Irina Efimova,² Fiona M. Gribble,³ Frank Reimann,³ Sigal Fishman,² Chen Varol,² and Daniel J. Drucker¹

Published December 26, 2024 - More info

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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 (GIPR)–GLP-1 receptor (GLP-1R) multi-agonists exemplified by tirzepatide and emerging GIPR antagonist-GLP-1R agonist therapeutics such as maritide is increasing interest in the extra-pancreatic actions of incretin therapies. Both GLP-1 and GIP modulate inflammation, with GLP-1 also acting locally to alleviate gut inflammation in part through anti-inflammatory 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 (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 non-immune cells, specifically stromal CD146⁺ cells. Hence, the extra-pancreatic 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.

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

Rola Hammoud,¹ Kiran Deep Kaur,¹ Jacqueline A. Koehler,¹ Laurie L. Baggio,¹ Chi Kin Wong,¹ Katie E. Advani,¹ Bernardo Yusta,¹ Irina Efimova,² Fiona M. Gribble,³ Frank Reimann,³ Sigal Fishman,² Chen Varol,² and Daniel J. Drucker¹

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

Rola Hammoud,1 Kiran Deep Kaur,1 Jacqueline A. Koehler,1 Laurie L. Baggio,1 Chi Kin Wong,1 Katie E. Advani,1 Bernardo Yusta,1 Irina Efimova,2 Fiona M. Gribble,3 Frank Reimann,3 Sigal Fishman,2 Chen Varol,2 and Daniel J. Drucker1

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Rola Hammoud,¹ Kiran Deep Kaur,¹ Jacqueline A. Koehler,¹ Laurie L. Baggio,¹ Chi Kin Wong,¹ Katie E. Advani,¹ Bernardo Yusta,¹ Irina Efimova,² Fiona M. Gribble,³ Frank Reimann,³ Sigal Fishman,² Chen Varol,² and Daniel J. Drucker¹