GLP-1R signaling modulates colonic energy metabolism, goblet cell number and survival in the absence of gut microbiota.

Objectives: Gut microbiota increases energy availability through fermentation of dietary fibers to short-chain fatty acids in conventionally raised mice. Energy deficiency in germ-free (GF) mice increases glucagon-like peptide-1 (GLP-1) levels, which slows intestinal transit. To further analyze the role of GLP-1-mediated signaling in this model of energy deficiency, we re-derived mice lacking GLP-1 receptor (GLP-1R KO) as GF.
Methods: GLP-1R KO mice were rederived as GF through hysterectomy and monitored for 30 weeks. Mice were subjected to rescue experiments either through feeding an energy-rich diet or colonization with a normal cecal microbiota. Histology and intestinal function were assessed at different ages. Intestinal organoids were assessed to investigate stemness.
Results: Unexpectedly, 25% of GF GLP-1R KO mice died before 20 weeks of age, associated with enlarged ceca, increased cecal water content, increased colonic expression of apical ion transporters, reduced number of goblet cells and loss of colonic epithelial integrity. Colonocytes from GLP-1R KO mice were energy-deprived and exhibited increased ER-stress; mitochondrial fragmentation, increased oxygen levels and loss of stemness. Restoring colonic energy levels either by feeding a Western-style diet or colonization with a normal gut microbiota normalized gut phenotypes and prevented lethality.
Conclusions: Our findings reveal a heretofore unrecognized role for GLP-1R signaling in the maintenance of colonic physiology and survival during energy deprivation.
Competing Interests: Declaration of competing interest F.B. receives research support from Biogaia AB, is founder and shareholder of Implexion Pharma AB, Roxbiosens Inc, and on the scientific advisory board for Bactolife A/S. D.J.D. has served as a consultant or speaker within the past 12 months to Altimmune, Amgen, Kallyope, Merck Research Laboratories, Novo Nordisk Inc., Pfizer Inc. and Sanofi Inc.. Neither D.J.D. nor his family members hold issued stock directly or indirectly in any of these companies. D.J.D holds non-exercised options in Kallyope.
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