Antibiotic-induced gut microbiota depletion enhances glucose tolerance linked to GLP-1 signaling

Alexandra Kellenberger¹Revati Dewal¹Alice de Wouters²Andreas Sichert²Markus Heine³Marceline Manka Fuh³Emma Slack²Tenagne Delessa Challa^1*Christian Wolfrum^1*

• ¹Institute of Food, Nutrition and Health, Laboratory of Translational Nutrition Biology, Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, Switzerland
• ²Institute of Food, Nutrition and Health, Laboratory for Mucosal Immunology, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
• ³Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Depletion of the gut microbiota is known to improve glucose metabolism and modify thermogenic capacity in mice. However, the underlying mechanisms remain unclear. In this study, we aimed to determine whether the browning effect observed after antibiotic treatment contributes to metabolic modifications and to investigate the potential central role of GLP-1 in enhancing glucose metabolism. Using an inducible Ucp1DTR mouse model to transiently ablate UCP1+ cells, we demonstrate that gut microbiota depletion improved glucose tolerance independent of UCP1+ cell presence and increased cold sensitivity. Moreover, antibiotic treatment increased circulating active GLP-1 levels within one day. This increase was also observed in germ-free mice, supporting the suggestion that GLP-1 elevation is driven by gut microbiota depletion. The improvement in glucose tolerance was lost in GLP1R KO mice upon oral glucose ingestion. Bile acid profiling in wild-type mice treated with antibiotics identified several regulated bile acids, which were subsequently tested in an in vitro STC-1 cell assay, leading to the identification of two potential basal GLP-1 secretion inhibitors. Our findings suggest that the metabolic improvements following gut microbiota depletion are primarily driven by GLP-1 signaling, rather than UCP1+ cell activation. These results highlight the complex interplay between the gut microbiome and metabolic health, offering insights into potential therapeutic targets for improving glucose metabolism through modulation of basal GLP-1 signaling.