The microbial tryptophan metabolite indole acts on the gastrointestinal tract to improve glucose homeostasis in a mouse model of diabetes by enhancing GLP-1 secretion and L cell differentiation
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Aims/hypothesis
Growing evidence implicates gut microbiota-derived metabolites in metabolic homeostasis. Indole, a microbial tryptophan metabolite, has been reported to enhance glucagon-like peptide-1 (GLP-1) secretion in vitro, and its derivatives have been inversely associated with risk of type 2 diabetes. We hypothesised that indole acts via the gastrointestinal tract to modulate glucose homeostasis, and tested this hypothesis using in vitro and in vivo models.
Methods
We measured GLP-1 secretion from cultured murine enteroendocrine cells, and evaluated intraperitoneal glucose tolerance and hormone secretion in mice following indole treatment. Subsequently, the impact of indole on intestinal epithelial cell fate and L cell number was examined using murine ileal organoid cultures and in vivo. Finally, we explored the effect of chronic indole administration on metabolic outcomes in a murine model of type 2 diabetes.
Results
Indole stimulated in vitro GLP-1 secretion in a concentration-dependent manner, and improved acute glucose management in vivo. Additionally, we demonstrate that indole drives enteroendocrine L cell differentiation in murine ileal organoids, resulting in increased L cell density and longer-term glucoregulatory benefits in vivo. Finally, sub-chronic indole administration improved glucose tolerance and insulin sensitivity in a diabetic mouse model.
Conclusions/interpretation
Our findings identify indole as a glucose-lowering molecule that acts on the gut, and raise the possibility of incorporating indole into nutraceutical supplements to aid in the treatment or prevention of type 2 diabetes. This study highlights the importance of gut microbiota-derived metabolites in metabolic health and opens new avenues for developing novel strategies to combat type 2 diabetes.
Data availability
RNA sequencing data are available from the Gene Expression Omnibus under accession number GSE306720.
Growing evidence implicates gut microbiota-derived metabolites in metabolic homeostasis. Indole, a microbial tryptophan metabolite, has been reported to enhance glucagon-like peptide-1 (GLP-1) secretion in vitro, and its derivatives have been inversely associated with risk of type 2 diabetes. We hypothesised that indole acts via the gastrointestinal tract to modulate glucose homeostasis, and tested this hypothesis using in vitro and in vivo models.
Methods
We measured GLP-1 secretion from cultured murine enteroendocrine cells, and evaluated intraperitoneal glucose tolerance and hormone secretion in mice following indole treatment. Subsequently, the impact of indole on intestinal epithelial cell fate and L cell number was examined using murine ileal organoid cultures and in vivo. Finally, we explored the effect of chronic indole administration on metabolic outcomes in a murine model of type 2 diabetes.
Results
Indole stimulated in vitro GLP-1 secretion in a concentration-dependent manner, and improved acute glucose management in vivo. Additionally, we demonstrate that indole drives enteroendocrine L cell differentiation in murine ileal organoids, resulting in increased L cell density and longer-term glucoregulatory benefits in vivo. Finally, sub-chronic indole administration improved glucose tolerance and insulin sensitivity in a diabetic mouse model.
Conclusions/interpretation
Our findings identify indole as a glucose-lowering molecule that acts on the gut, and raise the possibility of incorporating indole into nutraceutical supplements to aid in the treatment or prevention of type 2 diabetes. This study highlights the importance of gut microbiota-derived metabolites in metabolic health and opens new avenues for developing novel strategies to combat type 2 diabetes.
Data availability
RNA sequencing data are available from the Gene Expression Omnibus under accession number GSE306720.
Date Issued
2026-06-01
Date Acceptance
2025-10-30
Citation
Diabetologia, 2026, 69, pp.1659-1674
ISSN
0012-186X
Publisher
Springer Science and Business Media LLC
Start Page
1659
End Page
1674
Journal / Book Title
Diabetologia
Volume
69
Copyright Statement
© The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41776124
PII: 10.1007/s00125-026-06688-4
Subjects
Glucagon-like peptide-1
Glucose homeostasis
Transient receptor potential channel subtype A1
Publication Status
Published
Coverage Spatial
Germany
Date Publish Online
2026-03-04