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

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.