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bioRxiv · 10.1101/2025.06.24.661421

The microbial tryptophan metabolite indole acts on the gastrointestinal tract to improve glucose homeostasis by enhancing GLP-1 secretion and L-cell differentiation

Phuah, P.·Norton, M.·Cheng, S.·Roberts, A.·Meyer, L.·Chung, P.-E.·Dunsterville, C.·Karwowski, R.·Lam, B. Y.·Otsubo, E.·Aleksashina, S.·Gribble, F. M.·Reimann, F.·Hanyaloglu, A. C.·Yeo, G. S. H.·Bewick, G. A.·Jones, B.·Owen, B.·Murphy, K. G.
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Abstract

Aims/hypothesisGrowing 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 (T2D). We hypothesised that indole acts via the gastrointestinal tract to modulate glucose homeostasis, and aimed to test this hypothesis using in vitro and in vivo models. MethodsThe acute effects of indole on GLP-1 secretion in vitro, and on glucose tolerance and hormone secretion in mice, were determined. Subsequently, the effects of indole on intestinal epithelial cell fate and L-cell differentiation in murine ileal organoids and in vivo were studied. Finally, the utility of chronic indole administration in a murine model of T2D was explored. ResultsIndole stimulated in vitro GLP-1 secretion in a concentration-dependent manner, and improved acute glucose control 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 diabetic mice. Conclusions/interpretationOur findings identify indole as an anti-diabetic molecule that acts on the gut, and raise the possibility of incorporating indole into nutraceutical supplements to aid in the treatment or prevention of T2D. This highlights the importance of gut microbiota-derived metabolites in metabolic health and opens new avenues for developing novel strategies to combat T2D. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIGut microbiota-derived metabolites play a role in metabolic homeostasis. C_LIO_LIIndole, a microbial tryptophan metabolite, enhances GLP-1 secretion in vitro. C_LIO_LIIndole derivatives are inversely associated with type 2 diabetes (T2D) risk. C_LI What is the key question?O_LIDoes indole act on the gut to modulate glucose homeostasis? C_LI What are the new findings?O_LIIndole stimulates GLP-1 secretion and improves acute glucose control in vivo. C_LIO_LIIndole drives enteroendocrine L-cell differentiation in murine ileal organoids, increasing L-cell density and long-term glucoregulatory benefits. C_LIO_LISub-chronic indole administration improves glucose tolerance and insulin sensitivity in mice with type 2 diabetes, showing the potential of gut microbiota-derived metabolites as therapeutic targets. C_LI How might this impact clinical practice in the foreseeable future?O_LIIndole could be incorporated into nutraceutical supplements for T2D prevention or treatment. C_LI

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Phuah, P., Norton, M., Cheng, S., Roberts, A., Meyer, L., Chung, P.-E., Dunsterville, C., Karwowski, R., Lam, B. Y., Otsubo, E., Aleksashina, S., Gribble, F. M., Reimann, F., Hanyaloglu, A. C., Yeo, G. S. H., Bewick, G. A., Jones, B., Owen, B., Murphy, K. G.. 2025-06-27. The microbial tryptophan metabolite indole acts on the gastrointestinal tract to improve glucose homeostasis by enhancing GLP-1 secretion and L-cell differentiation. https://doi.org/10.1101/2025.06.24.661421

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