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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u00a0cell 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u00a0cell differentiation in murine ileal organoids, resulting in increased L\u00a0cell density and longer-term glucoregulatory benefits in vivo. Finally, sub-chronic indole administration improved glucose tolerance and insulin sensitivity in a diabetic mouse model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Data availability<\/jats:title>\n                    <jats:p>RNA sequencing data are available from the Gene Expression Omnibus under accession number GSE306720.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06688-4","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T03:34:56Z","timestamp":1772595296000},"page":"1659-1674","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["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\u00a0cell differentiation"],"prefix":"10.1007","volume":"69","author":[{"given":"Phyllis","family":"Phuah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Norton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijing","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna G.","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Pirri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-En","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Dunsterville","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafal","family":"Karwowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian Y. 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Rothery of the Facility for Imaging by Light Microscopy at Imperial College London for his support and assistance in this work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"All data, methods and unique\/stable reagents generated in this study will be made available from the corresponding author upon reasonable request, but may require a completed Materials Transfer Agreement. RNA sequencing data are available from the Gene Expression Omnibus under accession number GSE306720.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"The Section of Endocrinology and Investigative Medicine, Hammersmith Hospital, London, is funded by grants from the MRC, BBSRC and NIHR, and is supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the authors and not necessarily those of the MRC or BBSRC, the NHS, the NIHR or the Department of Health and Social Care. PP is funded by a National Science Scholarship from A*STAR, Singapore. KGM is supported by Diabetes UK (18\/0005886 and 20\/0006295), the BBSRC (BB\/W001497\/1 and BB\/X017273\/1), the MRC (MR\/Y013980\/1) and the Wellcome Trust (310835\/Z\/24\/Z). BJ acknowledges funding support from the Medical Research Council (MR\/Y00132X\/1 and MR\/X021467\/1), the Wellcome Trust (301619\/Z\/23\/Z), Diabetes UK, the Eli Lilly LRAP programme and Metsera Inc. BYHL and GSHY are supported by BBSRC project grant BB\/S017593\/1 and the MRC Metabolic Diseases Unit (MC_UU_00014\/1). Next-generation sequencing was performed at the IMS Genomics and Bioinformatics Core, supported by the MRC (MC_UU_00014\/5 and RGAG\/542 MC_UU_00039), the Wellcome Trust (208363\/Z\/17\/Z and RGAG\/546 226800\/Z\/22\/Z), and the Cancer Research UK Cambridge Institute Genomics Core. The FR\/FMG laboratories were funded by the Wellcome Trust (220271\/Z\/20\/Z) and the MRC (MRC_MC_UU_12012\/3). The study\u2019s funders were not involved in the design of the study, the collection, analysis and interpretation of data, or writing the report, and did not impose any restrictions regarding publication of the report.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"BYHL provides remunerated consultancy for Nuntius Therapeutics. GSHY receives grant funding from Novo Nordisk and Amgen Inc; he also consults for both Novo Nordisk and Eli Lilly and Company. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"PP was responsible for conceptualisation, investigation, formal analysis, project administration, and the writing of the original draft. MN contributed to methodology and investigation. SC, AGR, DP, LM, P-EC, CD, EO and SA were involved in investigation. RK carried out investigation and formal analysis. BYHL contributed to methodology, visualisation and formal analysis. FMG and FR provided resources and helped to design the experiments and interpret data. ACH contributed to methodology. GSHY also assisted with methodology. GAB contributed to visualisation and formal analysis. BJ was involved in methodology and provision of resources. BO contributed to methodology. KGM was responsible for conceptualisation, formal analysis, data curation, manuscript review and editing, supervision, and funding acquisition. All authors were involved in drafting the article or reviewing it critically for important intellectual content, and gave final approval of the version to be published. KGM is the guarantor of this work.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}