Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

Ara Koh, Antonio Molinaro, Marcus Ståhlman, Muhammad Tanweer Khan, Caroline Schmidt, Louise Mannerås-Holm, Hao Wu, Alba Carreras, Heeyoon Jeong, Louise E. Olofsson, Per-Olof Bergh, Victor Gerdes, Annick Hartstra, Maurits de Brauw, Rosie Perkins, Max Nieuwdorp, G. ran Bergström, Fredrik Bäckhed

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Interactions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidine-derived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38γ MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes. Imidazole propionate, a metabolite produced by the gut microbiota, is elevated in type 2 diabetes and can directly impair glucose tolerance and insulin signaling.
Original languageEnglish
Pages (from-to)947-961.e17
JournalCell
Volume175
Issue number4
DOIs
Publication statusPublished - 2018

Cite this

Koh, A., Molinaro, A., Ståhlman, M., Khan, M. T., Schmidt, C., Mannerås-Holm, L., ... Bäckhed, F. (2018). Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1. Cell, 175(4), 947-961.e17. https://doi.org/10.1016/j.cell.2018.09.055