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Cited by 824Gut microbiota and healthAdipokines, Inflammation, and Metabolic DiseasesMetabolomics and Mass Spectrometry Studies

Microbially Produced Imidazole Propionate Impairs Insulin Signaling through mTORC1

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Koh, Ara, Molinaro, Antonio, Ståhlman, Marcus, Khan, Muhammad Tanweer, Schmidt, Caroline, Mannerås-Holm, Louise, Wu, Hao, Carreras, Alba +10 more·2018·Cell
DOI 10.1016/j.cell.2018.09.055
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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.

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  • Multi-faceted studies using different methods and research platforms can enable more mechanistic understandings of associations between microbes and host phenotypes.

    “An additional advantage of multi-faceted studies using different methods and research platforms is that they can enable more mechanistic understandings of associations between microbes and host phenotypes 37-39 .”

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Authors
Koh, A., Molinaro, A., Ståhlman, M., Khan, M. T., Schmidt, C., Mannerås-Holm, L., Wu, H., Carreras, A., Jeong, H., Olofsson, L. E., Bergh, P.-O., Gerdes, V., Hartstra, A., de Brauw, M., Perkins, R., Nieuwdorp, M., Bergström, G., & Bäckhed, F.
Affiliations
  • Sahlgrenska University Hospital (SE)
  • Pohang University of Science and Technology (KR)
  • Slotervaartziekenhuis (NL)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • University of Copenhagen (DK)
Corresponding author
Bäckhed, Fredrik
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2018-11
Volume
175
Issue
4
Pages
947-961.e17
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2018.09.055
OpenAlex
W2898599254
Cited by
824
References
7
Citations by year
2026: 98 · 2025: 109 · 2024: 111 · 2023: 100 · 2022: 130 · 2021: 134 · 2020: 90 · 2019: 48 · 2018: 3
FWCI
24.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Pure Amsterdam UMC (acceptedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders
  • Novo Nordisk Foundation (NNF15OC0016798)
  • Swedish Research Council
  • Swedish Diabetes Foundation
  • Swedish Heart Lung Foundation
  • Göran Gustafsson’s Foundation
  • IngaBritt och Arne Lundberg’s Foundation
  • Knut and Alice Wallenberg Foundation
  • Swedish Foundation for Strategic Research
  • FP7 (305312)
  • Region Västra Götaland
  • Sahlgrenska University Hospital
  • JPI (2017-01996_3)
  • Leducq Foundation (17CVD01)
  • Wenner-Gren Foundations
  • ZONMW-VIDI grant 2013 (016.146.327)
  • CVON Young Talent grant 2012
  • ERC (615362)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
Keywords
imidazole propionate, gut microbiota, type 2 diabetes, insulin signaling, insulin receptor substrate, p38 MAPK, mTORC1, glucose tolerance, liver, microbial metabolites, metabolic disorders
MeSH terms
Gastrointestinal Microbiome, Sequestosome-1 Protein, Mechanistic Target of Rapamycin Complex 1, Animals, Cells, Cultured, Diabetes Mellitus, Type 2, Histidine, Humans, Imidazoles, Insulin, Liver, Male, Mice, Inbred C57BL, Signal Transduction, p38 Mitogen-Activated Protein Kinases, Mice, HEK293 Cells

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