Plasma metabolites related to peripheral and hepatic insulin sensitivity are not directly linked to gut microbiota composition

Annefleur M. Koopen, Nicolien C. de Clercq, Moritz V. Warmbrunn, Hilde Herrema, Mark Davids, Pieter F. de Groot, Ruud S. Kootte, Kristien E. C. Bouter, Max Nieuwdorp, Albert K. Groen, Andrei Prodan

Research output: Contribution to JournalArticleAcademicpeer-review

4 Citations (Scopus)


Plasma metabolites affect a range of metabolic functions in humans, including insulin sensitivity (IS). A subset of these plasma metabolites is modified by the gut microbiota. To identify potential microbial–metabolite pathways involved in IS, we investigated the link between plasma metabolites, gut microbiota composition, and IS, using the gold-standard for peripheral and hepatic IS measurement in a group of participants with metabolic syndrome (MetSyn). In a cross-sectional study with 115 MetSyn participants, fasting plasma samples were collected for untargeted metabolomics analysis and fecal samples for 16S rRNA gene amplicon sequencing. A two-step hyperinsulinemic euglycemic clamp was performed to assess peripheral and hepatic IS. Collected data were integrated and potential interdependence between metabolites, gut microbiota, and IS was analyzed using machine learning prediction models. Plasma metabolites explained 13.2% and 16.7% of variance in peripheral and hepatic IS, respectively. Fecal microbiota composition explained 4.2% of variance in peripheral IS and was not related to hepatic IS. Although metabolites could partially explain the variances in IS, the top metabolites related to peripheral and hepatic IS did not significantly correlate with gut microbiota composition (both on taxonomical level and alpha-diversity). However, all plasma metabolites could explain 18.5% of the variance in microbial alpha-diversity (Shannon); the top 20 metabolites could even explain 44.5% of gut microbial alpha-diversity. In conclusion, plasma metabolites could partially explain the variance in peripheral and hepatic IS; however, these metabolites were not directly linked to the gut microbiota composition, underscoring the intricate relation between plasma metabolites, the gut microbiota, and IS in MetSyn.
Original languageEnglish
Article number2308
Pages (from-to)1-12
Number of pages12
Issue number8
Publication statusPublished - 1 Aug 2020


  • Diabetes
  • Gut microbiota
  • Insulin sensitivity
  • Metabolic syndrome
  • Plasma metabolites

Cite this