Relationship between gut microbiota and circulating metabolites in population-based cohorts

Abstract

Gut microbiota has been implicated in major diseases affecting the human population and has also been linked to triglycerides and high-density lipoprotein levels in the circulation. Recent development in metabolomics allows classifying the lipoprotein particles into more details. Here, we examine the impact of gut microbiota on circulating metabolites measured by Nuclear Magnetic Resonance technology in 2309 individuals from the Rotterdam Study and the LifeLines-DEEP cohort. We assess the relationship between gut microbiota and metabolites by linear regression analysis while adjusting for age, sex, body-mass index, technical covariates, medication use, and multiple testing. We report an association of 32 microbial families and genera with very-low-density and high-density subfractions, serum lipid measures, glycolysis-related metabolites, ketone bodies, amino acids, and acute-phase reaction markers. These observations provide insights into the role of microbiota in host metabolism and support the potential of gut microbiota as a target for therapeutic and preventive interventions.

Fig. 1. Results of association analysis between metabolites and microbial genera and families assessed by linear regression analysis (n = 2309).

Association results after adjustment for age, sex, body mass index, technical covariates, and medication use are displayed on panel (a), while association results after additional adjustment for smoking and alcohol consumption are shown on panel (b). Metabolites are displayed on x-axis, whereas microbial genera and families are shown on y-axis. Lipoprotein classes include very-low-density lipoprotein particles (VLDL), intermediate lipoprotein particles (IDL), low-density lipoprotein particles (LDL), and high-density lipoprotein particles (HDL) of very low (XS), low (S), medium (M), large (L), very large (XL), and extremely large (XXL) size. Blue color stands for inverse association. Red color denotes positive associations. Symbols on the plot represent the level of significance with hash denoting Bonferroni significant associations at p value < 4.93 × 10⁻⁶. Source data are provided as a Source Data file.

Fig. 2. Results of association analysis between metabolites and alpha diversity (n = 2309).

Metabolites are displayed on x-axis whereas microbial diversity in the RS, LLD, and combined meta-analysis is shown on y-axis. Lipoprotein classes, include very-low-density lipoprotein particles (VLDL), low-density lipoprotein particles (LDL), and high-density lipoprotein particles (HDL) of very low (XS), low (S), medium (M), large (L), very large (XL), and extremely large (XXL) size. The colors represent effect estimates. Blue color stands for inverse association. Red color denotes positive associations. Symbols on the plot represent level of significance with hash denoting Bonferroni significant associations.