Relationships and Mendelian Randomization of Gut Microbe-Derived Metabolites with Metabolic Syndrome Traits in the METSIM Cohort

Abstract

The role of gut microbe-derived metabolites in the development of metabolic syndrome (MetS) remains unclear. This study aimed to evaluate the associations of gut microbe-derived metabolites and MetS traits in the cross-sectional Metabolic Syndrome In Men (METSIM) study. The sample included 10,194 randomly related men (age 57.65 ± 7.12 years) from Eastern Finland. Levels of 35 metabolites were tested for associations with 13 MetS traits using lasso and stepwise regression. Significant associations were observed between multiple MetS traits and 32 metabolites, three of which exhibited particularly robust associations. N-acetyltryptophan was positively associated with Homeostatic Model Assessment for Insulin Resistant (HOMA-IR) (β = 0.02, p = 0.033), body mass index (BMI) (β = 0.025, p = 1.3 × 10^-16), low-density lipoprotein cholesterol (LDL-C) (β = 0.034, p = 5.8 × 10^-10), triglyceride (0.087, p = 1.3 × 10^-16), systolic (β = 0.012, p = 2.5 × 10^-6) and diastolic blood pressure (β = 0.011, p = 3.4 × 10^-6). In addition, 3-(4-hydroxyphenyl) lactate yielded the strongest positive associations among all metabolites, for example, with HOMA-IR (β = 0.23, p = 4.4 × 10^-33), and BMI (β = 0.097, p = 5.1 × 10^-52). By comparison, 3-aminoisobutyrate was inversely associated with HOMA-IR (β = -0.19, p = 3.8 × 10^-51) and triglycerides (β = -0.12, p = 5.9 × 10^-36). Mendelian randomization analyses did not provide evidence that the observed associations with these three metabolites represented causal relationships. We identified significant associations between several gut microbiota-derived metabolites and MetS traits, consistent with the notion that gut microbes influence metabolic homeostasis, beyond traditional risk factors.

Keywords: GWAS; Mendelian randomization; gut metabolites; gut microbes; insulin resistance; metabolic syndrome.

Figure 1

Pearson’s correlation heatmap showing correlations of gut microbe-derived metabolites and metabolic syndrome traits (n = 10,194). Metabolic syndrome traits are shown on x-axis whereas metabolites are displayed on y-axis. Purple color stands for inverse correlations. Red color denotes positive correlations. HOMA-IR, homeostatic model assessment of insulin resistance; HbA1C, hemoglobin A1c; BMI, body mass index; WHR, waist-to-hip ratio; LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; * p.val < 0.05, ** p.val < 0.01, *** p.val < 0.001.

Figure 2

Heatmap showing association between gut microbe-derived metabolites and metabolic symptom traits after adjustments for age, BMI (body mass index), physical activity, medication use, batch effect, alcohol consumption, and smoking. Metabolic syndrome traits are shown on x-axis whereas metabolites are displayed on y-axis. Purple color stands for inverse association. Red color denotes positive associations. HOMA-IR, homeostatic model assessment of insulin resistance; BMI, body mass index; WHR, waist-to-hip ratio; LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; data were analyzed using Lasso and stepwise regression. * p.val < 0.05, ** p.val < 0.01, *** p.val < 0.001.

Figure 3

The Venn diagrams are representations of metabolites common to metabolic syndrome traits based on stepwise regression models. Each circle indicates the total number of metabolites associated with the specific trait. The overlapping regions represent the number of metabolites shared between those traits. HOMA-IR, homeostatic model assessment of insulin resistance; BMI, body mass index; WHR, waist-to-hip ratio; LDL, low-density lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol.