Relationships and Mendelian Randomization of Gut Microbe-Derived Metabolites with Metabolic Syndrome Traits in the METSIM Cohort
Sahereh Mirzaei,
Holli A. DeVon,
Rita M. Cantor,
Arjen J. Cupido,
Calvin Pan,
Sung Min Ha,
Lilian Fernandes Silva,
James R. Hilser,
Jaana Hartiala,
Hooman Allayee,
Federico E. Rey,
Markku Laakso,
Aldons J. Lusis
Affiliations
Sahereh Mirzaei
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90055, USA
Holli A. DeVon
School of Nursing, University of California, Los Angeles, CA 90095, USA
Rita M. Cantor
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Arjen J. Cupido
Department of Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Cardiovascular Sciences, 1007 AZ Amsterdam, The Netherlands
Calvin Pan
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90055, USA
Sung Min Ha
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA
Lilian Fernandes Silva
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90055, USA
James R. Hilser
Department of Population & Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
Jaana Hartiala
Department of Population & Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
Hooman Allayee
Department of Population & Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
Federico E. Rey
Department of Bacteriology, University of Wisconsin-Madison, Madison, WI 53706, USA
Markku Laakso
Department of Clinical Medicine, Internal Medicine, University of Eastern Finland, 70210 Kuopio, Finland
Aldons J. Lusis
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90055, USA
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.
