Gut Microbe-derived Metabolites and the Risk of Cardiovascular Disease in the METSIM Cohort

Overview

Journal Front Microbiol

Specialty Microbiology

Date 2024 Aug 16

PMID 39149211

Authors

Sahereh Mirzaei

Holli A DeVon

Rita M Cantor

Arjen Cupido

Lilian Fernandes Silva

Markku Laakso

Aldons J Lusis

Affiliations

Soon will be listed here.

Abstract

Background: An association between gut microbes and cardiovascular disease (CVD) has been established, but the underlying mechanisms remain largely unknown.

Methods: We conducted a secondary analysis of the cross-sectional data obtained from the Metabolic Syndrome in Men (METSIM) population-based cohort of 10,194 Finnish men (age = 57.65 ± 7.12 years). We tested the levels of circulating gut microbe-derived metabolites as predictors of CVD, ischemic cerebrovascular accident (CVA), and myocardial infarction (MI). The Kaplan-Meier method was used to estimate the time from the participants' first outpatient clinic visit to the occurrence of adverse outcomes. The associations between metabolite levels and the outcomes were assessed using Cox proportional hazard models.

Results: During a median follow-up period of 200 months, 979 participants experienced CVD, 397 experienced CVA, and 548 experienced MI. After adjusting for traditional risk factors and correcting for multiple comparisons, higher plasma levels of succinate [quartile 4 vs. quartile 1; adjusted hazard ratio, aHR = 1.30, (confidence interval (CI), 1.10-1.53) = 0.0003, adjusted = 0.01] were significantly associated with the risk of CVD. High plasma levels of ursodeoxycholic acid (UDCA) (quartile 3 vs. quartile 1); [aHR = 1.68, (CI, 1.26-2.2); = 0.0003, adj. = 0.01] were associated with a higher risk of CVA. Furthermore, as a continuous variable, succinate was associated with a 10% decrease in the risk of CVD [aHR = 0.9; (CI, 0.84-0.97); = 0.008] and a 15% decrease in the risk of MI [aHR = 0.85, (CI, 0.77-0.93); = 0.0007].

Conclusion: Gut microbe-derived metabolites, succinate, and ursodeoxycholic acid were associated with CVD, MI, and CVA, respectively. Regulating the gut microbes may represent a potential therapeutic target for modulating CVD and CVA.

References

Drouin N, Kloots T, Schappler J, Rudaz S, Kohler I, Harms A . Electromembrane Extraction of Highly Polar Compounds: Analysis of Cardiovascular Biomarkers in Plasma. Metabolites. 2019; 10(1). PMC: 7022788. DOI: 10.3390/metabo10010004. View

Yu F, Li X, Feng X, Wei M, Luo Y, Zhao T . Phenylacetylglutamine, a Novel Biomarker in Acute Ischemic Stroke. Front Cardiovasc Med. 2022; 8:798765. PMC: 8733610. DOI: 10.3389/fcvm.2021.798765. View

Yu F, Feng X, Li X, Luo Y, Wei M, Zhao T . Gut-Derived Metabolite Phenylacetylglutamine and White Matter Hyperintensities in Patients With Acute Ischemic Stroke. Front Aging Neurosci. 2021; 13:675158. PMC: 8363199. DOI: 10.3389/fnagi.2021.675158. View

Parry G, Rodrigues C, Aranha M, Hilbert S, Davey C, Kelkar P . Safety, tolerability, and cerebrospinal fluid penetration of ursodeoxycholic Acid in patients with amyotrophic lateral sclerosis. Clin Neuropharmacol. 2009; 33(1):17-21. DOI: 10.1097/WNF.0b013e3181c47569. View

Aguiar C, Rocha-Franco J, Sousa P, Santos A, Ladeira M, Rocha-Resende C . Succinate causes pathological cardiomyocyte hypertrophy through GPR91 activation. Cell Commun Signal. 2014; 12:78. PMC: 4296677. DOI: 10.1186/s12964-014-0078-2. View

Fernandez-Veledo S, Ceperuelo-Mallafre V, Vendrell J . Rethinking succinate: an unexpected hormone-like metabolite in energy homeostasis. Trends Endocrinol Metab. 2021; 32(9):680-692. DOI: 10.1016/j.tem.2021.06.003. View

De Vadder F, Kovatcheva-Datchary P, Zitoun C, Duchampt A, Backhed F, Mithieux G . Microbiota-Produced Succinate Improves Glucose Homeostasis via Intestinal Gluconeogenesis. Cell Metab. 2016; 24(1):151-7. DOI: 10.1016/j.cmet.2016.06.013. View

Nemet I, Saha P, Gupta N, Zhu W, Romano K, Skye S . A Cardiovascular Disease-Linked Gut Microbial Metabolite Acts via Adrenergic Receptors. Cell. 2020; 180(5):862-877.e22. PMC: 7402401. DOI: 10.1016/j.cell.2020.02.016. View

Laakso M, Kuusisto J, Stancakova A, Kuulasmaa T, Pajukanta P, Lusis A . The Metabolic Syndrome in Men study: a resource for studies of metabolic and cardiovascular diseases. J Lipid Res. 2017; 58(3):481-493. PMC: 5335588. DOI: 10.1194/jlr.O072629. View

10.

Fernandez-Veledo S, Vendrell J . Gut microbiota-derived succinate: Friend or foe in human metabolic diseases?. Rev Endocr Metab Disord. 2019; 20(4):439-447. PMC: 6938788. DOI: 10.1007/s11154-019-09513-z. View

11.

Kushnir M, Komaromy-Hiller G, Shushan B, Urry F, Roberts W . Analysis of dicarboxylic acids by tandem mass spectrometry. High-throughput quantitative measurement of methylmalonic acid in serum, plasma, and urine. Clin Chem. 2001; 47(11):1993-2002. View

12.

Rehner J, Schmartz G, Kramer T, Keller V, Keller A, Becker S . The Effect of a Planetary Health Diet on the Human Gut Microbiome: A Descriptive Analysis. Nutrients. 2023; 15(8). PMC: 10144214. DOI: 10.3390/nu15081924. View

13.

Tannahill G, Curtis A, Adamik J, Palsson-McDermott E, McGettrick A, Goel G . Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature. 2013; 496(7444):238-42. PMC: 4031686. DOI: 10.1038/nature11986. View

14.

Brown J, Hazen S . The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu Rev Med. 2015; 66:343-59. PMC: 4456003. DOI: 10.1146/annurev-med-060513-093205. View

15.

Abdelkader N, Safar M, Salem H . Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson's Disease: Modulation of Mitochondrial Perturbations. Mol Neurobiol. 2014; 53(2):810-817. DOI: 10.1007/s12035-014-9043-8. View

16.

Xu J, Zheng Y, Zhao Y, Zhang Y, Li H, Zhang A . Succinate/IL-1β Signaling Axis Promotes the Inflammatory Progression of Endothelial and Exacerbates Atherosclerosis. Front Immunol. 2022; 13:817572. PMC: 8901997. DOI: 10.3389/fimmu.2022.817572. View

17.

Witkowski M, Weeks T, Hazen S . Gut Microbiota and Cardiovascular Disease. Circ Res. 2020; 127(4):553-570. PMC: 7416843. DOI: 10.1161/CIRCRESAHA.120.316242. View

18.

Osuna-Prieto F, Martinez-Tellez B, Ortiz-Alvarez L, Di X, Jurado-Fasoli L, Xu H . Elevated plasma succinate levels are linked to higher cardiovascular disease risk factors in young adults. Cardiovasc Diabetol. 2021; 20(1):151. PMC: 8314524. DOI: 10.1186/s12933-021-01333-3. View

19.

Benjamin E, Muntner P, Alonso A, Bittencourt M, Callaway C, Carson A . Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation. 2019; 139(10):e56-e528. DOI: 10.1161/CIR.0000000000000659. View

20.

Bubier J, Chesler E, Weinstock G . Host genetic control of gut microbiome composition. Mamm Genome. 2021; 32(4):263-281. PMC: 8295090. DOI: 10.1007/s00335-021-09884-2. View