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Gut Microbiota Derived Metabolites in Cardiovascular Health and Disease
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Gut Microbiota Derived Metabolites in Cardiovascular Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: 20 April 2025 | Viewed by 15279

Special Issue Editor

Dr. Zeneng Wang

E-Mail Website
Guest Editor
Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Interests: cardiovascular disease; gut flora metabolism

Special Issue Information

Dear Colleagues,

In recent years, the association between gut microbiota derived metabolites and cardiovascular disease has gained wide interest and targeting gut microbiome and metabolic pathway may become a potential therapeutic strategy to prevent and treat cardiovascular disease. Cardiovascular disease is the leading cause of death worldwide and takes one-third of all deaths globally each year. Atherosclerosis, a chronic inflammatory disease happened in artery wall, is the underlying mechanism of cardiovascular disease. The roles of gut microbiota derived metabolites in cardiovascular health and disease can be summarized as follows: modulation of cholesterol metabolism, lipid storage and energy metabolism, regulation of pro- or anti- inflammatory cytokine or chemokine biosynthesis and modulation of immunity. Hundreds of gut microbiota derived metabolites have been revealed to participate in cardiovascular disease pathogenesis. However, the molecular mechanisms need further investigation. Therefore, this Special Issue will be dedicated to publishing current advances on new gut microbiota derived metabolite discovery and its metabolic pathway, the microbes which encode this specific metabolic pathway, and molecular mechanisms linking to atherosclerosis and cardiovascular disease pathogenesis.

Dr. Zeneng Wang
Guest Editor

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Keywords

  • gut microbiota-derived metabolites such as: short-chain fatty acids, trimethylamine n-oxide, amide lipid, aromatic amino acid derivatives, polyamines, hydrogen sulfide, lipopolysaccharide, polyphenols, secondary bile acids
  • receptor recognition and signal transduction induced by metabolites
  • metabolites initiating atherosclerosis
  • microbial enzymes catalyzing biosynthesis of the metabolites
  • inhibitors, prebiotic and probiotic modulation of the metabolite production
  • transcriptomic, proteomic, metabolic profile changes induced by metabolites

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Published Papers (6 papers)

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Research

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27 pages, 3731 KiB  
Article
Silicon-Enriched Meat Ameliorates Diabetic Dyslipidemia by Improving Cholesterol, Bile Acid Metabolism and Ileal Barrier Integrity in Rats with Late-Stage Type 2 Diabetes
by Marina Hernández-Martín, Alba Garcimartín, Aránzazu Bocanegra, Adrián Macho-González, Rosa A. García-Fernández, Sonia de Pascual-Teresa, Rocío Redondo-Castillejo, Sara Bastida, Francisco J. Sánchez-Muniz, Juana Benedí and Mª Elvira López-Oliva
Int. J. Mol. Sci. 2024, 25(21), 11405; https://doi.org/10.3390/ijms252111405 - 23 Oct 2024
Viewed by 770
Abstract
Silicon as a functional ingredient of restructured meat (RM) shows antidiabetic and hypocholesterolemic effects in a type 2 diabetes mellitus (T2DM) rat model. The present paper investigated the mechanisms involved in this cholesterol-lowering effect by studying the impact of silicon-RM consumption on bile [...] Read more.
Silicon as a functional ingredient of restructured meat (RM) shows antidiabetic and hypocholesterolemic effects in a type 2 diabetes mellitus (T2DM) rat model. The present paper investigated the mechanisms involved in this cholesterol-lowering effect by studying the impact of silicon-RM consumption on bile acid (BA) and cholesterol metabolism. In addition, the main effects of cecal BA and short-chain fatty acids derived from the microbiota on intestinal barrier integrity were also tested. Rats were fed an RM high-saturated-fat, high-cholesterol diet (HSFHCD) combined with a low dose of streptozotocin plus nicotinamide injection (LD group) and for an 8 wk. period. Silicon-RM was included in the HSFHCD as a functional food (LD-Si group). An early-stage T2DM group fed a high-saturated-fat diet (ED group) was used as a reference. Silicon decreased the BA pool with a higher hydrophilic BA profile and a lower ability to digest fat and decreased the damaging effects, increasing the occludin levels and the integrity of the intestinal barrier. The ileal BA uptake and hepatic BA synthesis through CYP7A1 were reduced by FXR/FGF15 signaling activation. The silicon up-regulated the hepatic and ileal FXR and LXRα/β, improving transintestinal cholesterol (TICE), biliary BA and cholesterol effluxes. The inclusion of silicon in meat products could be used as a new therapeutic nutritional tool in the treatment of diabetic dyslipidemia. Full article
(This article belongs to the Special Issue Gut Microbiota Derived Metabolites in Cardiovascular Health and Disease)
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13 pages, 3699 KiB  
Article
Sodium Butyrate as Key Regulator of Mitochondrial Function and Barrier Integrity of Human Glomerular Endothelial Cells
by Maria Novella Nicese, Roel Bijkerk, Anton Jan Van Zonneveld, Bernard M. Van den Berg and Joris I. Rotmans
Int. J. Mol. Sci. 2023, 24(17), 13090; https://doi.org/10.3390/ijms241713090 - 23 Aug 2023
Cited by 2 | Viewed by 3127
Abstract
The gut microbiota has emerged as an important modulator of cardiovascular and renal homeostasis. The composition of gut microbiota in patients suffering from chronic kidney disease (CKD) is altered, where a lower number of bacteria producing short chain fatty acids (SCFAs) is observed. [...] Read more.
The gut microbiota has emerged as an important modulator of cardiovascular and renal homeostasis. The composition of gut microbiota in patients suffering from chronic kidney disease (CKD) is altered, where a lower number of bacteria producing short chain fatty acids (SCFAs) is observed. It is known that SCFAs, such as butyrate and acetate, have protective effects against cardiovascular diseases and CKD but their mechanisms of action remain largely unexplored. In the present study, we investigated the effect of butyrate and acetate on glomerular endothelial cells. Human glomerular microvascular endothelial cells (hgMVECs) were cultured and exposed to butyrate and acetate and their effects on cellular proliferation, mitochondrial mass and metabolism, as well as monolayer integrity were studied. While acetate did not show any effects on hgMVECs, our results revealed that butyrate reduces the proliferation of hgMVECs, strengthens the endothelial barrier through increased expression of VE-cadherin and Claudin-5 and promotes mitochondrial biogenesis. Moreover, butyrate reduces the increase in oxygen consumption induced by lipopolysaccharides (LPS), revealing a protective effect of butyrate against the detrimental effects of LPS. Taken together, our data show that butyrate is a key player in endothelial integrity and metabolic homeostasis. Full article
(This article belongs to the Special Issue Gut Microbiota Derived Metabolites in Cardiovascular Health and Disease)
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20 pages, 2624 KiB  
Article
Trimethylamine N-Oxide Response to a Mixed Macronutrient Tolerance Test in a Cohort of Healthy United States Adults
by Kristen L. James, Erik R. Gertz, Catherine P. Kirschke, Hooman Allayee, Liping Huang, Mary E. Kable, John W. Newman, Charles B. Stephensen and Brian J. Bennett
Int. J. Mol. Sci. 2023, 24(3), 2074; https://doi.org/10.3390/ijms24032074 - 20 Jan 2023
Cited by 2 | Viewed by 2716
Abstract
Plasma trimethylamine n-oxide (TMAO) concentration increases in responses to feeding TMAO, choline, phosphatidylcholine, L-carnitine, and betaine but it is unknown whether concentrations change following a mixed macronutrient tolerance test (MMTT) with limited amounts of TMAO precursors. In this proof-of-concept study, we provided healthy [...] Read more.
Plasma trimethylamine n-oxide (TMAO) concentration increases in responses to feeding TMAO, choline, phosphatidylcholine, L-carnitine, and betaine but it is unknown whether concentrations change following a mixed macronutrient tolerance test (MMTT) with limited amounts of TMAO precursors. In this proof-of-concept study, we provided healthy female and male adults (n = 97) ranging in age (18–65 years) and BMI (18–44 kg/m2) a MMTT (60% fat, 25% sucrose; 42% of a standard 2000 kilo calorie diet) and recorded their metabolic response at fasting and at 30 min, 3 h, and 6 h postprandially. We quantified total exposure to TMAO (AUC-TMAO) and classified individuals by the blood draw at which they experienced their maximal TMAO concentration (TMAO-response groups). We related AUC-TMAO to the 16S rRNA microbiome, to two SNPs in the exons of the FMO3 gene (rs2266782, G>A, p.Glu158Lys; and rs2266780, A>G, p.Glu308Gly), and to a priori plasma metabolites. We observed varying TMAO responses (timing and magnitude) and identified a sex by age interaction such that AUC-TMAO increased with age in females but not in males (p-value = 0.0112). Few relationships between AUC-TMAO and the fecal microbiome and FMO3 genotype were identified. We observed a strong correlation between AUC-TMAO and TNF-α that depended on TMAO-response group. These findings promote precision nutrition and have important ramifications for the eating behavior of adults who could benefit from reducing TMAO exposure, and for understanding factors that generate plasma TMAO. Full article
(This article belongs to the Special Issue Gut Microbiota Derived Metabolites in Cardiovascular Health and Disease)
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22 pages, 4565 KiB  
Article
Metabolites Analysis of Anti-Myocardial Ischemia Active Components of Saussurea involucrata Based on Gut Microbiota—Drug Interaction
by Hang Yu, Jie Fu, Hui-Hui Guo, Li-Bin Pan, Hui Xu, Zheng-Wei Zhang, Jia-Chun Hu, Xin-Yu Yang, Hao-Jian Zhang, Meng-Meng Bu, Yuan Lin, Jian-Dong Jiang and Yan Wang
Int. J. Mol. Sci. 2022, 23(13), 7457; https://doi.org/10.3390/ijms23137457 - 5 Jul 2022
Cited by 4 | Viewed by 2749
Abstract
Saussurea involucrata has been reported to have potential therapeutic effects against myocardial ischemia. The pharmacological effects of oral natural medicines may be influenced by the participation of gut microbiota. In this study, we aimed to investigate the bidirectional regulation of gut microbiota and [...] Read more.
Saussurea involucrata has been reported to have potential therapeutic effects against myocardial ischemia. The pharmacological effects of oral natural medicines may be influenced by the participation of gut microbiota. In this study, we aimed to investigate the bidirectional regulation of gut microbiota and the main components of Saussurea involucrata. We first established a quantitative method for the four main components (chlorogenic acid, syringin, acanthoside B, rutin) which were chosen by fingerprint using liquid chromatography tandem mass spectrometry (LC-MS/MS), and found that gut microbiota has a strong metabolic effect on them. Meanwhile, we identified five major rat gut microbiota metabolites (M1–M5) using liquid chromatography tandem time-of-flight mass spectrometry (LC/MSn-IT-TOF). The metabolic properties of metabolites in vitro were preliminarily elucidated by LC-MS/MS for the first time. These five metabolites of Saussurea involucrata may all have potential contributions to the treatment of myocardial ischemia. Furthermore, the four main components (10 μg/mL) can significantly stimulate intestinal bacteria to produce short chain fatty acids in vitro, respectively, which can further contribute to the effect in myocardial ischemia. In this study, the therapeutic effect against myocardial ischemia of Saussurea involucrata was first reported to be related to the intestinal flora, which can be useful in understanding the effective substances of Saussurea involucrata. Full article
(This article belongs to the Special Issue Gut Microbiota Derived Metabolites in Cardiovascular Health and Disease)
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Review

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49 pages, 1652 KiB  
Review
Low-Molecular-Weight Compounds Produced by the Intestinal Microbiota and Cardiovascular Disease
by Lorena Cuervo, Patrick L. McAlpine, Carlos Olano, Javier Fernández and Felipe Lombó
Int. J. Mol. Sci. 2024, 25(19), 10397; https://doi.org/10.3390/ijms251910397 - 27 Sep 2024
Viewed by 1409
Abstract
Cardiovascular disease is the main cause of mortality in industrialized countries, with over 500 million people affected worldwide. In this work, the roles of low-molecular-weight metabolites originating from the gut microbiome, such as short-chain fatty acids, hydrogen sulfide, trimethylamine, phenylacetic acid, secondary bile [...] Read more.
Cardiovascular disease is the main cause of mortality in industrialized countries, with over 500 million people affected worldwide. In this work, the roles of low-molecular-weight metabolites originating from the gut microbiome, such as short-chain fatty acids, hydrogen sulfide, trimethylamine, phenylacetic acid, secondary bile acids, indoles, different gases, neurotransmitters, vitamins, and complex lipids, are discussed in relation to their CVD-promoting or preventing activities. Molecules of mixed microbial and human hepatic origin, such as trimethylamine N-oxide and phenylacetylglutamine, are also presented. Finally, dietary agents with cardioprotective effects, such as probiotics, prebiotics, mono- and poly-unsaturated fatty acids, carotenoids, and polyphenols, are also discussed. A special emphasis is given to their gut microbiota-modulating properties. Full article
(This article belongs to the Special Issue Gut Microbiota Derived Metabolites in Cardiovascular Health and Disease)
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21 pages, 2651 KiB  
Review
A Metabolite Perspective on the Involvement of the Gut Microbiota in Type 2 Diabetes
by Yifeng Fu, Siying Li, Yunhua Xiao, Gang Liu and Jun Fang
Int. J. Mol. Sci. 2023, 24(19), 14991; https://doi.org/10.3390/ijms241914991 - 8 Oct 2023
Cited by 8 | Viewed by 2825
Abstract
Type 2 diabetes (T2D) is a commonly diagnosed condition that has been extensively studied. The composition and activity of gut microbes, as well as the metabolites they produce (such as short-chain fatty acids, lipopolysaccharides, trimethylamine N-oxide, and bile acids) can significantly impact diabetes [...] Read more.
Type 2 diabetes (T2D) is a commonly diagnosed condition that has been extensively studied. The composition and activity of gut microbes, as well as the metabolites they produce (such as short-chain fatty acids, lipopolysaccharides, trimethylamine N-oxide, and bile acids) can significantly impact diabetes development. Treatment options, including medication, can enhance the gut microbiome and its metabolites, and even reverse intestinal epithelial dysfunction. Both animal and human studies have demonstrated the role of microbiota metabolites in influencing diabetes, as well as their complex chemical interactions with signaling molecules. This article focuses on the importance of microbiota metabolites in type 2 diabetes and provides an overview of various pharmacological and dietary components that can serve as therapeutic tools for reducing the risk of developing diabetes. A deeper understanding of the link between gut microbial metabolites and T2D will enhance our knowledge of the disease and may offer new treatment approaches. Although many animal studies have investigated the palliative and attenuating effects of gut microbial metabolites on T2D, few have established a complete cure. Therefore, conducting more systematic studies in the future is necessary. Full article
(This article belongs to the Special Issue Gut Microbiota Derived Metabolites in Cardiovascular Health and Disease)
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