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Published in final edited form as: Crit Rev Food Sci Nutr. 2023 Aug 31;64(33):12411–12419. doi: 10.1080/10408398.2023.2251616

Breaking Bugs: Gut Microbes Metabolize Dietary Components and Modulate Vascular Health

Adhini Kuppuswamy Satheesh Babu 1,#, Harini Srinivasan 1,#, Pon Velayutham Anandh Babu 1,*
PMCID: PMC10902197  NIHMSID: NIHMS1928708  PMID: 37651204

Abstract

Gut microbiota modulates host physiology and pathophysiology through the production of microbial metabolites. Diet is a crucial factor in shaping the microbiome, and gut microbes interact with the host by producing beneficial or detrimental diet-derived microbial metabolites. Evidence from our lab and others indicates that the interaction between diet and gut microbes plays a pivotal role in modulating vascular health. Diet-derived microbial metabolites such as short-chain fatty acids and metabolites of phenolic acids improve vascular health, whereas trimethylamine oxide and certain amino acid-derived microbial metabolites impair the vasculature. These metabolites have been shown to regulate blood pressure, vascular inflammation, and atherosclerosis by acting on multiple targets. Nonetheless, there are substantial gaps in knowledge within this field. The microbial enzymes essential for the production of diet-derived metabolites, the role of the food matrix in regulating the bioavailability of metabolites, and the structure-activity relationships between metabolites and biomolecules in the vasculature are largely unknown. Potential diet-derived metabolites to improve vascular health can be identified through future studies that investigate the causal relationship between dietary components, gut microbes, diet-derived metabolites, and vascular health by using radiolabeled compounds, metabolomics, transcriptomics, and proteomics techniques.

Keywords: Diet-derived microbial metabolites, gut microbes, short chain fatty acids, trimethylamine oxide, polyphenols, amino acid derived metabolites

Introduction

The human gut microbiota is crucial for maintaining good health as it produces essential vitamins, regulates metabolism, inhibits the proliferation of harmful microorganisms, and modulates the immune system. Importantly, gut microbiota modulates host physiology and pathophysiology through the production of diet-derived microbial metabolites (Agus et al., 2021). These metabolites act as central regulators and impact chronic diseases (Agus et al., 2021). Diet is a crucial factor in shaping the microbiome, and gut microbes interact with the host by producing beneficial or detrimental diet-derived microbial metabolites such as short-chain fatty acids (SCFA), trimethylamine oxide (TMAO), and phenolic acids (Agus et al., 2021). A two-way relationship exists between dietary components and gut microbes (Miller et al., 2022). Gut microbes help to metabolize certain dietary components that are not digested by human digestive enzymes, whereas dietary components, such as fermentable polysaccharides, support the growth of gut microbes (Miller et al., 2022). An alteration in the composition and function of the gut microbiome (dysbiosis) affects microbial metabolite production, which adversely impacts the host and promotes the onset of chronic diseases, such as cardiovascular disease (CVD), diabetes, and cancer (Agus et al., 2021). CVD disease is the leading cause of death worldwide (Virani et al., 2020) and evidence from our lab and others indicates that the interaction between diet and gut microbes plays a pivotal role in modulating vascular health (Istas et al., 2018; Miller et al., 2022; Simo and Garcia-Canas, 2020). Hence, diet-derived microbial metabolites may be a potential target to prevent and treat vascular complications. The present review highlights the recent developments in our understanding of the role of diet-derived microbial metabolites on cardiovascular health, with special emphasis on the molecular mechanisms involved. In addition, knowledge gaps, research challenges, and the future direction in this field will be discussed.

Gut microbes and vascular health

Atherosclerosis is the major risk factor for cardiovascular disease, characterized by the gradual build-up of plaques formed due to the accumulation of lipids, fibrous tissues, inflammatory cells, and cellular debris within the walls of arteries. The plaques become weak over time and rupture, allowing the binding of clotting factors and thrombin to the rupture site (Hopkins, 2013). This process narrows the vascular lumen leading to restricted blood flow and resulting in heart attack and stroke (Hopkins, 2013; Su, 2015). Atherosclerosis is initiated by endothelial inflammation and dysfunction, which is triggered by cardiovascular risk factors such as diabetes, dyslipidemia, and smoking (Hopkins, 2013). The endothelium in the interior walls of the vasculature plays a pivotal role in the vascular homeostasis (Su, 2015). Endothelial-derived nitric oxide (NO) regulate vasodilation and is synthesized by a homodimeric enzyme endothelial nitric oxide synthase (eNOS) (Su, 2015). NO enters the smooth muscle cells and activates soluble guanylate cyclase to release the second messenger cyclic guanosine monophosphate (cGMP), which mediates smooth muscle relaxation leading to vasodilation (Cutler et al., 2017). In addition to vasodilation, endothelial NO exhibits anti-inflammatory, anti-platelet, anti-proliferative, and anti-migration properties (Cutler et al., 2017; Su, 2015). Hence, a defective eNOS and/or reduced NO production can lead to endothelial dysfunction resulting in arterial stiffness, increased blood pressure, and the development of atherosclerosis (Cutler et al., 2017). In pathological conditions, eNOS is uncoupled, and the resulting eNOS monomer produces superoxide instead of NO (Cutler et al., 2017). Superoxide interacts with NO to form peroxynitrite (ONOO-), which reduces the bioavailability of NO (Cutler et al., 2017; Hopkins, 2013). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are another source of superoxide and oxidative stress. Oxidative stress and reduced NO availability in the vasculature induce vascular inflammation and atherosclerosis by up-regulating the expression of a number of pro-inflammatory chemokines and adhesion molecules [interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1) and E-selectin] (Cutler et al., 2017; Park and Park, 2015). These inflammatory molecules accelerate monocyte binding to the vasculature, followed by the migration of monocytes to the subendothelial space, where these monocytes differentiate into macrophage foam cells by their uptake of several lipid and oxidized low-density lipoprotein molecules (Cutler et al., 2017; Hopkins, 2013). Nuclear factor ĸB (NFĸB) is a pro-inflammatory transcription factor induced by ROS (Cutler et al., 2017). In homeostatic conditions, the NFĸB subunits p50/p65 are retained in the cytoplasm by binding to inhibitor IĸBα. During inflammatory conditions, IĸB kinase (IĸKβ) phosphorylates IĸBα resulting in the dissociation of IĸBα and nuclear translocation of p50/65. In the nucleus, p50/65 binds to the promotor regions and upregulates NFĸB-dependent inflammatory genes leading to vascular inflammation and atherosclerosis (Cutler et al., 2017; Hopkins, 2013).

Recent studies indicate that glycocalyx, which covers the vascular endothelium and acts as a biologically active barrier for the vasculature, also plays a key role in atherosclerosis. Glycocalyx is composed of proteoglycans, glycoproteins, and plasma proteins. The proteoglycans of glycocalyx have core proteins with glycosaminoglycans, and the most abundant glycosaminoglycans are heparan sulfate proteoglycans (Becker et al., 2015; Kolsen-Petersen, 2015). An intact glycocalyx protects the vasculature by preventing endothelial inflammation, enhancing NO bioavailability, and promoting vessel dilation through activation of eNOS via shear stress which is a tangential force exerted by the flowing blood on the endothelial surface of a blood vessel (Becker et al., 2015; Kolsen-Petersen, 2015). Diabetes and metabolic disorders affect the structure and function of the glycocalyx (Cutler et al., 2018). A compromised glycocalyx enhances monocyte binding to the endothelium leading to vascular inflammation and atherosclerosis (Cutler et al., 2018).

Gut dysbiosis is characterized by an alteration in the structure and functions of the microbiome composition, including decreased microbial diversity, increased opportunistic microbes, and decreased commensal microbes (Miller et al., 2022). Gut dysbiosis contributes to the pathogenesis of cardiovascular diseases, possibly through diet-derived microbial metabolites such as TMAO. Gut microbes increase or decrease the risk of vascular inflammation and atherosclerosis by modulating oxidative stress, inflammatory molecules, eNOS signaling, inflammatory molecules, and NFĸB signaling via diet-derived microbial metabolites (Fukae et al., 2005; Istas et al., 2018; Liu and Dai, 2020; Miller et al., 2022; Simo and Garcia-Canas, 2020; Tedelind et al., 2007; Wang et al., 2021; Yang et al., 2019; Zhao and Wang, 2020; Zhu et al., 2020).

Diet-derived microbial metabolites and vascular health

Emerging evidence indicates the role of gut microbes and diet-derived microbial metabolites in developing or preventing vascular complications such as hypertension and atherosclerosis. Gut microbes are efficient in metabolizing dietary compounds using microbial enzymes and releasing a number of diet-derived microbial metabolites such as SCFA, TMAO, and polyphenol-derived metabolites. SCFA and polyphenol-derived metabolites are beneficial, whereas TMAO is detrimental to vascular health (Figure).

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Gut Microbes Metabolize Dietary Components and Modulate Vascular Health

SCFA

SCFAs are the end product metabolites formed by the fermentation of non-digestible dietary carbohydrates (oligosaccharides, plant cell wall polysaccharides, and starches) from anaerobic gut microbes in the colon (Chambers et al., 2018). SCFA production depends on both fermentable fibers and an individual’s microbiota. SCFA-producing bacteria include species belonging to the genera such as Bifidobacterium, Lactobacillus, Prevotella, Facalibacterium, and Eubacterium, etc. (Portincasa et al., 2022). Acetate, butyrate, and propionate are the most prevalent SCFA synthesized by the gut microbiome, accounting for > 95% of intestinal SCFA (Canfora et al., 2015). The physiological function of SCFAs differs as their number of carbon atoms is different. In addition to providing energy to the host, SCFA act as signaling molecules and carry out diverse physiological functions (Ohira et al., 2017). This includes regulating autonomic systems, inflammatory responses, chemotaxis, phagocytosis, reactive oxygen species, and alterations of the intestinal barrier integrity (Ohira et al., 2017). Acetate and butyrate play a crucial role in maintaining epithelial barrier function, while butyrate also contributes to host energy metabolism, augmentation of mucus production, and the expression of tight junction proteins (Ohira et al., 2017).

SCFAs regulate cardiovascular health by playing a key role in blood pressure regulation, suppressing vascular inflammation, and improving atherosclerosis (Baxter et al., 2019; Pluznick et al., 2013). SCFAs differentially modulate blood pressure and vascular tone by activating two different G-protein coupled receptors [G-protein receptor 41 (GRP41) and olfactory receptor 78 (Olfr78)] (Miyamoto et al., 2016). The activation of Olfr78 by propionate and acetate increases blood pressure by releasing renin and reducing vascular resistance (Pluznick et al., 2013). However, these SCFA decrease blood pressure when acting through GPR41 (Pluznick et al., 2013). The contradictory responses create a protective buffering effect that helps regulate blood pressure fluctuations resulting from normal physiological changes in SCFA (Pluznick et al., 2013). In addition, propionate in drinking water reduces angiotensin-II-induced hypertension in both wild-type mice and Apo E−/− mice (a well-established model of human atherosclerosis) through the expansion of the splenic Treg cell population (Bartolomaeus et al., 2019). Consistently, supplementation of a high-fiber diet or acetate reduced blood pressure in the deoxycorticosterone acetate-salt mouse model (Marques et al., 2017). A recent human study indicated that butyrate-producing gut bacteria (Odoribacter) are negatively associated with blood pressure in obese pregnant women suggesting that increasing the abundance of Odoribacter and subsequently increasing butyrate-producing capacity may reduce the complications of blood pressure in pregnant women (Gomez-Arango et al., 2016).

SCFAs also ameliorate vascular inflammation and atherosclerosis. Acetate, butyrate, and propionate possess efficient anti-inflammatory properties by inhibiting the NFκB pathway and modifying inflammatory responses (Fukae et al., 2005; Tedelind et al., 2007). Butyrate supplementation was shown to suppress atherosclerotic lesions in Apo E−/− mice (Aguilar et al., 2014; Aguilar et al., 2016). Moreover, butyrate was found to decrease the production of chemotaxis protein-1 (CCL2/MCP-1), VCAM1, and matrix metalloproteinase-2 at the lesion site, which led to reduced macrophage migration, increased collagen deposition, and enhanced plaque stability (Aguilar et al., 2014). Butyrate-treated mice also demonstrated lower levels of ROS and nitric oxide release by peritoneal macrophages (Aguilar et al., 2016). Butyrate protects against high‐fat diet‐induced atherosclerosis via up‐regulating ABCA1 expression in Apo E−/− mice (Du et al., 2020). Indeed, a negative relationship exists between the butyrate-producing bacteria Roseburia intestinalis and atherosclerosis / systemic inflammation in Apo E−/− mice (Kasahara et al., 2018). Butyrate improves atherosclerosis by decreasing NFκB activation, reducing macrophage adhesion and migration, and alleviating inflammation (Aguilar et al., 2014; Aguilar et al., 2016). Supplementation of propionate in drinking water was shown to attenuate vascular inflammation, improve vascular dysfunction, reduce hypertension, and decrease atherosclerotic lesions in Apo E−/− mice, mainly via regulatory T cells (Bartolomaeus et al., 2019).

CVD contributes to mortality among individuals with diabetes, and uncontrolled hyperglycemia plays a substantial role in inducing vascular inflammation and fostering the development of atherosclerosis in diabetic patients (Muzurovic and Mikhailidis, 2021; Pippitt et al., 2016). Recent human studies have established an association between SCFAs and the emergence of vascular complications in the diabetes (Muradi et al., 2022; Tanase et al., 2020). These studies suggest the possible role of SCFAs in reducing vascular inflammation and atherosclerosis in diabetes. Beyond their direct impact on the vasculature, SCFAs might also alleviate vascular complications by exerting an effect on hyperglycemia, and the influence of SCFAs on glycemic regulation is well-established in humans (Cherta-Murillo et al., 2022).

Collectively, these findings indicate a significant physiological connection between SCFAs and vascular health. SCFAs influence multiple targets and modulate blood pressure, vascular inflammation, and atherosclerosis. Consequently, modulating SCFA production could be a potential strategy to improve vascular health.

TMA and TMAO

TMAO is an oxidation product of the microbial metabolite trimethyl amine (TMA) and is produced through a microbiome-host metabolic axis. Evidence indicates that circulating TMAO is associated with an increased risk of atherosclerotic burden and death due to arterial diseases (Roncal et al., 2019; Wang et al., 2021). Indeed, TMAO is a potential biomarker for CVD and predicts cardiovascular outcomes such as peripheral artery disease, coronary artery disease, acute coronary syndrome, and heart failure (Agus et al., 2021; Witkowski et al., 2020). An increased circulating TMAO concentration is positively associated with the risk of hypertension. Furthermore, a significant positive dose-dependent association between circulating TMAO concentrations and hypertension risk has been reported in previous studies (Ge et al., 2020; Nie et al., 2018).

Red meat, egg yolk, fish, and dairy products are major sources of TMA precursors, such as phosphatidylcholine, choline, and L-carnitine, that possess a TMA moiety. Gut microbes metabolize these nutrients to TMA by using microbial enzymes. Gut microbes convert choline to TMA using choline TMA lyases encoded by functional microbial genes cut C/D (Janeiro et al., 2018). The human microbiome project identified 16 bacterial species that encode TMA lyase, and 4 out of these 16 species belong to the genera Desulfovibrio (Zhao and Wang, 2020). Choline can also be converted to betaine using two enzymes (choline dehydrogenase and betaine aldehyde dehydrogenase) which is then converted to TMA by a reductase (Janeiro et al., 2018). Dietary L-carnitine is converted to TMA by microbial carnitine oxidoreductase (Janeiro et al., 2018). TMA can also be produced from ergothioneine, rich in mushrooms and legumes (Janeiro et al., 2018). TMA produced by the action of microbial enzymes in the colon is transported to the liver, where it is oxidized into TMAO by the hepatic flavin monooxygenases (FMO) such as FMO3 (Chen et al., 2019; Zhao and Wang, 2020). TMAO returns to the bloodstream from the liver via portal circulation and circulates throughout the body. In addition, the intake of TMAO-rich foods (fish and shellfish) leads to a direct absorption of TMAO from the gastrointestinal tract (Simo and Garcia-Canas, 2020). TMAO in circulation can be stored in cells or cleared through kidneys (Chen et al., 2019). The role of gut microbiota in TMAO production is well-documented in humans, and dysbiosis associated with an increased intake of TMA precursors elevates plasma TMAO (Agus et al., 2021; Koeth et al., 2019; Tang et al., 2013). TMAO production is affected by diet, gut microbiota, drugs, age, and liver enzyme activity (Chen et al., 2019; Zhao and Wang, 2020). TMA-producing microbes and FMO3 are reported to be altered in pathological conditions. TMA-lyase gene is overabundant in CVD, and FMO3 is increased in diabetic patients (Miao et al., 2015; Zhao and Wang, 2020).

TMAO actively participates in vascular inflammation, vascular dysfunction, progression of atherosclerosis, platelet activation, and thrombus formation (Liu and Dai, 2020; Wang et al., 2021; Yang et al., 2019; Zhao and Wang, 2020; Zhu et al., 2020). TMAO-induced ROS production induces NFκB signaling, activates the NLRP3 inflammasome, and impairs endothelial nitric oxide synthase (eNOS)/ nitric oxide (NO) signaling (Brunt et al., 2020; Chen et al., 2017; Seldin et al., 2016). This leads to the upregulation of vascular inflammation and dysfunction, followed by the development of atherosclerosis (Brunt et al., 2020; Chen et al., 2017; Seldin et al., 2016). TMAO increases inflammatory markers and enhances monocyte binding to aortic endothelium by activating NFκB in Ldlr−/− mice (low-density lipoprotein receptor knockout mice) fed a choline-rich diet (Seldin et al., 2016). TMAO promotes vascular inflammation and dysfunction by activating NLRP3 inflammatory bodies, and the specific molecular mechanisms may be the inhibition of the Sirtuin 3-superoxide dismutase 2-mitochondrial ROS pathway and the activation of ROS-thioredoxin interactive protein axis (Chen et al., 2017; Sun et al., 2016). TMAO induces vascular inflammation and foam cell formation by upregulation MAPK/JNK pathway (Geng et al., 2018). Endothelial cells treated with TMAO showed increased VCAM1 and monocyte binding to the endothelium, possibly through NFκB signaling (Ma et al., 2017). TMAO enhances the adhesion ability of monocytes to promote atherosclerosis by activating the protein kinase C/ NFκB/vascular cell adhesion molecule-1 pathway (Ma et al., 2017). TMAO can also induce the development of atherosclerosis by modulating lipid metabolism. TMAO can upregulate CD36 expression, class A1 scavenger receptor, and cholesterol migration-related gene ATP-binding cassette transporter A1 in macrophages, resulting in cholesterol accumulation (Wang et al., 2022). TMAO inhibits the synthesis of bile acids and accelerates the formation of aortic lesions in Apo E−/− mice through the activation of FXR and small heterodimer partners (Ding et al., 2018). Microbial choline TMA lyase inhibitor 3,3-dimethyl-1-butanol suppresses TMAO formation, macrophage foam cell formation, and atherosclerosis in vivo (Wang et al., 2015). 3,3-Dimethyl-1-butanol is a structural analog of choline and shown to inhibit choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in Apo E−/− mice. This study suggests that gut microbial production of TMA specifically, and non-lethal microbial inhibitors in general, may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases (Wang et al., 2015).

Platelets play an important role in the occurrence and development of atherosclerosis. TMAO promotes platelet hyperactivity and thrombosis by increasing the intracellular Ca2+ release (Zhu et al., 2016). Oral administration of cut C/D inhibitor reduces plasma TMAO levels and improves diet-induced platelet hyperreactivity and thrombosis in the preclinical model (Roberts et al., 2018). These studies reveal that mechanism-based inhibition of gut microbial TMA and TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective nonlethal targeting of gut microbial enzymes linked to host disease by limiting systemic exposure of the inhibitor in the host. FMO3 knockout mice showed a decreased systemic TMAO and thrombosis potential (Shih et al., 2019). Recent studies suggest that TMAO may be directly responsible for platelet hyperreactivity which increases thrombosis risk in patients with high plasma TMAO concentrations (Zhu et al., 2016).

Taken together, these studies suggest that TMAO triggers vascular inflammation, atherosclerosis, platelet activation, and the formation of thrombi. Hence, inhibiting TMA/TMAO signaling pathway emerges as a promising strategy for reducing vascular complications.

Amino acid-derived metabolites

Dietary proteins that reach the large intestine undergo proteolytic fermentation by microbial enzymes resulting in the production of amino acid derived microbial metabolites. Beef, pork, chicken, and fish proteins are dietary sources of aromatic amino acids such as phenylalanine, tryptophan, and tyrosine (Zhang and Gerard, 2022). Evidence indicates aromatic amino acid derived microbial metabolites, such as phenylalanine-derived metabolite phenyl acetyl glutamine and tryptophan-derived metabolite indoxyl sulfate, negatively impact vascular health. Gut microbes such as Clostridium sporogenes convert phenylalanine to phenylacetic acid, which is then converted to phenylacetylglutamine in the liver (Nemet et al., 2020; Zhu et al., 2023). In animal models of arterial injury, phenylacetylglutamine binds to GPR on the surface of the platelet cells leading to hyperstimulation of the platelets, which then become hyperresponsive and accelerate platelet aggregation and the thrombosis process (Nemet et al., 2020). Phenylacetylglutamine is linked to adverse cardiac events such as myocardial infarction and coronary artery disease (Nemet et al., 2020; Ottosson et al., 2020). Tryptophan-derived metabolite indoxyl sulfate has been shown to induce endothelial dysfunction and predict cardiovascular events in patients with chronic kidney disease. Indoxyl sulfate activates the aryl hydrocarbon receptor mediating oxidative stress and endothelial dysfunction via activation of the CYP1A1 pathway (Nguyen et al., 2022). Aortic rings exposed to indoxyl sulfate increased the expression of CYP1A1, nitro-tyrosine, NOX4, superoxide, and reduced eNOS expression (Nguyen et al., 2022). Further, indole- and phenyl-derived microbial metabolites are linked to advanced atherosclerosis and postoperative cardiovascular complications in individuals who have undergone procedures such as open infrainguinal leg revascularization, carotid endarterectomy, or major leg amputation for critical limb ischemia (Cason et al., 2018). Indole compounds are ligands for aryl hydrocarbon receptors, and activation of this receptor was shown to promote atherosclerosis in Apo E−/− mice (Wu et al., 2011). A recent targeted metabolic study was performed to identify the influence of indole and phenyl-derived microbial metabolites in vascular health (Cason et al., 2018). This study found that the plasma concentration of many of these metabolites is altered in patients with advanced atherosclerosis and correlated with postoperative outcomes in patients with advanced atherosclerosis. Specifically, indole-derived metabolites such as indole-3-propionic acid and indole-3-aldehyde had an inverse relationship with advanced atherosclerosis in humans. This study suggests that a different receptor mediates these metabolites in humans. A microbiota derivative of tryptophan dramatically reduced plasma in people with advanced atherosclerosis. Tryptophan is converted to indole, I3A, and I3P by bacterial enzymatic pathways (Cason et al., 2018). Tryptophan is metabolized by serotonin or the kynurenine pathway where it is converted to indole-2,3-deoxygenase and then to Kynureinine (Le Floc’h et al., 2011). The indole-2,3-deoxygenase deficiency was shown to reduce atherosclerotic plaque in Apo E−/− mice (Cole et al., 2015).

Collectively, these findings indicate the adverse effects of microbial metabolites derived from aromatic amino acids on the vasculature. Therefore, modulating the gut microbes responsible for producing these metabolites holds the potential for alleviating vascular complications.

Polyphenol-derived metabolites

Polyphenols are natural bioactive compounds abundant in most fruits and vegetables. The major classes of polyphenols include phenolic acids, flavonoids, stilbenes, and lignans. The health-promoting effects of polyphenols are well documented in epidemiological, clinical, and preclinical studies. Most of these polyphenols are not digested by human digestive enzymes, and 90–95% of polyphenols reach the large intestine where gut microbes metabolize them using several microbial enzymes (Kawabata et al., 2019). Evidence indicates that gut microbes belonging to the genera such as Eubacterium, Lactobacillus, and Bifidobacterium play a crucial role in metabolizing polyphenols into bioactive metabolites (Pasinetti et al., 2018). The resulting diet-derived gut metabolites, such as phenolic acids, enter circulation and mediate the biological activities of the polyphenols. Hence, the effect of bioactive polyphenolic compounds on the host mostly depends on gut microbes (Duda-Chodak et al., 2015). Polyphenols metabolized by gut microbes produce intermediate metabolites such as phenyl propionic acid, phenylacetic acid, and benzoic acid, which are common among the subgroups (Pei et al., 2020). Interestingly, the carbohydrate component released from the polyphenol glycosides during this process provides energy for the microbes, and hence many of the polyphenols act as prebiotics (Miller et al., 2022). Indeed, there is a two-way relationship that exists between polyphenols and gut microbes. Gut microbes increase the bioavailability of polyphenol-derived microbial metabolites, whereas polyphenols support the growth of commensal microbes (Miller et al., 2022). The structural difference between the different subgroups of polyphenols allows them to regulate different metabolic pathways and eventually modulate metabolites produced in the body (Pei et al., 2020).

Ellagitannin is a polyphenol present in pomegranates, berries, and walnuts. Gut microbes metabolize ellagitannin to urolithins. The beneficial effects of Urolithin A on vasculature are well documented in clinical studies (D’Amico et al., 2021; Istas et al., 2018). A human intervention study found that plasma urolithin A metabolites correlated with improvements in endothelial function following red raspberry consumption (Istas et al., 2018). Further, the effect of urolithin A on the improvement of vascular endothelial function correlated with specific gut microbes (Nishimoto et al., 2022). Urolithin is responsible for the beneficial vascular effects observed in the consumption of ellagitannin-containing foods.

Clinical studies indicate consumption of blueberries and strawberries improves vascular health. In a human study, an increase in endothelium-dependent vascular function and a decrease in NOX were accompanied by increases in the plasma concentrations of phenolic metabolites of blueberries (Rodriguez-Mateos et al., 2013). An in vitro study showed that a mixture of blueberry metabolites (at physiologically relevant concentrations that circulates in human plasma during the observed biological effect) attenuate lipotoxicity or diabetes-induced endothelial inflammation in human aortic endothelial cells as shown by a reduced monocyte binding to endothelial cells and pro-inflammatory markers (Bharat et al., 2018). This study suggests that the beneficial effects of these metabolites on vascular endothelium are possibly mediated through increased nitric oxide production and reduced NOX4, ROS, and NFκB signaling. Further, in an ex vivo study, these blueberry metabolites ameliorate lipotoxicity-induced vascular dysfunction and increase endothelium-dependent vessel relaxation (Bharat et al., 2018). In addition, blueberry metabolites reduce endothelial inflammation by improving glycosaminoglycans in vascular endothelial cells from diabetic patients (Cutler et al., 2018). Consistent with these studies, protocatechuic acid (a key polyphenol-derived microbial metabolite) at physiologically relevant concentrations has been shown to increase endothelium-dependent vessel relaxation in diabetic mice and suppress diabetes-induced endothelial inflammation (Chook et al., 2023). In this study, protocatechuic acid reduced ROS, suppressed pro-inflammatory chemokines (MCP1, VCAM1, and ICAM1), and increased the expression of phosphorylated eNOS (Chook et al., 2023).

Taken together, these investigations indicate that gut microbes extensively metabolize dietary polyphenols, and it is likely that the favorable vascular impacts attributed to dietary polyphenols might be mediated by their microbial metabolites.

Concluding remarks and future prospective

The impact of diet-derived microbial metabolites on vascular health is well documented. However, there are significant knowledge gaps in this field. (1) The specific microbes and microbial enzymes essential for the production of diet-derived metabolites are largely unknown. Future studies using germ-free or gnotobiotic mice may identify these enzymes. (2) Understanding the role of the food matrix in regulating the bioavailability of metabolite production by gut microbes is important. (3) Studies focusing on the structure-activity relationships of diet-derived microbial metabolites are required to understand the interaction between metabolites and biomolecules in the vasculature. (4) Identifying the causal association between dietary compounds, gut microbes, diet-derived metabolites, and vascular health using radiolabeled parent compounds, metabolomics, transcriptomics, and proteomics will move this field significantly forward. (5) Most studies used animal models, and a well-designed human clinical trial may be required to identify the vascular effects of diet-derived microbial metabolites. The potential diet-derived metabolites to improve vascular health can be identified through future studies that investigate the causal relationship between dietary components, gut microbes, diet-derived metabolites, and vascular health using techniques such as radiolabeled parent compounds, metabolomics, transcriptomics, and proteomics.

Acknowledgments

The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Funding

PVAB is supported by the National Institute of Health under Grant No. R01AT010247 and USDA-National Institute of Foods and Agriculture under Grant No. 2019-67017-29253.

Footnotes

Disclosure statement

The authors declare that they have no competing interests. All authors have read and approved the submission of the manuscript and have provided consent for publication.

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