Role of Gut Microbial Metabolites in Cardiovascular Diseases-Current Insights and the Road Ahead.

Cardiovascular diseases (CVDs) are the leading cause of premature morbidity and mortality globally. The identification of novel risk factors contributing to CVD onset and progression has enabled an improved understanding of CVD pathophysiology. In addition to the conventional risk factors like high blood pressure, diabetes, obesity and smoking, the role of gut microbiome and intestinal microbe-derived metabolites in maintaining cardiovascular health has gained recent attention in the field of CVD pathophysiology. The human gastrointestinal tract caters to a highly diverse spectrum of microbes recognized as the gut microbiota, which are central to several physiologically significant cascades such as metabolism, nutrient absorption, and energy balance. The manipulation of the gut microbial subtleties potentially contributes to CVD, inflammation, neurodegeneration, obesity, and diabetic onset. The existing paradigm of studies suggests that the disruption of the gut microbial dynamics contributes towards CVD incidence. However, the exact mechanistic understanding of such a correlation from a signaling perspective remains elusive. This review has focused upon an in-depth characterization of gut microbial metabolites and their role in varied pathophysiological conditions, and highlights the potential molecular and signaling mechanisms governing the gut microbial metabolites in CVDs. In addition, it summarizes the existing courses of therapy in modulating the gut microbiome and its metabolites, limitations and scientific gaps in our current understanding, as well as future directions of studies involving the modulation of the gut microbiome and its metabolites, which can be undertaken to develop CVD-associated treatment options. Clarity in the understanding of the molecular interaction(s) and associations governing the gut microbiome and CVD shall potentially enable the development of novel druggable targets to ameliorate CVD in the years to come.

Dietary Polyphenols and Gut Microbiota Cross-Talk: Molecular and Therapeutic Perspectives for Cardiometabolic Disease: A Narrative Review.

The intricate interplay between the gut microbiota and polyphenols has emerged as a captivating frontier in understanding and potentially harnessing the therapeutic potential of these bioactive compounds. Phenolic compounds, renowned for their antioxidant, anti-inflammatory, antidiabetic, and anticancer properties, are subject to intricate transformations within the gut milieu, where the diverse microbial ecosystem exerts profound effects on their metabolism and bioavailability. Conversely, polyphenols exhibit a remarkable capacity to modulate the composition and activity of the gut microbiota, fostering a bidirectional relationship that extends beyond mere nutrient processing. This symbiotic interaction holds significant implications for human health, particularly in cardiometabolic diseases such as diabetes mellitus, metabolic-dysfunction-associated steatotic liver disease, and cardiovascular disease. Through a comprehensive exploration of molecular interactions, this narrative review elucidates the reciprocal dynamics between the gut microbiota and polyphenols, unveiling novel avenues for therapeutic intervention in cardiometabolic disorders. By unravelling the intricate cross-talk between these two entities, this review underscores the multifaceted roles of polyphenols in overall health and the pivotal role of gut microbiota modulation as a promising therapeutic strategy in mitigating the burden of cardiometabolic diseases.

Human Gut Microbiota in Cardiovascular Disease.

The gut ecosystem, termed microbiota, is composed of bacteria, archaea, viruses, protozoa, and fungi and is estimated to outnumber human cells. Microbiota can affect the host by multiple mechanisms, including the synthesis of metabolites and toxins, modulating inflammation and interaction with other organisms. Advances in understanding commensal organisms' effect on human conditions have also elucidated the importance of this community for cardiovascular disease (CVD). This effect is driven by both direct CV effects and conditions known to increase CV risk, such as obesity, diabetes mellitus (DM), hypertension, and renal and liver diseases. Cardioactive metabolites, such as trimethylamine N -oxide (TMAO), short-chain fatty acids (SCFA), lipopolysaccharides, bile acids, and uremic toxins, can affect atherosclerosis, platelet activation, and inflammation, resulting in increased CV incidence. Interestingly, this interaction is bidirectional with microbiota affected by multiple host conditions including diet, bile acid secretion, and multiple diseases affecting the gut barrier. This interdependence makes manipulating microbiota an attractive option to reduce CV risk. Indeed, evolving data suggest that the benefits observed from low red meat and Mediterranean diet consumption can be explained, at least partially, by the changes that these diets may have on the gut microbiota. In this article, we depict the current epidemiological and mechanistic understanding of the role of microbiota and CVD. Finally, we discuss the potential therapeutic approaches aimed at manipulating gut microbiota to improve CV outcomes. © 2024 American Physiological Society. Compr Physiol 14:5449-5490, 2024.

Cardiovascular events after invasive pneumococcal disease: a retrospective cohort study.

OBJECTIVES: This study aims to understand the magnitude of and mechanisms underlying the development of cardiovascular events (CVEs) in patients with invasive pneumococcal disease (IPD). We aimed to identify factors that contribute to the occurrence of CVEs within 1 year after admission and discuss implications for patient care. METHODS: A multicentered cohort study included adult patients from four Dutch hospitals who had a positive blood culture for Streptococcus pneumoniae and any type of clinical manifestation between 2012 and 2020. Disease characteristics and microbiological data were systematically collected from electronic patient files. The main outcome measures were the occurrence of stroke and acute coronary syndromes (ACS). RESULTS: Of 914 eligible patients, 4.2% experienced a CVE within 1 year after admission for IPD. ACS mainly occurred in the first 2 weeks, whereas stroke developed throughout follow-up. Although ACS was positively associated with disease severity, the sole independent predictor was alcohol abuse (odds ratio [OR] 3.840, 95% confidence interval [CI] 1.108-13.303). Although stroke occurred in 6.3% of meningitis cases, the best clinical predictor of stroke was a body temperature >39.5 °C at admission (OR 3.117 [1.154-8.423]). In the adult IPD population aged <70 years, pneumococcal serotypes were the primary predictors of ACS (7F; OR 15.733 [1.812-136.632]) and stroke (22F; OR 7.320 [1.193-44.903]). CONCLUSIONS: Adverse CVEs were not uncommon after IPD diagnosis and deserve attention, especially in the high-risk groups we identified in our study population. Whether specific serotypes play a role in the development of CVE requires substantiation in further research.

Urinary Equol and Equol-Predicting Microbial Species Are Favorably Associated With Cardiometabolic Risk Markers in Chinese Adults.

BACKGROUND: The association between soy isoflavones intake and cardiometabolic health remains inconclusive. We investigated the associations of urinary biomarkers of isoflavones including daidzein, glycitein, genistein, equol (a gut microbial metabolite of daidzein), and equol-predicting microbial species with cardiometabolic risk markers. METHODS AND RESULTS: In a 1-year study of 305 Chinese community-dwelling adults aged ≥18 years, urinary isoflavones, fecal microbiota, blood pressure, blood glucose and lipids, and anthropometric data were measured twice, 1 year apart. Brachial-ankle pulse wave velocity was also measured after 1 year. A linear mixed-effects model was used to analyze repeated measurements. Logistic regression was used to calculate the adjusted odds ratio (aOR) and 95% CI for the associations for arterial stiffness. Each 1 µg/g creatinine increase in urinary equol concentrations was associated with 1.47%, 0.96%, and 3.32% decrease in triglycerides, plasma atherogenic index, and metabolic syndrome score, respectively (all P<0.05), and 0.61% increase in high-density lipoprotein cholesterol (P=0.025). Urinary equol was also associated with lower risk of arterial stiffness (aOR, 0.28 [95% CI, 0.09-0.90]; Ptrend=0.036). We identified 21 bacterial genera whose relative abundance was positively associated with urinary equol (false discovery rate-corrected P<0.05) and constructed a microbial species score to reflect the overall equol-predicting capacity. This score (per 1-point increase) was inversely associated with triglycerides (percentage difference=-1.48%), plasma atherogenic index (percentage difference=-0.85%), and the risk of arterial stiffness (aOR, 0.27 [95% CI, 0.08-0.88]; all P<0.05). CONCLUSIONS: Our findings suggest that urinary equol and equol-predicting microbial species may improve cardiometabolic risk parameters in Chinese adults.

Analysis of Alterations in Intestinal Flora in Chinese Elderly with Cardiovascular Disease and Its Association with Trimethylamine.

To investigate the changes in the intestinal flora in the Chinese elderly with cardiovascular disease (CVD) and its correlation with the metabolism of trimethylamine (TMA), the intestinal flora composition of elderly individuals with CVD and healthy elderly individuals was analyzed using 16S rRNA sequencing, the TMA levels in the feces of elderly were detected using headspace-gas chromatography (HS-GC), and four kinds of characterized TMA-producing intestinal bacteria in the elderly were quantified using real-time fluorescence quantitative polymerase chain reaction (qPCR). The results showed that Firmicutes, Actinobacteria, Proteobacteria, Bacteroidetes, and Verrucomicrobia are the dominant microorganisms of the intestinal flora in the Chinese elderly. And there were significant differences in the intestinal bacteria composition between healthy elderly individuals and those with CVD, accompanied by a notable difference in the TMA content. The richness and diversity of the intestinal flora in the elderly with CVD were higher than those in the healthy elderly. Correlation analysis indicated that certain significantly different intestinal flora were associated with the TMA levels. Our findings showed a significant difference in TMA-producing intestinal flora between healthy elderly individuals and those with CVD. The TMA levels were found to be positively and significantly correlated with Klebsiella pneumoniae, suggesting that this bacterium is closely linked to the production of TMA in the elderly gut. This may have implications for the development and progression of CVD in the elderly population.

Divergent age-associated and metabolism-associated gut microbiome signatures modulate cardiovascular disease risk.

Insight into associations between the gut microbiome with metabolism and aging is crucial for tailoring interventions to promote healthy longevity. In a discovery cohort of 10,207 individuals aged 40-93 years, we used 21 metabolic parameters to classify individuals into five clusters, termed metabolic multimorbidity clusters (MCs), that represent different metabolic subphenotypes. Compared to the cluster classified as metabolically healthy (MC1), clusters classified as 'obesity-related mixed' (MC4) and 'hyperglycemia' (MC5) exhibited an increased 11.1-year cardiovascular disease (CVD) risk by 75% (multivariable-adjusted hazard ratio (HR): 1.75, 95% confidence interval (CI): 1.43-2.14) and by 117% (2.17, 1.72-2.74), respectively. These associations were replicated in a second cohort of 9,061 individuals with a 10.0-year follow-up. Based on analysis of 4,491 shotgun fecal metagenomes from the discovery cohort, we found that gut microbial composition was associated with both MCs and age. Next, using 55 age-specific microbial species to capture biological age, we developed a gut microbial age (MA) metric, which was validated in four external cohorts comprising 4,425 metagenomic samples. Among individuals aged 60 years or older, the increased CVD risk associated with MC4 or MC5, as compared to MC1, MC2 or MC3, was exacerbated in individuals with high MA but diminished in individuals with low MA, independent of age, sex and other lifestyle and dietary factors. This pattern, in which younger MA appears to counteract the CVD risk attributable to metabolic dysfunction, implies a modulating role of MA in cardiovascular health for metabolically unhealthy older people.

Gut microbiome and cardiometabolic comorbidities in people living with HIV.

BACKGROUND: Despite modern antiretroviral therapy (ART), people living with HIV (PLWH) have increased relative risk of inflammatory-driven comorbidities, including cardiovascular disease (CVD). The gut microbiome could be one of several driving factors, along with traditional risk factors and HIV-related risk factors such as coinfections, ART toxicity, and past immunodeficiency. RESULTS: PLWH have an altered gut microbiome, even after adjustment for known confounding factors including sexual preference. The HIV-related microbiome has been associated with cardiometabolic comorbidities, and shares features with CVD-related microbiota profiles, in particular reduced capacity for short-chain fatty acid (SCFA) generation. Substantial inter-individual variation has so far been an obstacle for applying microbiota profiles for risk stratification. This review covers updated knowledge and recent advances in our understanding of the gut microbiome and comorbidities in PLWH, with specific focus on cardiometabolic comorbidities and inflammation. It covers a comprehensive overview of HIV-related and comorbidity-related dysbiosis, microbial translocation, and microbiota-derived metabolites. It also contains recent data from studies in PLWH on circulating metabolites related to comorbidities and underlying gut microbiota alterations, including circulating levels of the SCFA propionate, the histidine-analogue imidazole propionate, and the protective metabolite indole-3-propionic acid. CONCLUSIONS: Despite recent advances, the gut microbiome and related metabolites are not yet established as biomarkers or therapeutic targets. The review gives directions for future research needed to advance the field into clinical practice, including promises and pitfalls for precision medicine. Video Abstract.

Unravelling the Gut Microbiome Role in Cardiovascular Disease: A Systematic Review and a Meta-Analysis.

A notable shift in understanding the human microbiome's influence on cardiovascular disease (CVD) is underway, although the causal association remains elusive. A systematic review and meta-analysis were conducted to synthesise current knowledge on microbial taxonomy and metabolite variations between healthy controls (HCs) and those with CVD. An extensive search encompassing three databases identified 67 relevant studies (2012-2023) covering CVD pathologies from 4707 reports. Metagenomic and metabolomic data, both qualitative and quantitative, were obtained. Analysis revealed substantial variability in microbial alpha and beta diversities. Moreover, specific changes in bacterial populations were shown, including increased Streptococcus and Proteobacteria and decreased Faecalibacterium in patients with CVD compared with HC. Additionally, elevated trimethylamine N-oxide levels were reported in CVD cases. Biochemical parameter analysis indicated increased fasting glucose and triglycerides and decreased total cholesterol and low- and high-density lipoprotein cholesterol levels in diseased individuals. This study revealed a significant relationship between certain bacterial species and CVD. Additionally, it has become clear that there are substantial inconsistencies in the methodologies employed and the reporting standards adhered to in various studies. Undoubtedly, standardising research methodologies and developing extensive guidelines for microbiome studies are crucial for advancing the field.

The gut-immune axis during hypertension and cardiovascular diseases.

The gut-immune axis is a relatively novel phenomenon that provides mechanistic links between the gut microbiome and the immune system. A growing body of evidence supports it is key in how the gut microbiome contributes to several diseases, including hypertension and cardiovascular diseases (CVDs). Evidence over the past decade supports a causal link of the gut microbiome in hypertension and its complications, including myocardial infarction, atherosclerosis, heart failure, and stroke. Perturbations in gut homeostasis such as dysbiosis (i.e., alterations in gut microbial composition) may trigger immune responses that lead to chronic low-grade inflammation and, ultimately, the development and progression of these conditions. This is unsurprising, as the gut harbors one of the largest numbers of immune cells in the body, yet is a phenomenon not entirely understood in the context of cardiometabolic disorders. In this review, we discuss the role of the gut microbiome, the immune system, and inflammation in the context of hypertension and CVD, and consolidate current evidence of this complex interplay, whilst highlighting gaps in the literature. We focus on diet as one of the major modulators of the gut microbiota, and explain key microbial-derived metabolites (e.g., short-chain fatty acids, trimethylamine N-oxide) as potential mediators of the communication between the gut and peripheral organs such as the heart, arteries, kidneys, and the brain via the immune system. Finally, we explore the dual role of both the gut microbiome and the immune system, and how they work together to not only contribute, but also mitigate hypertension and CVD.

Microbiome miracles and their pioneering advances and future frontiers in cardiovascular disease.

Cardiovascular diseases (CVDs) represent a significant global health challenge, underscoring the need for innovative approaches to prevention and treatment. Recent years have seen a surge in interest in unraveling the complex relationship between the gut microbiome and cardiovascular health. This article delves into current research on the composition, diversity, and impact of the gut microbiome on CVD development. Recent advancements have elucidated the profound influence of the gut microbiome on disease progression, particularly through key mediators like Trimethylamine-N-oxide (TMAO) and other microbial metabolites. Understanding these mechanisms reveals promising therapeutic targets, including interventions aimed at modulating the gut microbiome's interaction with the immune system and its contribution to endothelial dysfunction. Harnessing this understanding, personalized medicine strategies tailored to individuals' gut microbiome profiles offer innovative avenues for reducing cardiovascular risk. As research in this field continues to evolve, there is vast potential for transformative advancements in cardiovascular medicine, paving the way for precision prevention and treatment strategies to address this global health challenge.

Mechanistic Review on the Role of Gut Microbiota in the Pathology of Cardiovascular Diseases.

Cardiovascular diseases (CVDs), which stand as the primary contributors to illness and death on a global scale, include vital risk factors like hyperlipidemia, hypertension, diabetes, and smoking, to name a few. However, conventional cardiovascular risk factors offer only partial insight into the complexity of CVDs. Lately, a growing body of research has illuminated that the gut microbiome and its by-products are also of paramount importance in the initiation and progression of CVDs. The gastrointestinal tract houses trillions of microorganisms, commonly known as gut microbiota, that metabolize nutrients, yielding substances like trimethylamine-N-oxide (TMAO), bile acids (BAs), short-chain fatty acids (SCFAs), indoxyl sulfate (IS), and so on. Strategies aimed at addressing these microbes and their correlated biological pathways have shown promise in the management and diagnosis of CVDs. This review offers a comprehensive examination of how the gut microbiota contributes to the pathogenesis of CVDs, particularly atherosclerosis, hypertension, heart failure (HF), and atrial fibrillation (AF), explores potential underlying mechanisms, and highlights emerging therapeutic prospects in this dynamic domain.

The Mediterranean Diet, Its Microbiome Connections, and Cardiovascular Health: A Narrative Review.

The Mediterranean diet (MD), rich in minimally processed plant foods and in monounsaturated fats but low in saturated fats, meat, and dairy products, represents one of the most studied diets for cardiovascular health. It has been shown, from both observational and randomized controlled trials, that MD reduces body weight, improves cardiovascular disease surrogates such as waist-to-hip ratios, lipids, and inflammation markers, and even prevents the development of fatal and nonfatal cardiovascular disease, diabetes, obesity, and other diseases. However, it is unclear whether it offers cardiovascular benefits from its individual components or as a whole. Furthermore, limitations in the methodology of studies and meta-analyses have raised some concerns over its potential cardiovascular benefits. MD is also associated with characteristic changes in the intestinal microbiota, mediated through its constituents. These include increased growth of species producing short-chain fatty acids, such as Clostridium leptum and Eubacterium rectale, increased growth of Bifidobacteria, Bacteroides, and Faecalibacterium prausnitzii species, and reduced growth of Firmicutes and Blautia species. Such changes are known to be favorably associated with inflammation, oxidative status, and overall metabolic health. This review will focus on the effects of MD on cardiovascular health through its action on gut microbiota.

Gut microbial metabolism is linked to variations in circulating non-high density lipoprotein cholesterol.

BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-c) was a strong risk factor for incident cardiovascular diseases and proved to be a better target of lipid-lowering therapies. Recently, gut microbiota has been implicated in the regulation of host metabolism. However, its causal role in the variation of non-HDL-c remains unclear. METHODS: Microbial species and metabolic capacities were assessed with fecal metagenomics, and their associations with non-HDL-c were evaluated by Spearman correlation, followed by LASSO and linear regression adjusted for established cardiovascular risk factors. Moreover, integrative analysis with plasma metabolomics were performed to determine the key molecules linking microbial metabolism and variation of non-HDL-c. Furthermore, bi-directional mendelian randomization analysis was performed to determine the potential causal associations of selected species and metabolites with non-HDL-c. FINDINGS: Decreased Eubacterium rectale but increased Clostridium sp CAG_299 were causally linked to a higher level of non-HDL-c. A total of 16 microbial capacities were found to be independently associated with non-HDL-c after correcting for age, sex, demographics, lifestyles and comorbidities, with the strongest association observed for tricarboxylic acid (TCA) cycle. Furthermore, decreased 3-indolepropionic acid and N-methyltryptamine, resulting from suppressed capacities for microbial reductive TCA cycle, functioned as major microbial effectors to the elevation of circulating non-HDL-c. INTERPRETATION: Overall, our findings provided insight into the causal effects of gut microbes on non-HDL-c and uncovered a novel link between non-HDL-c and microbial metabolism, highlighting the possibility of regulating non-HDL-c by microbiota-modifying interventions. FUNDING: A full list of funding bodies can be found in the Sources of funding section.

Gut Microbes in Polycystic Ovary Syndrome and Associated Comorbidities; Type 2 Diabetes, Non-Alcoholic Fatty Liver Disease (NAFLD), Cardiovascular Disease (CVD), and the Potential of Microbial Therapeutics.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine anomalies among females of reproductive age, highlighted by hyperandrogenism. PCOS is multifactorial as it can be associated with obesity, insulin resistance, low-grade chronic inflammation, and dyslipidemia. PCOS also leads to dysbiosis by lowering microbial diversity and beneficial microbes, such as Faecalibacterium, Roseburia, Akkermenisa, and Bifidobacterium, and by causing a higher load of opportunistic pathogens, such as Escherichia/Shigella, Fusobacterium, Bilophila, and Sutterella. Wherein, butyrate producers and Akkermansia participate in the glucose uptake by inducing glucagon-like peptide-1 (GLP-1) and glucose metabolism, respectively. The abovementioned gut microbes also maintain the gut barrier function and glucose homeostasis by releasing metabolites such as short-chain fatty acids (SCFAs) and Amuc_1100 protein. In addition, PCOS-associated gut is found to be higher in gut-microbial enzyme ß-glucuronidase, causing the de-glucuronidation of conjugated androgen, making it susceptible to reabsorption by entero-hepatic circulation, leading to a higher level of androgen in the circulatory system. Overall, in PCOS, such dysbiosis increases the gut permeability and LPS in the systemic circulation, trimethylamine N-oxide (TMAO) in the circulatory system, chronic inflammation in the adipose tissue and liver, and oxidative stress and lipid accumulation in the liver. Thus, in women with PCOS, dysbiosis can promote the progression and severity of type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). To alleviate such PCOS-associated complications, microbial therapeutics (probiotics and fecal microbiome transplantation) can be used without any side effects, unlike in the case of hormonal therapy. Therefore, this study sought to understand the mechanistic significance of gut microbes in PCOS and associated comorbidities, along with the role of microbial therapeutics that can ease the life of PCOS-affected women.

Role of the microbiota-gut-heart axis between bile acids and cardiovascular disease.

Bile acid (BA) receptors (e.g., farnesoid X-activated receptor, muscarinic receptor) are expressed in cardiomyocytes, endothelial cells, and vascular smooth muscle cells, indicating the relevance of BAs to cardiovascular disease (CVD). Hydrophobic BAs are cardiotoxic, while hydrophilic BAs are cardioprotective. For example, fetal cardiac insufficiency in maternal intrahepatic cholestasis during pregnancy, and the degree of fetal cardiac abnormality, is closely related to the level of hydrophobic BAs in maternal blood and infant blood. However, ursodeoxycholic acid (the most hydrophilic BA) can reverse/prevent these detrimental effects of increased levels of hydrophobic BAs on the heart. The gut microbiota (GM) and GM metabolites (especially secondary BAs) have crucial roles in hypertension, atherosclerosis, unstable angina, and heart failure. Herein, we describe the relationship between CVD and the GM at the BA level. We combine the concept of the "microbiota-gut-heart axis" (MGHA) and postulate the role and mechanism of BAs in CVD development. In addition, the strategies for treating CVD with BAs under the MGHA are proposed.

Gut microbiota and its relationship with early vascular ageing in a Spanish population (MIVAS study).

BACKGROUND: Gut microbiota and its by-products are increasingly recognized as having a decisive role in cardiovascular diseases. The aim is to study the relationship between gut microbiota and early vascular ageing (EVA). METHODS: A cross-sectional study was developed in Salamanca (Spain) in which 180 subjects aged 45-74 years were recruited. EVA was defined by the presence of at least one of the following: carotid-femoral pulse wave velocity (cf-PWV), cardio-ankle vascular index (CAVI) or brachial-ankle pulse wave velocity (ba-PWV) above the 90th percentile of the reference population. All other cases were considered normal vascular ageing (NVA). MEASUREMENTS: cf-PWV was measured by SphygmoCor® System; CAVI and ba-PWV were determined by Vasera 2000® device. Gut microbiome composition in faecal samples was determined by 16S rRNA Illumina sequencing. RESULTS: Mean age was 64.4 ± 6.9 in EVA group and 60.4 ± 7.6 years in NVA (p < .01). Women in EVA group were 41% and 53% in NVA. There were no differences in the overall composition of gut microbiota between the two groups when evaluating Firmicutes/Bacteriodetes ratio, alfa diversity (Shannon Index) and beta diversity (Bray-Curtis). Bilophila, Faecalibacterium sp.UBA1819 and Phocea, are increased in EVA group. While Cedecea, Lactococcus, Pseudomonas, Succiniclasticum and Dielma exist in lower abundance. In logistic regression analysis, Bilophila (OR: 1.71, 95% CI: 1.12-2.6, p = .013) remained significant. CONCLUSIONS: In the studied Spanish population, early vascular ageing is positively associated with gut microbiota abundance of the genus Bilophila. No relationship was found between phyla abundance and measures of diversity.