Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia/hypercapnia (IHC), affects predominantly obese individuals, and increases atherosclerosis risk. Since we and others have implicated gut microbiota and metabolites in atherogenesis, we dissected their contributions to OSA-induced atherosclerosis. Atherosclerotic lesions were compared between conventionally-reared specific pathogen free (SPF) and germ-free (GF) Apoe-/- mice following a high fat high cholesterol diet (HFHC), with and without IHC conditions. The fecal microbiota and metabolome were profiled using 16S rRNA gene amplicon sequencing and untargeted tandem mass spectrometry (LC-MS/MS) respectively. Phenotypic data showed that HFHC significantly increased atherosclerosis as compared to regular chow (RC) in both aorta and pulmonary artery (PA) of SPF mice. IHC exacerbated lesions in addition to HFHC. Differential abundance analysis of gut microbiota identified an enrichment of Akkermansiaceae and a depletion of Muribaculaceae (formerly S24-7) family members in the HFHC-IHC group. LC-MS/MS showed a dysregulation of bile acid profiles with taurocholic acid, taurodeoxycholic acid, and 12-ketodeoxycholic acid enriched in the HFHC-IHC group, long-chain N-acyl amides, and phosphatidylcholines. Interestingly, GF Apoe-/- mice markedly reduced atherosclerotic formation relative to SPF Apoe-/- mice in the aorta under HFHC/IHC conditions. In contrast, microbial colonization did not show a significant impact on the atherosclerotic progression in PA. In summary, this research demonstrated that (1) IHC acts cooperatively with HFHC to induce atherosclerosis; (2) gut microbiota modulate atherogenesis, induced by HFHC/IHC, in the aorta not in PA; (3) different analytical methods suggest that a specific imbalance between Akkermansiaceae and Muribaculaceae bacterial families mediate OSA-induced atherosclerosis; and (4) derived bile acids, such as deoxycholic acid and lithocholic acid, regulate atherosclerosis in OSA. The knowledge obtained provides novel insights into the potential therapeutic approaches to prevent and treat OSA-induced atherosclerosis.

Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD) is increasing in prevalence worldwide and has become the greatest potential risk for cirrhosis and hepatocellular liver cancer. Currently, the role of gut microbiota in the development of MASLD has become a research hotspot. The development of MASLD can affect the homeostasis of gut microbiota, and significant changes in the composition or abundance of gut microbiota and its metabolite abnormalities can influence disease progression. The regulation of gut microbiota is an important strategy and novel target for the treatment of MASLD with good prospects. In this paper, we summarize the role of gut microbiota and its metabolites in the pathogenesis of MASLD, and describe the potential preventive and therapeutic efficacy of gut microbiota as a noninvasive marker to regulate the pathogenesis of MASLD based on the "gut-hepatic axis", which will provide new therapeutic ideas for the clinic.

Natural flavonoids may be utilized as an important therapy for cardiovascular diseases (CVDs) caused by intestinal barrier damage. More research is being conducted on the protective properties of natural flavonoids against intestinal barrier injury, although the underlying processes remain unknown. Thus, the purpose of this article is to present current research on natural flavonoids to reduce the incidence of CVDs by protecting intestinal barrier injury, with a particular emphasis on intestinal epithelial barrier integrity (inhibiting oxidative stress, regulating inflammatory cytokine expression, and increasing tight junction protein expression). Furthermore, the mechanisms driving intestinal barrier injury development are briefly explored, as well as natural flavonoids having CVD-protective actions on the intestinal barrier. In addition, natural flavonoids with myocardial protective effects were docked with ZO-1 targets to find natural products with higher activity. These natural flavonoids can improve intestinal mechanical barrier function through anti-oxidant or anti-inflammatory mechanism, and then prevent the occurrence and development of CVDs.

We live in a world increasingly dominated by plastic, leading to the generation of microplastic particles that pose significant global health concerns. Microplastics can enter the body via ingestion, inhalation, and direct contact, accumulating in various tissues and potentially causing harm. Despite this, the specific cellular mechanisms and signaling pathways involved remain poorly understood. Macrophages are essential in absorbing, distributing, and eliminating microplastics, playing a key role in the body's defense mechanisms. Recent evidence highlights oxidative stress signaling as a key pathway in microplastic-induced macrophage dysfunction. The accumulation of microplastics generates reactive oxygen species (ROS), disrupting normal macrophage functions and exacerbating inflammation and organ damage. This review serves as the first comprehensive examination of the interplay between microplastics, macrophages, and oxidative stress. It discusses how oxidative stress mediates macrophage responses to microplastics and explores the interactions with gut microbiota. Additionally, it reviews the organ damage resulting from alterations in macrophage function mediated by microplastics and offers a novel perspective on the defense, assessment, and treatment of microplastic-induced harm from the viewpoint of macrophages.

Traditional cardiovascular risk factors, combined with persistent systemic inflammation, contribute to the increased prevalence of atherosclerotic cardiovascular disease (ASCVD) in people with HIV (PWH). This review highlights key findings from the REPRIEVE trial on statin-based primary prevention of major adverse cardiovascular events in PWH. It explores HIV-specific immune mechanisms contributing to residual cardiovascular risk.

In REPRIEVE, statin therapy used for primary prevention of major adverse cardiovascular events in PWH decreased the plasma lipoprotein-associated phospholipase A2, oxidized low-density lipoprotein, and high-sensitivity C-reactive protein (hs-CRP). However, several inflammatory markers including soluble CD14 (sCD14), sCD163, interleukin (IL)-1β, interleukin (IL)-6, IL-10, and caspase 1 did not change. The HIV reservoir, dysfunctional CD4+ T cells, immunoglobulin G N-glycans, antiapolipoprotein A1 autoantibodies, trained immunity, and clonal hematopoiesis of indeterminate potential may contribute to residual inflammation.

Despite antiretroviral and statin therapy, residual ASCVD risk in PWH underscores the need for targeted interventions. Anti-inflammatory therapies, including IL-6 and IL-1β inhibitors, CCR5 antagonists (e.g., maraviroc, cenicriviroc mesylate), and immunomodulatory agents like methotrexate and colchicine, are being explored. Understanding HIV-driven immune dysregulation may lead to novel strategies to mitigate cardiovascular risk in this population.

Cardiovascular diseases (CVDs) remain a leading global health concern, responsible for substantial morbidity and mortality. In recent years, as our understanding of the multifaceted nature of CVDs has increased, it has become increasingly evident that traditional risk factors alone do not account for the entirety of cardiovascular morbidity and mortality. Environmental toxins, a heterogeneous group of substances ubiquitous in our surroundings, have now entered the spotlight as offenders in the development and progression of CVDs. Environmental toxins include heavy metals, air pollutants, pesticides, and endocrine-disrupting chemicals, among others. Upon exposure, they can elicit oxidative stress, a condition characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's ability to detoxify and repair the resulting damage. Oxidative stress triggers a cascade of events, including inflammation, endothelial dysfunction, lipid peroxidation, and vascular remodeling, which can contribute to the development of atherosclerosis, hypertension, and other cardiovascular pathologies. This article delves into the molecular mechanisms underpinning oxidative stress-mediated cardiovascular damage induced by environmental toxins, emphasizing the role of specific toxins in this process. Further research is necessary to understand how individual susceptibility and genotype influence the impact of environmental toxins on oxidative stress and the risk of CVD.

Micro-/nanoplastics (MNPLs) are widely found in the environment and have toxic effects on various organs and systems. However, the role of the gut-cardiac axis in cardiotoxicity induced by MNPLs has not yet been elucidated through research.

In this study, we examined the effects of 80 nm polystyrene nanoplastics (PS-NPs) on the heart and human cardiomyocytes (AC16) cells. Histopathological examination showed that NPs caused impaired cardiac function and increased myocardial collagen deposition. In view of the potential influence of gut microbiota and its metabolites on cardiac function, we conduct this study to investigate the specific effects they have on cardiac function. Analysis of cecal contents by 16 s ribosomal RNA (rRNA) and short chain fatty acids (SCFAs) revealed that colonic tissue damage, intestinal flora disorder, and reduction of propionic acid induced by PS-MPs were closely related to cardiac function. Further transcriptomic analysis of heart and colon tissues indicated that propionic acid may reduce cardiac function by reducing the expression of fructose-1, 6-biphosphatase 1 (FBP1). The hypothesis was further verified by in vitro intervention experiments with sodium propionate and FBP1 activator (BML-275).

In summary, our study systematically demonstrated the role of gut-heart axis in NPs-induced cardiac injury, and the specific process was that NPs exposure reduced propionate level, which in turn inhibited FBP1 expression to impair cardiac function. These findings provide new insights into NPs-induced cardiotoxicity and identifie potential therapeutic targets, providing clues for the prevention and treatment of NPs-induced cardiac injury in the future.

Menopause is characterized by the cessation of menstruation and a decline in reproductive function, which is an intrinsic component of the aging process. However, it has been a frequently overlooked field of women's health. The oral and gut microbiota, constituting the largest ecosystem within the human body, are important for maintaining human health and notably contribute to the healthy aging of menopausal women. Therefore, a comprehensive review elucidating the impact of the gut and oral microbiota on menopause for healthy aging is of paramount importance. This paper presents the current understanding of the microbiome during menopause, with a particular focus on alterations in the oral and gut microbiota. Our study elucidates the complex interplay between the microbiome and sex hormone levels, explores microbial crosstalk dynamics, and investigates the associations between the microbiome and diseases linked to menopause. Additionally, this review explores the potential of microbiome-targeting therapies for managing menopause-related diseases. Given that menopause can last for approximately 30 years, gaining insights into how the microbiome and menopause interact could pave the way for innovative interventions, which may result in symptomatic relief from menopause and an increase in quality of life in women.

Preventing new cardiovascular events in patients with established cardiovascular disease (CVD) is a daunting task for clinicians. Intestinal microbiota may help identify patients at risk, thus improving the strategies of secondary prevention. The aim of this study was to evaluate the baseline differences between the gut microbiota from coronary heart disease (CHD) patients suffering new major adverse cardiovascular events (MACEs) in the following 7 years, compared with CHD patients who did not undergo new MACE in this period, and to build a score associated with the risk of suffering new MACE.

Within the framework of the CORDIOPREV study, a clinical trial that involved 1002 patients with CHD, intestinal microbiota was examined in patients with available faecal samples (n = 679, 132 MACE), through 16S metagenomics on the Illumina MiSeq and Quiime2 software. Lipopolysaccharide (LPS) was measured using limulus amoebocyte lysate test.

Random survival forest identified 10 bacterial taxa with a higher predictive power for MACE incidence. Receiver operating characteristic curves yielded an area under the curve of 65.2% (59.1%-71.3%) in the training set and 68.6% (59.3%-77.9%) in the validation set. The intestinal microbiota risk score was associated with a MACE incidence hazard ratio of 2.01 (95% confidence interval 1.37-3.22). Lipopolysaccharide analysis showed a greater LPS post-prandial fold change in the MACE group (P = .005).

These results reinforce the relationship between intestinal microbiota and CVD and suggest that a microbiota profile is associated with MACE in CHD patients, in addition to higher endotoxaemia.

Cardiac fibrosis is a prevalent characteristic of various cardiovascular diseases and poses a significant global health challenge. Recent research has established a robust correlation between gut microbiota and cardiovascular diseases. Hesperidin has been shown to possess cardioprotective properties to some extent. Furthermore, studies suggest that hesperidin may enhance overall health by regulating intestinal flora. However, there is a lack of reports regarding the effects of hesperidin on cardiac fibrosis. This study aimed to investigate the mechanisms by which hesperidin ameliorates cardiac fibrosis through the regulation of gut microbiota and associated metabolites. Cardiac fibrosis was induced in C57BL/6 mice via subcutaneous injection of isoproterenol (5 mg/kg per day) for a duration of 7 days. Echocardiography was used to assess cardiac function, while Masson staining, western blot analysis, and real-time polymerase chain reaction were used to evaluate fibrosis-related indicators. Changes in gut microbiota were analyzed through 16S ribosomal RNA gene sequencing. Our findings indicate that hesperidin significantly mitigates cardiac fibrosis in mice. These beneficial effects are associated with improvements in the dysbiosis of intestinal microbiota observed in fibrotic mouse models. The involvement of gut microbiota in cardiac fibrosis was further corroborated by administering hesperidin therapy to mice depleted of gut microbiota. To our knowledge, this study provides the first evidence that the modulation of gut microbiota by hesperidin contributes to improved outcomes in cardiac fibrosis. The use of traditional Chinese medicine to modulate gut microbiota presents a promising strategy for the treatment of cardiac fibrosis. SIGNIFICANCE STATEMENT: The work is extremely interesting because it acts on a frontier of science that relates the influence of the intestinal microbiota with human physiological systems and associated pathologies. This study provides the first evidence that the modulation of gut microbiota by hesperidin contributes to improved outcomes in cardiac fibrosis.

Mucins, heavily O-glycosylated glycoproteins, are a key component of mucus, and certain gut microbiota, including Akkermansia muciniphila, can utilise mucin glycans as a carbon source. Akkermansia muciniphila produces the O-glycopeptidase enzyme OgpA, which cleaves peptide bonds at the N-terminus of serine (Ser) or threonine (Thr) residues carrying O-glycan substitutions, with selectivity influenced by the O-glycan functional groups. Using molecular dynamics (MD) simulations and quantum chemistry calculations, we explored how different O-glycan groups affect OgpA's selectivity. Our results show that peptides bind to the enzyme via hydrogen bonds, π-π interactions, van der Waals forces and electrostatic interactions, with key residues, including Tyr90, Val138, Gly176, Tyr210 and Glu91, playing important roles. The primary determinant of selectivity is the interaction between the peptide's functional group and the enzyme's binding cavity, while peptide-enzyme interface interactions are secondary. Quantum chemistry calculations reveal that OgpA prefers peptides with a lower electrophilic character. This study provides new insights into mucin degradation by gut microbiota enzymes, advancing our understanding of this critical biological process.

Depression is a debilitating and poorly understood mental disorder. There is an urgency to explore new potential biological mechanisms of depression and the gut microbiota is a promising research area.

Our study was aim to understand regional heterogeneity and potential molecular mechanisms underlying depression induced by dysbiosis of mucus-associated microbiota.

Here, we only selected female macaques because they are more likely to form a natural social hierarchy in a harem-like environment. Because high-ranking macaques rarely displayed depressive-like behaviors, we selected seven monkeys from high-ranking individuals as control group (HC) and the same number of low-ranking ones as depressive-like group (DL), which displayed significant depressive-like behaviors. Then, we collected mucus from the duodenum, jejunum, ileum, cecum and colon of DL and HC monkeys for shotgun metagenomic sequencing, to profile the biogeography of mucus-associated microbiota along duodenum to colon.

Compared with HC, DL macaques displayed noticeable depressive-like behaviors such as longer duration of huddle and sit alone behaviors (negative emotion behaviors), and fewer duration of locomotion, amicable and ingestion activities (positive emotion behaviors). Moreover, the alpha diversity index (Chao) could predict aforementioned depressive-like behaviors along duodenum to colon. Further, we identified that genus Pseudomonas was consistently decreased in DL group throughout the entire intestinal tract except for the jejunum. Specifically, there were 10, 18 and 28 decreased Pseudomonas spp. identified in ileum, cecum and colon, respectively. Moreover, a bacterial module mainly composed of Pseudomonas spp. was positively associated with three positive emotion behaviors. Functionally, Pseudomonaswas mainly involved in microbiota derived lipid metabolisms such as PPAR signaling pathway, cholesterol metabolism, and fat digestion and absorption.

Different regions of intestinal mucus-associated microbiota revealed that depletion of genus Pseudomonas is associated with depressive-like behaviors in female macaques, which might induce depressive phenotypes through regulating lipid metabolism.

Atherosclerosis poses a significant threat to global health. This study aimed to investigate the effects of myricetin (MYR) on high-fat diet (HFD)-induced atherosclerosis in ApoE-/- mice. Our findings demonstrated that MYR treatment significantly reduced the formation of atherosclerotic plaques, particularly at a high dose of 100 mg kg-1 day-1. Additionally, MYR markedly attenuated lipid metabolism disorders in ApoE-/- mice by decreasing body weight, improving serum lipid profiles, and reducing lipid deposition. Analysis of 16S rRNA sequencing revealed that MYR treatment enhanced the abundance of probiotic g_Lachnospiraceae_NK4A136, while it reduced that of obesity-associated genera, including Rikenellaceae_RC9_gut_group and Alistipes. Metabolomic analysis and RT-qPCR tests indicated that MYR upregulated hepatic bile acid biosynthesis, evidenced by increased total bile acid levels and enhanced expression of key enzymes CYP7A1 and CYP8B1, particularly through the classical biosynthetic pathway. Spearman's correlation analysis revealed strong associations between the regulated bile acids and these aforementioned bacteria. Therefore, our results demonstrated that MYR exerts an anti-atherosclerotic effect by modulating the gut-liver axis.

Studies have shown that fecal occult blood is associated with an increased risk of ischemic stroke, but the relationship between fecal occult blood and cerebral small vessel disease (CSVD) remains largely unknown. This study aimed to identify predictors for CSVD, with fecal occult blood and its proxies as potential influencing factors in elderly patients.

Patients aged 65 years or older with various chronic diseases were enrolled. The presence of CSVD was evaluated by brain MRI results. Fecal occult blood was measured by fecal immunochemical test. Logistic regression analysis was used for the association between the presence of fecal occult blood and the risk of CSVD.

Logistic regression analysis indicated that a prevalence of positive fecal occult blood was related to CSVD (Model 1, adjusted OR=1.63, 95% CI: 1.15-2.29, P=0.006). We subsequently grouped all subjects as positive fecal occult blood (259, 16.48%) and negative fecal occult blood (1313, 83.52%), and logistic regression analysis indicated that a prevalence of CSVD was related to positive fecal occult blood (Model 2, adjusted OR=1.50, 95% CI: 1.08-2.08, P=0.015). In addition, the ratios of lacunes (67.18% vs. 53.85%, P<0.001) and enlarged perivascular spaces (43.63% vs. 34.42%, P=0.005) were higher in patients with positive fecal occult blood than in controls.

The presence of fecal occult blood is probably related to the risk of CSVD in elderly patients and could be used as a screening tool for CSVD in elderly populations.

Stroke represents a predominant cause of mortality and disability on a global scale, impacting millions annually and exerting a considerable strain on healthcare systems. The incidence of stroke exhibits regional variability, with ischemic stroke accounting for the majority of occurrences. Post-stroke complications, such as cognitive impairment, motor dysfunction, and recurrent stroke, profoundly affect patients' quality of life. Recent advancements have elucidated the microbiota-gut-brain axis (MGBA), underscoring the complex interplay between gut health and brain function. Dysbiosis, characterized by an imbalance in gut microbiota, is significantly linked to an elevated risk of stroke and unfavorable outcomes. The MGBA plays a crucial role in modulating immune function, neurotransmitter levels, and metabolic byproducts, which may intensify neuroinflammation and impair cerebral health. This review elucidates the role of MGBA in stroke pathophysiology and explores potential gut-targeted therapeutic strategies to reduce stroke risk and promote recovery, including probiotics, prebiotics, pharmacological interventions, and dietary modifications. However, the current prevention and treatment strategies based on intestinal flora still face many problems, such as the large difference of individual intestinal flora, the stability of efficacy, and the long-term safety need to be considered. Further research needs to be strengthened to promote its better application in clinical practice.

Cholesterol is an important lipid molecule that affects the gut microbiome upon ingestion. We systematically investigated the effects of cholesterol on the microbiota of the large and small intestines using ex vivo and in vivo models, combining flow cytometry, metabolomics, and metagenomics. The results showed that cholesterol directly causes a loss of bacterial membrane polarity and integrity, as well as a reduction in microbial metabolic activity. Cholesterol directly affected the global metabolism of the large and small intestinal microbiota, including amino acid, carbohydrate, and nucleotide metabolism. Ex vivo and in vivo studies shared similar results, showing that cholesterol increased the abundance of the primary bile acid-metabolizing bacteria Clostridium and Dorea in the large intestinal microbiota, confirming the enrichment effect of cholesterol on these bacteria. In the in vivo model, increased conjugated bile acids in the small intestine and decreased abundance of BSH-containing Bifidobacterium were observed due to cholesterol. Only in vivo models have demonstrated that cholesterol increases phosphatidylcholine levels in both the small and large intestines, which may be related to the effects of cholesterol on host metabolism. The pro-inflammatory capacity of the intestinal microbiota was enhanced by cholesterol, as evidenced by the increased levels of IL-1β and TNF-α in THP-1 cells upon stimulation with cholesterol-treated microbiota. This study comprehensively elucidates the effects of cholesterol on the composition and metabolic functions of the microbiota in both the large and small intestines. It offers a novel perspective on the ways in which cholesterol affects host metabolism via the gut microbiome.

Accumulating evidence indicates that patients with liver diseases exhibit distinct microbiological profiles, which can be attributed to the bidirectional relationship of the gut-liver axis. Porto-sinusoidal vascular disease (PSVD) has recently been introduced to describe a group of vascular diseases of the liver, involving the portal venules and sinusoids. Although the pathophysiology of PSVD is not yet fully understood, several predisposing conditions, including immunodeficiency, inflammatory bowel disease, abdominal bacterial infections are associated with the increasing in intestinal permeability and microbial translocation, supporting the role of altered gut microbiota and gut-derived endotoxins in PSVD etiopathogenesis. Recent studies have proposed that the gut microbiome may play a crucial role in the pathophysiology of intrahepatic vascular lesions, potentially influencing the onset and progression of PSVD in this context. This review aims to summarize the current understanding of the gut microbiome's potential role in the pathogenesis of hepatic microvascular abnormalities and thrombosis, and to briefly describe their interactions with PSVD. The insights into gut microbiota and their potential influence on the onset and progression of PSVD may pave the way for new diagnostic, prognostic, and therapeutic strategies.

Atherosclerosis (AS) is a chronic vascular disease primarily affecting large and medium-sized arteries, involving complex pathological mechanisms such as inflammatory responses, lipid metabolism disorders and vascular plaque formation. In recent years, several emerging research hotspots have appeared in the field of atherosclerosis, including gut microbiota, pyroptosis, ferroptosis, autophagy, cuproptosis, exosomes and non-coding RNA. Traditional lipid-lowering drugs play a crucial role in the treatment of AS but are not able to significantly reverse the pathological changes. This article aims to summarize the latest research progress in the pathogenesis of AS and the diagnosis and treatment of the disease by comprehensively analyzing relevant literature mainly from the past five years. Additionally, the mechanisms of action and research advances of statins, cholesterol absorption inhibitors, fibrates and novel lipid-lowering drugs are reviewed to provide new insights into the diagnosis and treatment of AS.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, mainly involved in detoxification. However, in the intestine, metabolites derived from the diet, which are converted by a wide range of bacteria can also activate the AHR. This intestinal AHR activation plays a key role in maintaining the gut barrier by, for example, upregulating antimicrobial peptides and anti-inflammatory cytokines. Since the gut barrier influences the gut-liver axis by regulating the leaking of metabolites, bacteria, and endotoxins into circulation and particularly into the liver, the AHR is a key factor in the gut-liver axis. Vice versa, certain liver pathologies also influence the gut microbiome, thereby altering bacteria-derived activation of the AHR. Additionally, bile acids can impact the gut via the liver and thereby also affect the AHR. The aryl hydrocarbon receptor (AHR) interacts with several molecular factors, one of which is the nuclear factor erythroid-derived 2-like 2 (NRF2), a transcription factor primarily associated with regulating antioxidant stress responses. The interplay between AHR and NRF2 has been investigated in the context of various diseases; this review highlights the significance of this interaction within the framework of the gut-liver axis.

Mounting evidence indicates that gut microbial metabolites are central hubs linking the gut microbiota to atherosclerosis (AS). Gut microbiota enriched with pathobiont bacteria responsible for producing metabolites like trimethylamine N-oxide and phenylacetylglutamine are related to an increased risk of cardiovascular events. Furthermore, gut microbiota enriched with bacteria responsible for producing short-chain fatty acids, indole, and its derivatives, such as indole-3-propionic acid, have demonstrated AS-protective effects. This study described AS-related gut microbial composition and how microbial metabolites affect AS. Summary findings revealed gut microbiota and their metabolites-targeted diets could benefit AS treatment. In conclusion, dietary interventions centered on the gut microbiota represent a promising strategy for AS treatment, and understanding diet-microbiota interactions could potentially be devoted to developing novel anti-AS therapies.

Despite significant advancements in prevention and treatment, cardiometabolic diseases continue to pose a high burden of incidence and mortality. The chronic progression of these diseases necessitates the identification of early and complementary therapeutic targets to elucidate and mitigate residual risks in patient care. The gut microbiota acts as a sentinel between internal and external environments, transmitting modified risks associated with these factors to the host. Imidazole propionate (ImP), a histidine metabolite originating from the gut microbiota, gained attention after being found to impair glucose tolerance and insulin signaling several years ago. Epidemiological studies over the past five years have demonstrated a robust correlation between ImP and an increased risk of onset of type 2 diabetes (T2D) and obesity, exacerbation of kidney traits in chronic kidney disease (CKD), progression of atherosclerotic plaques, and elevated mortality rates in heart failure (HF). These findings suggest that ImP may serve as a pivotal target for the prevention and treatment of cardiometabolic diseases. Mechanistic insights have uncovered associations between ImP and insulin resistance, impaired glucose metabolism, chronic inflammation, and intestinal barrier damage. This review provides a comprehensive summary of the current evidence regarding the association between ImP and cardiometabolic impairment, highlighting its potential in advancing personalized approaches to disease prevention and management, and exploring the intricate interplay of diet, gut microbiota, and ImP in cardiovascular metabolic impairment. Overall, this review offers valuable insights into the multifaceted roles of ImP in cardiometabolic diseases, identifies current knowledge gaps, and discusses future research directions.

Aims: Emerging evidence underscores the diet-microbiota-gut-brain axis as vital to brain health. The dietary index for gut microbiota (DI-GM), quantifying diet quality linked to gut microbiota diversity, reflects healthier gut microbiota with higher scores. Therefore, this study was designed to explore the unclear association between DI-GM and stroke. Methods: A cross-sectional analysis was conducted using data from 48 677 participants aged ≥20 years in the National Health and Nutrition Examination Survey (NHANES). Demographic and dietary data were collected, and multivariable weighted logistic regression analysis was performed to evaluate the association between the DI-GM and stroke. Additionally, restricted cubic spline (RCS), subgroup analyses, and receiver operating characteristic (ROC) curve were conducted. Results: In participants aged ≥20 years, the odds ratio (OR) was 0.96 (95% CI: 0.92-1.00, P = 0.075) in the crude model, but after adjustment, the OR was 0.93 (95% CI: 0.89-0.98, P = 0.003), while higher beneficial to gut microbiota scores were consistently associated with lower stroke prevalence with ORs of 0.87 (95% CI: 0.83-0.90, P < 0.001) in the crude model and 0.88 (95% CI: 0.83-0.93, P < 0.001) after adjustment. Among participants aged 20-29 years, no significant association was observed. For those aged ≥30 years, higher DI-GM and beneficial to gut microbiota scores were associated with lower stroke prevalence, with DI-GM showing ORs of 0.93 (95% CI: 0.89-0.97, P < 0.001) in the crude model and 0.93 (95% CI: 0.89-0.98, P = 0.003) after adjustment, and beneficial to gut microbiota scores showing ORs of 0.82 (95% CI: 0.79-0.86, P < 0.001) in the crude model and 0.88 (95% CI: 0.83-0.93, P < 0.001) after adjustment. RCS indicated a linear relationship between DI-GM and stroke. Conclusion: The DI-GM was inversely and linearly associated with stroke prevalence, particularly in adults aged 30 years and above.

Atherosclerosis (AS) is a cardiovascular disease caused by excessive accumulation of lipids in arterial walls. In this study, we developed an AS model in ApoE-/- mice using a high-fat, high-cholesterol diet and investigated the anti-AS mechanism of aged garlic oligosaccharides (AGOs) by focusing on the gut microbiota. Results revealed that AGOs exhibited significant anti-AS effects, reduced trimethylamine N-oxide levels from 349.9 to 189.2 ng/mL, and reduced aortic lipid deposition from 31.7 % to 9.5 %. AGOs significantly increased the levels of short-chain fatty acids in feces, in which acetic, propionic, and butyric acids were increased from 1.580, 0.364, and 0.469 mg/g to 2.233, 0.774, and 0.881 mg/g, respectively. An analysis of the gut microbiota indicated that AGOs restored alpha and beta diversity, decreased the Firmicutes/Bacteroidetes ratio, and promoted the dominance of the genus Akkermansia. A metagenomic analysis revealed that AGOs alleviated AS through the ABC transporter pathway and the lipopolysaccharide biosynthesis pathway.

The octadecanoids are a broad class of lipids consisting of the oxygenated products of 18-carbon fatty acids. Originally referring to production of the phytohormone jasmonic acid, the octadecanoid pathway has been expanded to include products of all 18-carbon fatty acids. Octadecanoids are formed biosynthetically in mammals via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) activity, as well as nonenzymatically by photo- and autoxidation mechanisms. While octadecanoids are well-known mediators in plants, their role in the regulation of mammalian biological processes has been generally neglected. However, there have been significant advancements in recognizing the importance of these compounds in mammals and their involvement in the mediation of inflammation, nociception, and cell proliferation, as well as in immuno- and tissue modulation, coagulation processes, hormone regulation, and skin barrier formation. More recently, the gut microbiome has been shown to be a significant source of octadecanoid biosynthesis, providing additional biosynthetic routes including hydratase activity (e.g., CLA-HY, FA-HY1, FA-HY2). In this review, we summarize the current field of octadecanoids, propose standardized nomenclature, provide details of octadecanoid preparation and measurement, summarize the phase-I metabolic pathway of octadecanoid formation in mammals, bacteria, and fungi, and describe their biological activity in relation to mammalian pathophysiology as well as their potential use as biomarkers of health and disease.

Cardiovascular disease (CVD) is more prevalent in men than women, but the mechanisms responsible for this are not fully understood. We aimed to evaluate differences in trimethylamine (TMA), a microbial metabolite and its oxidized form, trimethylamine N-oxide (TMAO), which is thought to promote atherosclerosis, between men and women with coronary heart disease (CHD), using as a reference a non-CVD population.

This study was carried out within the framework of the CORDIOPREV study (NCT00924937; June 19, 2009), a clinical trial which included 827 men and 175 women with CHD, with a non-CVD population of 375 individuals (270 men and 105 women) as a reference group. Plasma TMA and TMAO were measured by HPLC-MS/MS. The carotid study was ultrasonically assessed bilaterally by the quantification of intima-media thickness of both common carotid arteries (IMT-CC).

We found higher TMAO levels and TMAO/TMA ratio in CHD men than CHD women (p=0.034 and p=0.026, respectively). No TMA sex differences were found in CHD patients. The TMA and TMAO levels and TMAO/TMA ratio were lower, and no differences between sexes were found in the non-CVD population. TMAO levels in CHD patients were consistent with higher IMT-CC and more carotid plaques (p=0.032 and p=0.037, respectively) and lower cholesterol efflux in CHD men than CHD women (p<0.001).

Our results suggest that CHD men have augmented TMAO levels compared with CHD women, presumably as a consequence of higher rate of TMA to TMAO oxidation, which could be associated with CVD, as these sex differences are not observed in a non-CVD population.

The pathophysiology of cardiovascular diseases encompasses a complex interplay of genetic and environmental risk factors. Even if traditional risk factors are treated to target, there remains a residual risk.

This manuscript reviews the potential role of gut microbiota in the development of cardiovascular disease, and as potential target. A systematic search was conducted until 30 October 2024 on PubMed (MEDLINE), using the MeSH terms [Gut microbiota] + [Dysbiosis] + [Cardiovascular] + [TMAO] + [bile acids] + [short-chain fatty acids].

The term dysbiosis implies changes in equilibrium, with modifications in the composition and functionality of microbiota and a series of additional factors: reduced diversity and uniformity of microorganisms; reduced short-chain fatty acid-producing bacteria; increased gut permeability; release of metabolites, such as trimethylamine N-oxide, betaine, phenylalanine, tryptophan-kynurenine, phenylacetylglutamine, and lipopolysaccharides; and reduced secondary bile acid excretion, leading to inflammation, oxidative stress, and endothelial dysfunction and facilitating the onset of pathological conditions, including obesity, hypertension, diabetes, atherosclerosis, and heart failure. Attempts to restore gut microbiota balance through different interventions, mainly changes in diet, have been shown to positively affect individual components and metabolites and reduce the risk of cardiovascular disease. In addition, probiotics and prebiotics are potentially useful. Fecal microbiota transplantation is a promising therapy.

Atherosclerosis, a persistent inflammatory disease marked by the presence of atherosclerotic plaques or fibrous plaques, is a significant contributor to the onset of the development of cardiovascular disease. Tremella fuciformis Berk contains various active ingredients that have anti-inflammatory, antioxidant, and hypolipidemic properties. Nevertheless, the potential effects of T. fuciformis on atherosclerosis have not been systematically reported.

In this study, ApoE-/- mice were employed as models of atherosclerosis caused by a high-fat diet (HFD) to investigate the effect of T. fuciformis. Gut microbiota and serum metabolism analysis were performed to elucidate the potential mechanism of T. fuciformis for its anti-atherosclerosis effects.

T. fuciformis significantly decreased the aortic root wall thickness and the area of lipid droplets, regulated lipid levels, and inhibited fat accumulation to improve aortic root lesions. Furthermore, T. fuciformis significantly altered serum metabolite (including diethyl phthalate and succinate) levels, regulated the abundance of microbiota, such as Coriobacteriaceae_UCG-002 and Alistipes, and suppressed the inflammatory response to ameliorate atherosclerosis via the nuclear factor-kappa B (NF-κB)-mediated inflammatory response in HFD-induced ApoE-/- mice.

These results offer a theoretical basis and data to support T. fuciformis as a potential strategy for treating atherosclerosis.

The microbial community inhabiting the human gut resembles a bustling metropolis, wherein beneficial bacteria play pivotal roles in regulating our bodily functions. These microorganisms adeptly break down resilient dietary fibers to fuel our energy, synthesize essential vitamins crucial for our well-being, and maintain the delicate balance of our immune system. Recent research indicates a potential correlation between alterations in the composition and activities of these gut microbes and the development of coronary artery disease (CAD). Consequently, scientists are delving into the intriguing realm of manipulating these gut inhabitants to potentially mitigate disease risks. Various promising strategies have emerged in this endeavor. Studies have evidenced that probiotics can mitigate inflammation and enhance the endothelial health of our blood vessels. Notably, strains such as Lactobacilli and Bifidobacteria have garnered substantial attention in both laboratory settings and clinical trials. Conversely, prebiotics exhibit anti-inflammatory properties and hold potential in managing conditions like hypertension and hypercholesterolemia. Synbiotics, which synergistically combine probiotics and prebiotics, show promise in regulating glucose metabolism and abnormal lipid profiles. However, uncertainties persist regarding postbiotics, while antibiotics are deemed unsuitable due to their potential adverse effects. On the other hand, TMAO blockers, such as 3,3-dimethyl-1-butanol, demonstrate encouraging outcomes in laboratory experiments owing to their anti-inflammatory and tissue-protective properties. Moreover, fecal transplantation, despite yielding mixed results, warrants further exploration and refinement. In this comprehensive review, we delve into the intricate interplay between the gut microbiota and CAD, shedding light on the multifaceted approaches researchers are employing to leverage this understanding for therapeutic advancements.

Foam cells are primarily formed through scavenger receptors that mediate the uptake of various modified low-density lipoproteins (LDL) into cells. In addition to the receptor-dependent pathway, macropinocytosis is an essential nonreceptor endocytic pathway for vascular smooth muscle cells (VSMCs) to take up lipids. However, the molecular mechanisms underlying this process remain unclear. Primary cultured VSMCs were stimulated with 200 ng/mL lipopolysaccharide (LPS) and 200 µg/mL native LDL (nLDL). We observed a significant increase in Toll-like receptor 4 (TLR4) protein expression and a significant activation of macropinocytosis, which correlated with the highest uptake of nLDL and intracellular lipid deposition in WT VSMCs. However, macropinocytosis was inhibited and lipid accumulation decreased after treatment with macropinocytosis inhibitors and Syk inhibitors in WT VSMCs. Consistently, TLR4 knockout significantly suppressed macropinocytosis and lipid droplets accumulation in VSMCs. Taken together, our findings suggest a critical role of TLR4/Syk signaling in promoting receptor-independent macropinocytosis leading to VSMC-derived foam cells formation.

Biomolecules, prevalent in the marine environment, can readily adsorb onto the surface of micro(nano)plastics (MNPs), forming eco-corona. This study indicated that 50 nm polystyrene nanoplastics (NP50), whether wrapped with eco-corona or not, can passively enter embryos, whereas 5 µm polystyrene microplastics (MP5) cannot. Additionally, translocation of MP5 from the intestine to the liver was observed in larvae, a process facilitated by eco-corona. Notably, eco-corona prolonged the retention time of MNPs in larvae. However, NP50 was more challenging to purify than MP5, irrespective of the presence of eco-corona. Interestingly, eco-corona degraded in the intestine during the uptake of MNPs, and the hard coronae that readily formed on NP50 may restrict the degradation rate. Although NP50 significantly disrupted larval microbiota homeostasis compared with MP5, eco-corona was more likely to exacerbate MP5's damage to the intestine and liver by disrupting microbiota homeostasis. Additionally, NP50 caused more significant damage to immunity and energy metabolism compared with MP5, regardless of the presence of eco-corona. This study revealed that previously overlooked biomolecules in the marine environment can enhance the translocation of MNPs and subsequently exacerbate their toxic effects, providing theoretical support for assessing the ecological risks of MNPs in real environments.

Phthalate esters (PE), a significant class of organic compounds used in industry, can contaminate humans and animals by entering water and food chains. Recent studies demonstrate the influence of PE on the development and progression of heart diseases, particularly in obese people. Di-isobutyl phthalate (DIBP) was administered orally to normal and diet-induced obese mice in this research to assess cardiovascular risk. The modifications in the microbial composition and metabolites were examined using RNA sequencing and mass spectrometry analysis. Based on the findings, lean group rodents were less susceptible to DIBP exposure than fat mice because of their cardiovascular systems. Histopathology examinations of mice fed a high-fat diet revealed lesions and plagues that suggested a cardiovascular risk. In the chronic DIBP microbial remodeling metagenomics Faecalibaculum rodentium was the predominant genera in obese mice. According to metabolomics data, arachidonic acid (AA) metabolism changes caused by DIBP were linked to unfavorable cardiovascular events. Our research offers new understandings of the cardiovascular damage caused by DIBP exposure in obese people and raises the possibility that arachidonic acid metabolism could be used as a regulator of the gut microbiota to avert related diseases.

Chronic apical periodontitis (CAP) has been linked to the development of atherosclerosis, although the underlying mechanisms remain unclear. This study aimed to investigate the role of gut microbiota disruption in CAP-induced atherosclerosis development, focusing on trimethylamine N-oxide (TMAO)-related metabolites.

The study utilized fecal microbiota transplantation (FMT) to transfer gut microbiota from mice with CAP to healthy mice. Atherosclerosis development was assessed by analyzing lesions in the aortic arch and aortic root. Serum lipid and inflammatory factor levels were measured. Composition and diversity of gut microbiota were analyzed using targeted metabolomics, with a focus on the ratio of Firmicutes to Bacteroidetes. The expression of hepatic flavin-containing monooxygenase 3 (FMO3) and serum TMAO levels were also evaluated.

Mice receiving gut microbiota from CAP mice showed increased atherosclerotic lesions compared to controls, without significant differences in serum lipid or inflammatory factor levels. Alterations in gut microbiota composition were observed, characterized by an increase in the Firmicutes to Bacteroidetes ratio. Peptostreptococcaceae abundance positively correlated with atherosclerosis severity, while Odoribacteraceae showed a negative correlation. No significant differences were found in hepatic FMO3 expression or serum TMAO levels.

The study confirms the role of gut microbiota disruption in CAP-mediated atherosclerosis development, independent of serum lipid or TMAO levels. Alterations in gut microbiota composition, particularly increased Firmicutes to Bacteroidetes ratio and specific bacterial families, were associated with atherosclerosis severity. These findings highlight the intricate interplay between gut microbiota and cardiovascular health in the context of CAP.

Atherosclerosis, a major cause of cardiovascular diseases, is influenced by modifiable factors such as adiposity and blood cholesterol. Diet is crucial in these areas, particularly regarding antioxidant, inflammatory, and obesity effects. Coffee, a globally popular stimulant beverage, has garnered significant attention for its potential impact on cardiovascular diseases. Recent insights reinforce the need to re-examine the relationship between coffee consumption and atherosclerosis progression. Coffee's complex composition includes polyphenols, renowned for their antioxidant and anti-inflammatory properties as well as potential weight-reducing effects. In addition, studies have demonstrated that certain coffee compounds such as chlorogenic acid, caffeic, p-coumaric, and ferulic acid can prevent atherogenesis by preventing the oxidation of low-density lipoproteins. Conversely, diterpenes, found in some coffee brews, can elevate cholesterol levels, posing a risk to coronary health. Notably, coffee intake has been shown to influence gut microbiota diversity, potentially contributing to anti-obesity effects. This review explores the insights from preclinical and clinical studies investigating the potential mechanisms through which coffee consumption may reduce the risk of atherosclerosis-highlighting the potential benefits of moderate filtered coffee consumption and the potential risks associated with excessive coffee consumption. Understanding this relationship is crucial for informing public health recommendations and guiding future research.

In recent decades, it has become clear that the gut is more than just a digestive organ; it also functions as an immune organ with regulatory capabilities and acts as a "second brain" that influences brain function due to the presence and regulatory roles of the gut microbiota (GM). The GM is a crucial component of its host and significantly impacts human health. Dysbiosis, or microbial imbalance, has been closely linked to various diseases, including gastrointestinal, neurological, psychiatric, and metabolic disorders. The aim of this narrative review is to highlight the roles of the GM in maintaining metabolic health. Sleep is a vital biological necessity, with living organisms having evolved an internal sleep-wake rhythm that aligns with a roughly 24 h light/dark cycle, and this is known as the circadian rhythm. This cycle is essential for tissue repair, restoration, and overall optimal body functioning. Sleep irregularities have become more prevalent in modern society, with fast-paced lifestyles often disrupting normal sleep patterns. Urban living factors, such as fast food consumption, shift work, exposure to artificial light and nighttime noise, medications, and social activities, can adversely affect circadian rhythms, with dysbiosis being one of the many factors incriminated in the etiology of sleep disorders.

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia/hypercapnia (IHC), affects predominantly obese individuals, and increases atherosclerosis risk. Since we and others have implicated gut microbiota and metabolites in atherogenesis, we dissected their contributions to OSA-induced atherosclerosis.

Atherosclerotic lesions were compared between conventionally-reared specific pathogen free (SPF) and germ-free (GF) ApoE -/- mice following a high fat high cholesterol diet (HFHC), with and without IHC conditions. The fecal microbiota and metabolome were profiled using 16S rRNA gene amplicon sequencing and untargeted tandem mass spectrometry (LC-MS/MS) respectively. Phenotypic data showed that HFHC significantly increased atherosclerosis as compared to regular chow (RC) in both aorta and pulmonary artery (PA) of SPF mice. IHC exacerbated lesions in addition to HFHC. Differential abundance analysis of gut microbiota identified an enrichment of Akkermansiaceae and a depletion of Muribaculaceae (formerly S24-7) family members in the HFHC-IHC group. LC-MS/MS showed a dysregulation of bile acid profiles with taurocholic acid, taurodeoxycholic acid, and 12-ketodeoxycholic acid enriched in the HFHC-IHC group, long-chain N-acyl amides, and phosphatidylcholines. Interestingly, GF ApoE -/- mice markedly reduced atherosclerotic formation relative to SPF ApoE -/- mice in the aorta under HFHC/IHC conditions. In contrast, microbial colonization did not show a significant impact on the atherosclerotic progression in PA.

In summary, this research demonstrated that (1) IHC acts cooperatively with HFHC to induce atherosclerosis; (2) gut microbiota modulate atherogenesis, induced by HFHC/IHC, in the aorta not in PA; (3) different analytical methods suggest that a specific imbalance between Akkermansiaceae and Muribaculaceae bacterial families mediate OSA-induced atherosclerosis; and (4) derived bile acids, such as deoxycholic acid and lithocholic acid, regulate atherosclerosis in OSA. The knowledge obtained provides novel insights into the potential therapeutic approaches to prevent and treat OSA-induced atherosclerosis.

The human gut is a complex ecosystem that supports billions of living species, including bacteria, viruses, archaea, phages, fungi, and unicellular eukaryotes. Bacteria give genes and enzymes for microbial and host-produced compounds, establishing a symbiotic link between the external environment and the host at both the gut and systemic levels. The gut microbiome, which is primarily made up of commensal bacteria, is critical for maintaining the healthy host's immune system, aiding digestion, synthesizing essential nutrients, and protecting against pathogenic bacteria, as well as influencing endocrine, neural, humoral, and immunological functions and metabolic pathways. Qualitative, quantitative, and/or topographic shifts can alter the gut microbiome, resulting in dysbiosis and microbial dysfunction, which can contribute to a variety of noncommunicable illnesses, including hypertension, cardiovascular disease, obesity, diabetes, inflammatory bowel disease, cancer, and irritable bowel syndrome. While most evidence to date is observational and does not establish direct causation, ongoing clinical trials and advanced genomic techniques are steadily enhancing our understanding of these intricate interactions. This review will explore key aspects of the relationship between gut microbiota, eubiosis, and dysbiosis in human health and disease, highlighting emerging strategies for microbiome engineering as potential therapeutic approaches for various conditions.

Puerarin (PU) is a natural compound that exhibits limited oral bioavailability but has shown promise in the treatment of atherosclerosis (AS). However, the precise mechanisms underlying its therapeutic effects remain incompletely understood. This study aimed to investigate the effects of PU and its mechanisms in mitigating AS in both mice and humans.

The impact of PU on AS was examined in ApoE -/- mice fed a high-fat diet (HFD) and in human patients with carotid artery plaque. To explore the causal link between PU-associated gut microbiota and AS, faecal microbiota transplantation (FMT) and mono-colonisation of mice with Prevotella copri (P. copri) were employed.

PU alleviated AS by modulating the gut microbiota, as evidenced by alterations in gut microbiota composition and the amelioration of AS following FMT from PU-treated mice into ApoE-/- mice fed HFD. Specifically, PU reduced the abundance of P. copri, which exacerbated AS by producing trimethylamine (TMA). Prolonged mono-colonisation of P. copri undermines the beneficial effects of PU on AS. In clinical, the plaque scores of AS patients were positively correlated with the abundance of P. copri and plasma trimethylamine-N-oxide (TMAO) levels. A 1-week oral intervention with PU effectively decreased P. copri levels and reduced TMAO concentrations in patients with carotid artery plaque.

PU may provide therapeutic benefits in combating AS by targeting P. copri and its production of TMA.

ChiCTR1900022488.

The oral microbiome, comprising bacteria, fungi, viruses, and protozoa, is essential for maintaining both oral and systemic health. This complex ecosystem includes over 700 bacterial species, such as Streptococcus mutans, which contributes to dental caries through acid production that demineralizes tooth enamel. Fungi like Candida and pathogens such as Porphyromonas gingivalis are also significant, as they can lead to periodontal diseases through inflammation and destruction of tooth-supporting structures. Dysbiosis, or microbial imbalance, is a key factor in the development of these oral diseases. Understanding the composition and functions of the oral microbiome is vital for creating targeted therapies for these conditions. Additionally, the kynurenine pathway, which processes the amino acid tryptophan, plays a crucial role in immune regulation, neuroprotection, and inflammation. Oral bacteria can metabolize tryptophan, influencing the production of kynurenine, kynurenic acid, and quinolinic acid, thereby affecting the kynurenine system. The balance of microbial species in the oral cavity can impact tryptophan levels and its metabolites. This narrative review aims to explore the relationship between the oral microbiome, oral diseases, and the kynurenine system in relation to certain systemic diseases.

Cardiovascular disease (CVD) remains the leading cause of global morbidity and mortality. Extensive efforts have been invested to explicate mechanisms implicated in the onset and progression of CVD. Besides the usual suspects as risk factors (obesity, diabetes, and others), the gut microbiome has emerged as a prominent and essential factor in the pathogenesis of CVD. With its endocrine-like effects, the microbiome modulates many physiologic processes. As such, it is not surprising that dysbiosis-by generating metabolites, inciting inflammation, and altering secondary bile acid signaling- could predispose to or aggravate CVD. Nevertheless, various natural and synthetic compounds have been shown to modulate the microbiome. Prime among these molecules are flavonoids, which are natural polyphenols mainly present in fruits and vegetables. Accumulating evidence supports the potential of flavonoids in attenuating the development of CVD. The ascribed mechanisms of these compounds appear to involve mitigation of inflammation, alteration of the microbiome composition, enhancement of barrier integrity, induction of reverse cholesterol transport, and activation of farnesoid X receptor signaling. In this review, we critically appraise the methods by which the gut microbiome, despite being essential to the human body, predisposes to CVD. Moreover, we dissect the mechanisms and pathways underlying the cardioprotective effects of flavonoids.