Excessive intake of dietary fats is strongly associated with an increased risk of various chronic diseases, such as obesity, diabetes, hepatic metabolic disorders, cardiovascular disease, chronic intestinal inflammation, and certain cancers. A significant portion of the adverse effects of high-fat diet on disease risk is mediated through modifications in the gut microbiota. Specifically, high-fat diets are linked to reduced microbial diversity, an overgrowth of gram-negative bacteria, an elevated Firmicutes-to-Bacteroidetes ratio, and alterations at various taxonomic levels. These microbial alterations influence the intestinal metabolism of small molecules, which subsequently increases intestinal permeability, exacerbates inflammatory responses, disrupts metabolic functions, and impairs signal transduction pathways in the host. Consequently, diet-induced changes in the gut microbiota play a crucial role in the initiation and progression of chronic diseases. This review explores the relationship between high-fat diets and gut microbiota, highlighting their roles and underlying mechanisms in the development of chronic metabolic diseases. Additionally, we propose probiotic interventions may serve as a promising adjunctive therapy to counteract the negative effects of high-fat diet-induced alterations in gut microbiota composition.

Urbanization has significantly transformed dietary habits worldwide, contributing to a globally increased burden of non-communicable diseases and altered gut microbiota landscape. However, it is often overlooked that the adverse effects of these dietary changes can be transmitted from the mother to offspring during early developmental stages, subsequently influencing the predisposition to various diseases later in life. This review aims to delineate the detrimental effects of maternal urban-lifestyle diet (urbanized diet) on early-life health and gut microbiota assembly, provide mechanistic insights on how urbanized diet mediates mother-to-offspring transfer of bioactive substances in both intrauterine and extrauterine and thus affects fetal and neonatal development. Moreover, we also further propose a framework for developing microbiome-targeted precision nutrition and diet strategies specifically for pregnant and lactating women. The establishment of such knowledge can help develop proactive preventive measures from the beginning of life, ultimately reducing the long-term risk of disease and improving public health outcomes.

The primary objective of this study is to elucidate the role of FMO3, an important enzyme in drug metabolism, and its metabolites in Drug-induced liver injury (DILI).

We overexpressed hepatic FMO3 in mice by injecting AAV8 to examine their liver morphology under acetaminophen (APAP) or monocrotaline (MCT) treatment. We also detected the metabolite TMAO of FMO3 in patients and mice with DILI, and further verified its regulatory effects on the endoplasmic reticulum stress pathway in hepatocytes through in vivo and in vitro experiments.

We found that FMO3 is upregulated in patients and male mice with DILI and overexpression of hepatic FMO3 exacerbates APAP or MCT-induced acute liver injury in mice. Mechanistically, FMO3 binds to endoplasmic reticulum (ER) stress-related transcription factor CREB3 (cAMP response element-binding protein 3) and inhibits its nuclear transcription. The decreased activity of CREB3 reduces the expression of the downstream gene P4HB(prolyl 4-hydroxylase subunit beta), subsequently inducing ER stress and apoptosis. Trimethylamine N-Oxide (TMAO), as a metabolite of FMO3, is also significantly elevated in patients with pyrrolizidine alkaloids-induced acute liver injury and APAP or MCT-induced liver injury in male mice. TMAO triggers ER stress by activating the PERK signaling pathway, and inhibiting TMAO production in DILI mice mitigates liver injury.

Overall, the above findings identify FMO3 as a potential enzyme that facilitates the progression of DILI and exerts ER stress by CREB3/P4HB axis and its metabolites TMAO, which presents new therapeutic targets for DILI.

Circulating concentrations of the gut microbial-mammalian metabolite trimethylamine N-oxide (TMAO) are linked to atherosclerosis risk. TMAO biosynthesis begins when dietary choline is converted to trimethylamine (TMA) by gut microbial TMA lyase. TMA is transported to the liver, where flavin-containing monooxygenases convert it to TMAO. While dietary modifications regulate TMAO production, the impact of different intake methods, including oral gavage, dietary supplementation, and conditions such as fasting versus nonfasting, has not been fully explored. Twelve female Sprague-Dawley rats were divided into three diet groups (n = 4 per group): no-choline (0% choline), low-choline (0.08% choline), and high-choline (1% choline). Choline and TMAO fasting and nonfasting blood concentrations, and their kinetics following an acute choline challenge, were assessed before and after a 2-week dietary intervention with the distinct choline dietary levels. Fasting choline was under tight control, with little effect of dietary choline. Nonfasting choline was more variable, with high dietary choline reflected in higher blood choline. Greater levels of dietary choline were reflected in significantly greater levels of TMAO, particularly for nonfasting levels. Kinetic profiling demonstrated additional information regarding the appearance and clearance of these compounds from blood. These results suggest that acute oral choline gavage is likely most suitable for studies targeting acute (direct) inhibitors, whereas a choline-rich diet with assessment of fasting and nonfasting blood levels is more suitable for studying alterations to TMAO production capacity. Future research should examine the impact on atherosclerosis biomarkers and microbiome diversity to deepen the understanding of TMAO regulation and its cardiovascular implications.

Several studies have indicated that the dysregulation of microbial metabolites and the inflammatory environment resulting from microbial dysbiosis may contribute to the occurrence and progression of cardiovascular diseases. Therefore, restoring the disordered gut microbiota in patients with colorectal cancer by fecal microbiota transplantation (FMT) has the potential to reduce the incidence of cardiac disease. In this study, we identified cardiac dysfunction in azomethane and dextran sodium sulfate-induced colorectal cancer mice. Intestinal microbes from healthy mice were transferred to colorectal cancer mice, which vastly reversed the disorder of the gut microbiota and effectively alleviated cardiac dysfunction. Moreover, FMT regulated the expression of serum metabolites such as uridine triphosphate (UTP), tiamulin, andrographolide, and N-Acetyl-D-glucosamine, as well as cytokines like TGF-β, IRF5, and β-MHC in the heart. These findings uncover that the disturbed gut microbiota causes cardiac dysfunction in colorectal cancer mice by modulating the expression of serum metabolites and cytokines, which could be alleviated by treatment with FMT.

The gut microbiome refers to the collective genomes of the approximately 1,000-1,150 microbial species found in the human gut, called the gut microbiota. Changing the gut microbiota composition has been shown to affect cardiovascular health significantly. Numerous studies have demonstrated the part that gut microbiota and its metabolites play in the development and course of several illnesses, including colon cancer, heart failure, stroke, hypertension, and inflammatory bowel disease. With cardiovascular diseases responsible for more than 31% of all fatalities globally, conditions like hypertension, atherosclerosis, and heart failure are serious global health issues. Developing preventive measures to fight cardiovascular diseases requires understanding how the gut microbiota interacts with the cardiovascular system. Understanding the distinctive gut microbiota linked to cardiovascular diseases has been made possible by microbial sequencing analysis. The gut microbiota and cardiovascular diseases are closely related, and more profound knowledge of this association may result in treatment strategies and broad guidelines for enhancing cardiovascular health through gut microbiome modification. This review summarizes the role of gut microbiota in cardiovascular diseases, highlighting their influence on disease progression and potential therapeutic implications.

Heart failure is a global health issue with significant mortality and morbidity. There is increasing evidence that alterations in the gastrointestinal microbiome, gut epithelial permeability, and gastrointestinal disorders contribute to heart failure progression through various pathways, including systemic inflammation, metabolic dysregulation, and modulation of cardiac function. Moreover, several medications used to treat heart failure directly impact the microbiome. The relationship between the gastrointestinal tract and the heart is bidirectional, termed the gut-heart axis. It is increasingly understood that diet-derived microbial metabolites are key mechanistic drivers of the gut-heart axis. This includes, for example, trimethylamine N-oxide and short-chain fatty acids. This review discusses current insights into the interplay between heart failure, its associated risk factors, and the gut microbiome, focusing on key metabolic pathways, the role of dietary interventions, and the potential for gut-targeted therapies. Understanding these complex interactions could pave the way for novel strategies to mitigate heart failure progression and improve patient outcomes.

Cardiovascular diseases (CVDs) including heart failure (HF) is a major health, medical and social issue that needs to be resolved in Japan's super-aged society. Recent clinical and basic studies suggest that the gut microbiota and their metabolites play critical roles in the onset and progression of CVDs. We explored changes in gut microbiota composition and metabolite levels among Japanese patients to investigate their association with CVDs. Changes in specific bacteria were observed, with a decrease in phylum Bacteroidetes and increases in order Lactobacillus or genus Streptococcus in coronary artery disease patients. For HF patients, a reduction in phylum Bacteroidetes and increases in phylum Actinobacteria (e.g. Bifidobacterium) and Proteobacteria (e.g. Escherichia, Shigella, and Klebsiella) were noted. Elevated levels of gut microbiota-associated metabolites, such as trimethylamine N-oxide (TMAO) and indoxyl sulfate, were observed in CVD patients, suggesting potential effects on organ functions. Many studies have linked higher plasma TMAO levels to worse prognoses in CVDs, including HF and renal failure. However, the clinical significance and therapeutic potential of these findings require further investigation. In this manuscript, the author aims to review the current status of research on gut microbiota in CVDs, with a primary focus on the microbes themselves and their related metabolites. Further research is essential to comprehensively understand these intricacies and establish clear cause-and-effect relationships, ultimately paving the way for the development of innovative therapies for CVDs.

Elevated levels of trimethylamine-N-oxide (TMAO), a metabolite produced by gut microbiota, have been associated with cardiovascular diseases and complications in various populations. However, its role in vascular access dysfunction in hemodialysis patients remains underexplored. This study investigates the potential relationship between TMAO levels and vascular access dysfunction in maintenance hemodialysis patients.

This study included 80 hemodialysis patients. The baseline serum TMAO levels were measured, and clinical characteristics and dialysis-related data were collected. They were followed up on vascular access dysfunction events over a period of 1 year. The association between serum TMAO levels and vascular access dysfunction events were investigated.

In our cohort, we observed a wide distribution of serum concentrations, with a median concentration of 15.2 μmol/L and a maximum concentration of 245.3 μmol/L. Patients were stratified into a low-TMAO group and a high-TMAO group according to the median value of TMAO concentrations. Those in the high-TMAO group had a significantly higher incidence of vascular access dysfunction events (p = 0.023). TMAO was independently associated with vascular access dysfunction events after adjusting for some potential vascular access dysfunction risk factors.

This study suggests that elevated serum TMAO levels may serve as an independent risk factor for vascular access dysfunction in hemodialysis patients. Reducing TMAO levels may potentially decrease the incidence of vascular access dysfunction, warranting further investigation into this therapeutic approach.

The human body is habitat to a wide spectrum of microbial populations known as microbiota, which play an important role in overall health. The considerable research has mostly focused on the gut microbiota due to its potential to impact numerous physiological functions and its correlation with a variety of disorders, such as cardiovascular diseases (CVDs). Imbalances in the gut microbiota, known as dysbiosis, have been linked to the development and progression of CVDs through various processes, including the generation of metabolites like trimethylamine-N-oxide and short-chain fatty acids. Studies have also looked at the idea of using therapeutic interventions, like changing your diet, taking probiotics or prebiotics, or even fecal microbiota transplantation (FMT), to change the gut microbiota's make-up and how it works in order to prevent or treat CVDs. Exploring the cause-and-effect connection between the gut microbiota and CVDs offers a hopeful path for creating innovative microbiome-centered strategies to prevent and cure CVDs. This review presents an in-depth review of the correlation between the gut microbiota and CVDs, as well as potential therapeutic approaches for manipulating the gut microbiota to enhance cardiovascular health.

Methamphetamine (METH)-provoked psychiatric symptoms are a major health concern, with depression being a prevalent symptom among METH abusers. Recently, gut microbiota-derived metabolites have been involved in various psychosis pathogenesis, but their roles in METH-induced depression remain unclear. This study investigates the implication of gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) in METH-induced depressive-like behaviors (DLBs). We examined the circulating TMAO levels post-METH exposure besides exploring the impacts of TMAO on METH-triggered DLBs. Then, potential causes of TMAO alterations were explored, along with its effects on hippocampal neuronal damage and neuroinflammation. The findings showcased that METH-treated mice displayed DLBs accompanied by increased serum TMAO levels. Similarly, introducing TMAO to the drinking water elevated serum TMAO levels and induced DLBs. Although METH exposure did not notably alter the abundance of the gut microbiota, antibiotic (ABX) therapy suppressed the increased serum TMAO levels and the onset of DLBs. Additionally, choline and L-carnitine levels were elevated following METH exposure, which may be a potential mechanism for TMAO metabolic dysregulation. Elevated TMAO levels resulted in an elevation in Nissl-positive dead cells, the number of microglia, TNF-α, and IL-1β levels, along with TLR-4, NF-κB, and MyD88 expression in the hippocampal CA3 region. Inhibition of TMAO synthesis mitigated METH-provoked neuronal damage and neuroinflammation.

The microbially produced amino acid-derived metabolite imidazole propionate (ImP) contributes to the pathogenesis of type 2 diabetes. However, the effects of ImP on endothelial cell (EC) physiology and its role in atherosclerotic coronary artery disease are unknown. Using both human and animal model studies, we investigated the potential contributory role of ImP in the development of atherosclerosis.

Plasma levels of ImP were measured in patients undergoing elective cardiac angiography (n=831) by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. Odds ratios and corresponding 95% confidence intervals for coronary artery disease were calculated based on the ImP quartiles using both univariable and multivariable logistic regression models. The effects of ImP on functional properties of ECs were assessed using HAECs (human aortic endothelial cells). In a mouse model of carotid artery injury, the impact of ImP on vascular regeneration was examined. Additionally, atheroprone Apoe-/- mice fed a high-fat diet were treated with and without ImP (800 µg), and aortic atherosclerotic lesion area was evaluated after 12 weeks. Next-generation sequencing, Western blot analysis, small interfering RNA-based gene knockdown, and tamoxifen-inducible Cre-loxP experiments were performed to investigate ImP-mediated molecular mechanisms.

Plasma ImP levels in subjects undergoing cardiac evaluation were associated with increased risk of prevalent coronary artery disease. We found that ImP dose dependently impaired migratory and angiogenic properties of human ECs and promoted an increased inflammatory response. Long-term exposure to ImP compromised the repair potential of the endothelium after an arterial insult. In atheroprone Apoe-/- (apolipoprotein E-/-) mice, ImP increased atherosclerotic lesion size. Mechanistically, ImP attenuated insulin receptor signaling by suppressing the PI3K (phosphoinositide 3-kinase)/AKT pathway leading to sustained activation of the FOXO1 (forkhead box protein O1) transcription factor. Genetic inactivation of endothelial FOXO1 signaling in ImP-treated mice enhanced the angiogenic activity and preserved the vascular repair capacity of ECs after carotid injury.

Our findings reveal a hitherto unknown role of the microbially produced histidine-derived metabolite ImP in endothelial dysfunction and atherosclerosis, suggesting that ImP metabolism is a potential therapeutic target in atherosclerotic cardiovascular disease.

This systematic review investigates gut bacterial diversity and composition in patients with Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) and examines how these changes may contribute to cardiovascular complications.

A comprehensive search was conducted in PubMed, Web of Science, and Scopus up to March 2025. After removing duplicates, titles and abstracts were screened by two reviewers, and full texts were assessed for inclusion. Data extraction on study characteristics and outcomes was performed. Methodological quality was evaluated using the Joanna Briggs Institute checklist. α-diversity was assessed using richness and diversity indices, while β-diversity examined community structure differences. Meta-analysis was conducted using standardized mean differences (SMD) and confidence intervals (CIs), and heterogeneity was assessed with the Cochrane I2 test.

The review included 18 studies (16 adults, 2 pediatrics) examining the gut microbiome in OSAHS. Meta-analysis revealed significant reductions in α-diversity indices (Shannon, Chao1, observed species, ACE) in OSAHS patients, while Simpson's index showed no difference. β-diversity analyses showed distinct gut microbiome differences in OSA. Key differential bacteria included Bacteroides, Proteobacteria, Faecalibacterium, Ruminococcaceae, Megamonas, Oscillibacter, Dialister, Roseburia, and Lachnospira. Study quality was medium to high.

OSAHS is associated with significant gut microbiome alterations, including a reduction in beneficial bacteria and an increase in LPS-producing bacteria, leading to intestinal barrier dysfunction. These changes may contribute to systemic inflammation and elevate the risk of cardiovascular diseases.

Trimethylamine N-oxide (TMAO) is an endogenous osmolyte produced by enzymatic reactions starting in the human gut, where microbiota release trimethylamine (TMA) from foods, and ending in the liver, where TMA is oxidized to TMAO by flavin-containing monooxygenase 3 (FMO3). While physiological concentrations of TMAO help proteins preserve their folding, high levels of this metabolite are harmful and promote oxidative stress, inflammation, and atherosclerosis. In humans, elevated levels of circulating TMAO predispose individuals to cardiovascular diseases and chronic kidney disease and increase mortality risk, especially in the elderly. How TMAO exerts its negative effects has been only partially elucidated. In hypertensive rats, the eNOS substrate L-arginine and Taurisolo®, a nutraceutical endowed with TMAO-reducing activity, act synergistically to reduce arterial blood pressure. Here, we investigate the molecular mechanisms underpinning this synergism and prove that TMAO, the target of Taurisolo®, acts as direct inhibitor of endothelial nitric oxide synthase (eNOS) and competes with L-arginine at its catalytic site, ultimately inhibiting NO production and acetylcholine (Ach)-induced relaxation in murine aortas.

Breakthroughs in metabolomics technology have revealed the direct regulatory role of metabolites in physiology and disease. Recent data have highlighted the bioactive metabolites involved in the etiology and prevention and treatment of metabolic diseases such as obesity, nonalcoholic fatty liver disease, type 2 diabetes mellitus, and atherosclerosis. Numerous studies reveal that endogenous metabolites biosynthesized by host organisms or gut microflora regulate metabolic responses and disorders. Lipids, amino acids, and bile acids, as endogenous metabolic modulators, regulate energy metabolism, insulin sensitivity, and immune response through multiple pathways, such as insulin signaling cascade, chemical modifications, and metabolite-macromolecule interactions. Furthermore, the gut microbial metabolites short-chain fatty acids, as signaling regulators have a variety of beneficial impacts in regulating energy metabolic homeostasis. In this review, we will summarize information about the roles of bioactive metabolites in the pathogenesis of many metabolic diseases. Furthermore, we discuss the potential value of metabolites in the promising preventive and therapeutic perspectives of human metabolic diseases.

Background: Critical illness induces profound metabolic alterations, characterized by a hypermetabolic state, insulin resistance, protein catabolism, and gut barrier dysfunction, which contribute to increased morbidity and mortality. Emerging evidence highlights the role of the gut microbiome and its metabolites in modulating systemic inflammation and immune responses during critical illness. This narrative review explores the metabolic evolution of critically ill patients, the impact of gut dysbiosis on disease progression, and the potential role of nutrition in modulating metabolism and improving patient outcomes. Methods: A comprehensive literature search was conducted across PubMed and Google Scholar for articles published up to February 2025. Search terms included "critical illness", "metabolism", "gut microbiota", "nutrition", and related keywords. Articles published in English addressing metabolic alterations, microbiome changes, and nutritional strategies in critically ill patients were included. After screening for eligibility, relevant articles were synthesized to outline current knowledge and identify gaps. Results: Metabolic changes in critical illness progress through distinct phases, from catabolism-driven hypermetabolism to gradual recovery. Gut dysbiosis, characterized by a loss of microbial diversity and increased gut permeability, contributes to systemic inflammation and organ dysfunction. Nutritional strategies, including enteral nutrition, probiotics, prebiotics, and metabolomics-driven interventions, may help restore microbial balance, preserve gut barrier integrity, and modulate immune and metabolic responses. Future nutrition therapy should focus on metabolic modulation rather than solely addressing nutrient deficits. Conclusions: Advances in gut microbiome research and metabolomics offer new avenues for personalized nutrition strategies tailored to the metabolic demands of critically ill patients. Integrating these approaches may improve clinical and functional recovery while mitigating the long-term consequences of critical illness.

Trimethylamine oxide (TMAO) is a newly found intestinal microbiota metabolite. Here, we aimed to explore the effects of TMAO on calcium homeostasis and its implication in cardiac hypertrophy, especially focusing on the regulatory mechanism of TMAO on the key calcium transporter SERCA2a. Echocardiography and histological assessment showed that mice fed with TMAO or Choline for 8 weeks exhibited significant pathological changes of cardiac hypertrophy, which is accompanied by increased plasma levels of TMAO. The results indicated that TMAO could increase the intracellular Ca2+ level, up-regulate the expression of ANP and MYH7, and down-regulate SERCA2a expression, which could be reversed by overexpressing of SERCA2a and BAPTA-AM. Meanwhile, TMAO treatment promotes autophagy in vitro and in vivo. By employing immunofluorescence staining and immunoprecipitation assay, it was found that SERCA2a bound to ATG5 and transported to autophagosomes via the ATG5 complex for degradation under TMAO conditions. Furthermore, either 3MA or siATG5 could ameliorate TMAO-induced cardiomyocyte hypertrophy and SERCA2a degradation. Finally, in vivo intervention showed that 3MA could relieve cardiac hypertrophy and rescue the down-regulation of SERCA2a in TMAO-fed mice. The current study identifies a mechanism in which TMAO promotes cardiac hypertrophy via elevated intracellular Ca2+ levels and enhanced autophagy degradation of SERCA2a.

The intricate relationship between human health and gut microecology has emerged as a central theme in contemporary medical research. Postmenopausal osteoporosis, primarily driven by estrogen deficiency, remains a major health concern. Traditional Chinese herbal medicines have attracted significant interest for their promising role in osteoporosis treatment.

The effects of Isaria felina, derived from Cordyceps sinensis, on postmenopausal osteoporosis in rats are the focus of this study. Adult female Sprague-Dawley rats were categorized into control, postmenopausal osteoporosis (OVX), and Isaria felina-treated (IF+OVX) groups. Following a 12-week treatment period, various analyses, including micro-CT, histological assessments, 16S rDNA sequencing, untargeted metabolomics, flow cytometry, and ELISA, were performed.

Micro-CT and histological assessments indicated significant improvements in bone loss and obesity control in OVX rats treated with Isaria felina. 16S rDNA sequencing revealed that Isaria felina corrected gut microbiota dysbiosis, particularly in the Bacteroides and Ruminococcus genera. Untargeted metabolomics highlighted alterations in nucleotide and lipid metabolism. Flow cytometry and ELISA analyses demonstrated that Isaria felina modulated the Th17/Treg immune balance, resulting in reduced levels of inflammatory cytokines IL-17 and TNF-α.

These findings indicate that Isaria felina mitigates bone loss in postmenopausal osteoporosis through modulation of gut microbiota and immune responses, underscoring its potential as a therapeutic agent for osteoporosis treatment.

Purpose：Bariatric surgery can effectively alleviate obesity and diabetes by regulation of the gut microbiota. This study aimed to investigate the change in the gut microbiota metabolite TMAO and to explore its effect on glucose metabolism after sleeve gastrectomy (SG).

Materials and methods：Diet-induced obesity mouse models were established, and the mice were randomly divided into four groups: an SG group, a sham-operated group pair-fed with the SG group (PF), a sham-operated group fed ad libitum (AL), and a lean control group (C). At 10 weeks post-surgery, the changes in glycogen content of liver, gut microbiota and the level of FMO3 in the liver were evaluated, and their correlation with TMAO production was analysed. The expression levels of the TMAO/PERK/FOXO1 pathway and the gluconeogenic genes G6PC and PCK1 were measured.

Results：At 10 weeks post-surgery, hepatocyte glycogen levels were restored, and serum TMA and TMAO levels were significantly increased. Faecal metagenomic sequencing results showed that the abundances of Ruminococcaceae and Lachnospiraceae, which were positively correlated with TMAO production, were significantly increased after surgery. While the changes in FMO3, the key enzyme producing TMAO in the liver was found decreased significantly after SG. The expression levels of the TMAO/PERK/FOXO1 pathway and the gluconeogenic genes G6PC and PCK1 were measured. Inconsistent with the changing trend of TMAO, the expression of PERK, FOXO1, PCK, and G6PC significantly decreased after SG.

Conclusions：SG can significantly reduce obesity and restore glucose metabolism. After surgery, TMAO metabolites increased in a microbiota-dependent manner.

The immune system has long been recognized as a key driver in the progression of heart failure (HF). However, clinical trials targeting immune effectors have consistently failed to improve patient outcome across different HF aetiologies. The activation of the immune system in HF is complex, involving a broad network of pro-inflammatory and immune-modulating components, which complicates the identification of specific immune pathways suitable for therapeutic targeting. Increasing attention has been devoted to identifying gut microbial pathways that affect cardiac remodelling and metabolism and, thereby impacting the development of HF. In particular, gut microbiota-derived metabolites, absorbed by the host and transported to the peripheral circulation, can act as signalling molecules, influencing metabolism and immune homeostasis. Recent reports suggest that the gut microbiota plays a crucial role in modulating immune processes involved in HF. Here, we summarize recent advances in understanding the contributory role of gut microbiota in (auto-)immune pathways that critically determine the progression or alleviation of HF. We also thoroughly discuss potential gut microbiota-based intervention strategies to treat or decelerate HF progression.

Hypertension is a common chronic disease driven by multiple physiological mechanisms, primarily the overactivation of the renin-angiotensin system (RAS). Gamma-aminobutyric acid (GABA), a nonprotein amino acid, has well-documented health benefits, including antihypertensive and calming effects. This study evaluates the blood pressure-lowering effects of Lactiplantibacillus plantarum DPUL-F233 bacterial powder in spontaneously hypertensive rats (SHRs). The bacterial powder was produced using optimized fermentation and freeze-drying techniques. In the oral administration experiment on SHRs, the group treated with a high dose of bacterial powder via long-term gavage showed a significant reduction in blood pressure compared to the untreated group. Specifically, the final measurements of diastolic and systolic blood pressure were reduced to 206.0 ± 2.35 mm Hg and 145.0 ± 6.78 mm Hg, respectively. The angiotensin-converting enzyme I/Angiotensin II/AT1R axis was downregulated, while the angiotensin-converting enzyme II/Angiotensin 1-7/MasR axis was upregulated, rebalancing the RAS signaling pathway. The high-dose group also demonstrated protective effects on the heart and kidneys, with significant improvements observed in reducing cardiac hypertrophy and kidney damage. Additionally, molecular simulation studies indicated potential inhibition of ACE I by GABA. The results suggest that GABA-rich L. plantarum DPUL-F233 powder has significant potential as a natural antihypertensive supplement, particularly for use in functional food development.

Trimethylamine N-oxide (TMAO), a metabolite, is a co-metabolite produced by both gut microbiota and livers, originating from foods rich in choline or carnitine. Emerging evidence suggests that TMAO may play a role in the pathogenesis of various kidney diseases, including acute kidney injury and chronic kidney disease. Research has demonstrated that heightened levels of TMAO are correlated with a heightened likelihood of kidney disease advancement and cardiovascular incidents among individuals with chronic kidney disease. Furthermore, TMAO has been observed to stimulate inflammation, oxidative stress, and fibrosis in animal models of kidney disease. Mechanistically, TMAO may contribute to kidney disease pathogenesis by inhibiting autophagy, activating the NLRP3 inflammasome, and inducing mitochondrial dysfunction. Therefore, targeting TMAO may represent a promising therapeutic strategy for the treatment of kidney diseases. Future studies are needed to further investigate the role of TMAO in kidney disease pathogenesis and to develop TMAO-targeted therapies for the prevention and treatment of kidney diseases.

The effect of the gut microbiota extends beyond their habitant place from the gastrointestinal tract to distant organs, including the cardiovascular system. Research interest in the relationship between the heart and the gut microbiota has recently been emerging. The gut microbiota secretes metabolites, including Trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile acids (BAs), indole propionic acid (IPA), hydrogen sulfide (H2S), and phenylacetylglutamine (PAGln). In this review, we explore the accumulating evidence on the role of these secreted microbiota metabolites in the pathophysiology of ischemic and non-ischemic heart failure (HF) by summarizing current knowledge from clinical studies and experimental models. Elevated TMAO contributes to non-ischemic HF through TGF-ß/Smad signaling-mediated myocardial hypertrophy and fibrosis, impairments of mitochondrial energy production, DNA methylation pattern change, and intracellular calcium transport. Also, high-level TMAO can promote ischemic HF via inflammation, histone methylation-mediated vascular fibrosis, platelet hyperactivity, and thrombosis, as well as cholesterol accumulation and the activation of MAPK signaling. Reduced SCFAs upregulate Egr-1 protein, T-cell myocardial infiltration, and HDAC 5 and 6 activities, leading to non-ischemic HF, while reactive oxygen species production and the hyperactivation of caveolin-ACE axis result in ischemic HF. An altered BAs level worsens contractility, opens mitochondrial permeability transition pores inducing apoptosis, and enhances cholesterol accumulation, eventually exacerbating ischemic and non-ischemic HF. IPA, through the inhibition of nicotinamide N-methyl transferase expression and increased nicotinamide, NAD+/NADH, and SIRT3 levels, can ameliorate non-ischemic HF; meanwhile, H2S by suppressing Nox4 expression and mitochondrial ROS production by stimulating the PI3K/AKT pathway can also protect against non-ischemic HF. Furthermore, PAGln can affect sarcomere shortening ability and myocyte contraction. This emerging field of research opens new avenues for HF therapies by restoring gut microbiota through dietary interventions, prebiotics, probiotics, or fecal microbiota transplantation and as such normalizing circulating levels of TMAO, SCFA, BAs, IPA, H2S, and PAGln.

The world is experiencing a sudden surge in urban population, especially in developing Asian and African countries. Consequently, the global burden of cardio-metabolic disease (CMD) is also rising owing to gut microbiome dysbiosis due to urbanization factors such as mode of birth, breastfeeding, diet, environmental pollutants, and soil exposure. Dysbiotic gut microbiome indicated by altered Firmicutes to Bacteroides ratio and loss of beneficial short-chain fatty acids-producing bacteria such as Prevotella, and Ruminococcus may disrupt host-intestinal homeostasis by altering host immune response, gut barrier integrity, and microbial metabolism through altered T-regulatory cells/T-helper cells balance, activation of pattern recognition receptors and toll-like receptors, decreased mucus production, elevated level of trimethylamine-oxide and primary bile acids. This leads to a pro-inflammatory gut characterized by increased pro-inflammatory cytokines such as tumour necrosis factor-α, interleukin-2, Interferon-ϒ and elevated levels of metabolites or metabolic endotoxemia due to leaky gut formation. These pathophysiological characteristics are associated with an increased risk of cardio-metabolic disease. This review aims to comprehensively elucidate the effect of urbanization on gut microbiome-driven cardio-metabolic disease. Additionally, it discusses targeting the gut microbiome and its associated pathways via strategies such as diet and lifestyle modulation, probiotics, prebiotics intake, etc., for the prevention and treatment of disease which can potentially be integrated into clinical and professional healthcare settings.

Human-disease associated amyloidogenic proteins are not unique in their ability to form amyloid fibrillar structures. Numerous microbes produce amyloidogenic proteins that have distinct functions for their physiology in their amyloid form, rather than solely detrimental. Emerging data indicate associations between various microbial organisms, including those which produce functional amyloids, with neurodegenerative diseases. Here, we review some of the evidence suggesting that microbial amyloids impact amyloid disease in host organisms. Experimental data are building a foundation for continued lines of enquiry and suggest that that direct or indirect interactions between microbial and host amyloids may be a contributor to amyloid pathologies. Inhibiting microbial amyloids or their interactions with the host may therefore represent a tangible target to limit various amyloid pathologies.

The probiotic E. coli Nissle 1917 (EcN) alleviates the progression of various diseases, including colitis and tumors. However, EcN has not been studied in atherosclerosis. The study investigated the effects of EcN on atherosclerosis model mice and the potential mechanisms.

Mice in the high-fat diet (HFD) model were given EcN (1 × 109 CFU/g) or homocitrulline (150 mg/L) by oral administration for 12 weeks. The EcN + antibiotic group was set up to investigate the effects of EcN combined with antibiotics on gut microbiota. The control group was utilized as the negative control. Atherosclerosis status, pyroptosis, gut microbiota, and serum metabolites of mice were examined.

EcN treatment alleviated HFD-caused atherosclerotic plaque and lipid droplet production. EcN treatment reversed HFD-induced increases in total cholesterol, triglycerides, and low-density lipoprotein levels and decreases in high-density lipoprotein levels. EcN inhibited the HFD-caused rise in the expression of pyroptosis-related indicators (cleaved Caspase 1, GSDMD-N, NLRP3, IL-18, and IL-1β). The antibiotics partially reversed the effects of EcN on the model mice, suggesting that EcN regulated pyroptosis in the model mice through gut microbiota. Probiotic bacteria, such as Lactobacillus and Muribaculum, were mainly enriched in the EcN and EcN + antibiotic groups, while Helicobacter, Alistipes, and Rikenella were depleted, suggesting that EcN and EcN + antibiotics could alleviate disorders of gut microbiota in the model mice. EcN reversed the trend of HFD-induced decrease of some metabolites, such as 2-methyl-5-nitroimidazole-1-ethanol, methionine sulfoxide, and shikimate 3-phosphate, and inhibited the increase of some metabolites, such as kynurenine, oxoadipate, and homocitrulline. In addition, homocitrulline showed the opposite effects of EcN in the model mice. Homocitrulline could bind to pyroptosis-related proteins to aggravate ox-LDL-induced endothelial cell pyroptosis.

EcN could alleviate atherosclerosis development by ameliorating HFD-induced disorders of gut microbiota and serum metabolites (such as homocitrulline) to alleviate pyroptosis, which may be associated with homocitrulline/Caspase 1/NLRP3/GSDMD axis. Our study lays the foundation for the development of promising drugs for atherosclerosis in the future.

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.

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, driven by complex interactions among genetic, environmental, and lifestyle factors, with diet playing a pivotal role. Extra Virgin Olive Oil (EVOO), a cornerstone of the Mediterranean diet (MedDiet), is a plant-based fat that has garnered attention for its robust cardiovascular benefits, which are attributed to its unique composition of monounsaturated fatty acids (MUFAs), particularly oleic acid (OA); and bioactive polyphenols, such as Hydroxytyrosol (HT) and oleocanthal. These compounds collectively exert antioxidant, anti-inflammatory, vasodilatory, and lipid-modulating effects. Numerous clinical and preclinical studies have demonstrated that EVOO's properties reduce major modifiable cardiovascular risk factors, including hypertension, dyslipidemia, obesity, and type 2 diabetes. EVOO also promotes endothelial function by increasing nitric oxide (NO) bioavailability, thus favoring vasodilation, lowering blood pressure (BP), and supporting vascular integrity. Furthermore, it modulates biomarkers of cardiovascular health, such as C-reactive protein, low-density lipoprotein (LDL) cholesterol, and NT-proBNP, aligning with improved hemostatic balance and reduced arterial vulnerability. Emerging evidence highlights its interaction with gut microbiota, further augmenting its cardioprotective effects. This review synthesizes current evidence, elucidating EVOO's multifaceted mechanisms of action and therapeutic potential. Future directions emphasize the need for advanced extraction techniques, nutraceutical formulations, and personalized dietary recommendations to maximize its health benefits. EVOO represents a valuable addition to dietary strategies aimed at reducing the global burden of cardiovascular diseases.

The gut microbiota has emerged as an environmental risk factor that affects thrombotic phenotypes in several cardiovascular diseases. Evidence includes the identification of marker species by sequencing studies of the gut microbiomes of patients with thrombotic disease, the influence of antithrombotic therapies on gut microbial diversity, and preclinical studies in mouse models of thrombosis that have demonstrated the functional effects of the gut microbiota on vascular inflammatory phenotypes and thrombus formation. In addition to impaired gut barrier function promoting low-grade inflammation, gut microbiota-derived metabolites have been shown to act on vascular cell types and promote thrombus formation. Therefore, these meta-organismal pathways that link the metabolic capacities of gut microorganisms with host immune functions have emerged as potential diagnostic markers and novel drug targets. In this Review, we discuss the link between the gut microbiota, its metabolites and thromboembolic diseases.

Cardiovascular-kidney-metabolic (CKM) syndrome is a systemic clinical condition characterized by pathological and physiological interactions among metabolic abnormalities, chronic kidney disease, and cardiovascular diseases, leading to multi-organ dysfunction and a higher incidence of cardiovascular endpoints. Traditional approaches to managing CKM syndrome risk are inadequate in these patients, necessitating strategies targeting specific CKM syndrome risk factors. Increasing evidence suggests that addressing uremic toxins and/or pathways induced by uremic toxins may reduce CKM syndrome risk and treat the disease. This review explores the interactions among heart, kidney, and metabolic pathways in the context of uremic toxins and underscores the significant role of uremic toxins as potential therapeutic targets in the pathophysiology of these diseases. Strategies aimed at regulating these uremic toxins offer potential avenues for reversing and managing CKM syndrome, providing new insights for its clinical diagnosis and treatment.

The consumption of nutritive and non-nutritive sweeteners (NNS) has increased significantly in recent decades. The nutritional status of pregnant women plays a crucial role in determining the likelihood of their offspring developing hypertension in adulthood. While NNSs provide a sweet taste without adding to sugar intake, emerging evidence suggests that maternal consumption of not only nutritive sweeteners (such as fructose) but also NNS may lead to adverse outcomes in offspring, including hypertension. This review provides an overview of the latest research connecting maternal intake of sweeteners to the long-term risk of hypertension in offspring. We examine proposed mechanisms underlying the programming of offspring hypertension by sweeteners, encompassing oxidative stress, dysregulated nutrient sensing signals, abnormal renin-angiotensin system, transcriptome changes, and dysbiotic gut microbiota. Additionally, we outline preventive strategies that can help alleviate offspring hypertension programmed by maternal diets high in sweeteners. Recent advancements in understanding the mechanisms through which maternal consumption of nutritive and non-nutritive sweeteners contributes to offspring hypertension offer promise for addressing this widespread health concern at its developmental roots. Nonetheless, further research is needed to educate the public about the safety of sweetener consumption during pregnancy and lactation.

Alzheimer's disease (AD) is a pervasive neurodegenerative disorder, and new approaches for its prevention and therapy are critically needed. Here, we elucidate a gut-microbiome-brain axis that offers actionable perspectives for achieving this objective. Using the 5xFAD mouse model, we identify increased Clostridium abundance and decreased Bacteroides abundance as key features associated with β-amyloid (Aβ) burden. Treatment with Bacteroides ovatus, or its associated metabolite lysophosphatidylcholine (LPC), significantly reduces Aβ load and ameliorates cognitive impairment. Mechanistically, LPC acts through the orphan receptor GPR119, inhibiting ACSL4 expression, thereby suppressing ferroptosis and ameliorating AD pathologies. Analysis of fecal and serum samples from individuals with AD also reveals diminished levels of Bacteroides and LPC. This study thus identifies a B.ovatus-triggered pathway regulating AD pathologies and indicates that the use of single gut microbiota, metabolite, or small molecule compound may complement current prevention and treatment approaches for AD.

Trimethylamine N-oxide (TMAO), a metabolite dependent on intestinal microbiota, is closely related to the emergence, progression, and prognosis of cardiovascular disease (CVD), and has received increasing attention in recent years.

The current research hotspots and future development trends in TMAO and CVD field are found through bibliometrics analysis, which provides reference for further study.

The bibliometrics tools VOSviewer and CiteSpace were used to analyze the publications from the Web of Science Core Collection (WOSCC) database. The articles published from 2004 to 2024 about the relationship between TMAO and CVD were retrieved. Bibliometric analysis includes annual publications, countries/regions, institutions, authors and co-cited authors, journals and cited-journals, references and keywords.

After searching and screening, 1,466 publications were included for subsequent bibliometric analysis. Since 2014, the number of publications exposing the relationship between TMAO and CVD has increased rapidly, as has the frequency of citations. China, USA and Italy are the countries that publish the most relevant research. Cleveland Clinic is the leading institution in this field. Stanley L Hazen, Zeneng Wang and W H Wilson Tang are the most prolific authors in this field, and the latter two have the closest academic cooperation. American Journal of Clinical Nutrition and Journal of the American Heart Association are influential journals that publish research in this field. "Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk" is the most frequently cited article. Keyword analysis shows that gut microbiota, metabolism, phosphatidylcholine and atherosclerosis (AS) are the hotspots in this field.

This study summarizes the research situation of TMAO and CVD in the past 20 years, focusing on the effect of TMAO on pathogenesis of AS, predictive value of TMAO on CVD risk, and dietary and drug intervention for TMAO. Probiotics and natural products may be the research focus of preventing and treating CVD by intervening TMAO in the future.

Choline is an essential micronutrient critical for cellular and organismal homeostasis. As a core component of phospholipids and sphingolipids, it is indispensable for membrane architecture and function. Additionally, choline is a precursor for acetylcholine, a key neurotransmitter, and betaine, a methyl donor important for epigenetic regulation. Consistent with its pleiotropic role in cellular physiology, choline metabolism contributes to numerous developmental and physiological processes in the brain, liver, kidney, lung and immune system, and both choline deficiency and excess are implicated in human disease. Mutations in the genes encoding choline metabolism proteins lead to inborn errors of metabolism, which manifest in diverse clinical pathologies. While the identities of many enzymes involved in choline metabolism were identified decades ago, only recently has the field begun to understand the diverse mechanisms by which choline availability is regulated and fuelled via metabolite transport/recycling and nutrient acquisition. This review provides a comprehensive overview of choline metabolism, emphasizing emerging concepts and their implications for human health and disease.

Most tissues have the capacity for endogenous lipid synthesis. A crucial foundational pathway for lipid synthesis is de novo lipid synthesis (DNL), a ubiquitous and complex metabolic process that occurs at high levels in the liver, adipose and brain tissue. Under normal physiological conditions, DNL is vital in converting excess carbohydrates into fatty acids. DNL is linked to other pathways, including the endogenous synthesis of phospholipids and sphingolipids. However, abnormal lipid synthesis can contribute to various pathologies and clinical conditions. Experimental studies involving dietary restriction and in vivo genetic modifications provide compelling evidence demonstrating the significance of lipid synthesis in maintaining normal cardiovascular tissue function. Similarly, clinical investigations suggest altered lipid synthesis can harm cardiac and arterial tissues, thereby influencing cardiovascular disease (CVD) development and progression. Consequently, there is increased interest in exploring pharmacological interventions that target lipid synthesis metabolic pathways as potential strategies to alleviate CVD. Here we review the physiological and pathological impact of endogenous lipid synthesis and its implications for CVD. Since lipid synthesis can be targeted pharmacologically, enhancing our understanding of the molecular and biochemical mechanisms underlying lipid generation and cardiovascular function may prompt new insights into CVD and its treatment.

Trimethylamine N-oxide (TMAO) is a gut microbial metabolite derived from dietary l-carnitine and choline. High plasma TMAO levels are associated with cardiovascular disease and overall mortality, but little is known about the associations of TMAO and related metabolites with the risk of kidney function decline among patients with chronic kidney disease (CKD).

We prospectively followed 152 nondialysis patients with CKD stages 3-5 and measured plasma TMAO and related metabolites (trimethylamine [TMA], choline, carnitine, and γ-butyrobetaine) via liquid chromatography‒mass spectrometry. An estimated glomerular filtration rate (eGFR) slope >3 ml/min/per 1.73 m2 per year was defined as a rapid decline. We performed logistic regression to determine the probability of rapid or slow eGFR decline, with each metabolite as the main predictor. The gut microbiota was profiled via whole metagenomic sequencing.

The participants had a median age of 66 years, 41.4 % were women, 39.5 % had diabetes, and the median eGFR was 23 mL/min/1.73 m2. A rapid decrease in the eGFR occurred in 65 patients (42.8 %) over a median follow-up of 3.3 years. After adjustment for baseline eGFR, proteinuria, and clinical factors, plasma TMAO levels were independently associated with increased odds of rapid eGFR decline (odds ratio, 2.42; 95 % CI, 1.36-4.32), whereas plasma TMA, choline, carnitine, and γ-butyrobetaine levels were not. Patients who exhibited rapid eGFR decline had a distinct gut microbial composition characterized by increased α-diversity and an abundance of TMA-producing bacteria, including those of the genera Desulfovibrio and Collinsella tanakaei, as well as increased expression of the TMA-producing enzymes bbuA and cutC.

Our findings suggest the relevance of plasma TMAO in the progression of kidney disease among patients with CKD.

Trimethylaminuria (TMAU) is a rare recessive genetic disorder with limited global prevalence. To date, there have been no official reports of TMAU cases documented in Saudi Arabia.

In this study, we developed a liquid chromatography-mass spectrometry (LC-MS) method for the analysis of trimethylamine (TMA) and Trimethylamine N-Oxide (TMAO) in urine and plasma samples for the first reported case of TMAU in Saudi Arabia.

A 41-year-old Saudi man was diagnosed with TMAU in National Guard Hospital. Blood and urine samples were collected to confirm the diagnosis of TMAU. In this study, we have studied LC-MS, cell culture, flow cytometry, adhesion assay and Sanger sequencing analysis. Additionally, in this study, we have selected 5 healthy controls.

The results have revealed elevated TMA levels were present in both urine and plasma samples, while TMAO levels were significantly lower compared to control group. Further, we utilized plasma sample from the TMAU patient as novel model to investigate the potential effect of low TMAO on monocyte and endothelial cell function in vitro. DNA sequencing analysis identified a c.622G >T (p.Glu208*) which creates a premature stop codon in FMO3 gene.

Our findings revealed differential responses in monocytes and endothelial cells stimulated with plasma from the TMAU patient compared to plasma from non-TMAU patients. These distinct responses may be key modulators of endothelial function and contributes to vascular damage.