Elevated plasma levels of trimethylamine N-oxide (TMAO)-a compound derived from diet and the gut microbiome-have been widely studied for their association with diabetes risk and their potential role in disease pathophysiology and complications. However, clinical studies, both prospective and retrospective, have yielded conflicting results. For example, elevated levels of TMAO are frequently linked to an increased risk of cardiovascular and renal complications in individuals with diabetes. However, the robustness and independence of these associations differ across study populations and are influenced by the degree of adjustment for confounding risk factors. Considering insulin's regulatory effect on FMO3 activity in liver cells, TMAO may serve as a marker of hepatic insulin resistance, which could partially explain its association with diabetes risk. The role of TMAO in diabetes pathology remains controversial; while some studies emphasize its detrimental impact on insulin sensitivity and the progression of diabetes-related complications, others suggest potential protective effects. Investigating the largely unexplored role of TMAO's precursor, trimethylamine, may help elucidate these discrepancies. This review consolidates clinical and experimental findings to clarify TMAO's complex mechanistic contributions to diabetes pathology.

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.

The Dietary Inflammatory Index (DII), a novel tool for quantifying the inflammatory potential of one's diet, has been extensively employed in various chronic disease research. However, there remains no consensus regarding the association between DII and atherosclerosis (AS). This study aims to systematically evaluate the correlation between DII and the occurrence and progression of AS, thereby providing valuable insights for the prevention of cardiovascular and cerebrovascular diseases.

A comprehensive search was conducted in several databases, to identify observational studies investigating the correlation between DII and AS. The search was conducted from the inception of each database until October 1, 2024. Two independent researchers were responsible for the literature screening, quality assessment, and data extraction of the included studies. Meta-analysis was performed using Stata 17.0 software to synthesize the odds ratios (ORs) and 95 % confidence intervals (CIs). Subgroup analysis was also conducted based on factors.

This study included a total of seven studies from three different countries, encompassing a sample size of 2879 participants. The meta-analysis findings revealed a significant association between higher DII scores and an increased risk of AS.

A diet characterized by a high DII score may elevate the risk of developing AS, particularly in terms of its impact on plaque vulnerability. Therefore, increasing the intake of anti-inflammatory dietary components holds significant implications for the prevention and management of AS.

This study aims to investigate the impact of coal dust (silicon dioxide) exposure on dyslipidemia and its underlying mechanisms, with a focus on the association between coal dust exposure and hepatic metabolic disorders.

Clinical data were collected from 5433 coal mine workers to compare the incidence of dyslipidemia between the dust-exposed group and the non-exposed group. A mouse model of silicon dioxide exposure was established to observe hepatic fat accumulation and pathological changes. Liver tissue sequencing was performed to screen for key differential genes. In vitro cell experiments were utilized to identify the molecular mechanisms underlying hepatocyte metabolic abnormalities induced by silicon dioxide exposure.

Clinical data revealed that 69.2% of miners in the dust-exposed group developed dyslipidemia, which was higher than the 30.7% in the non-exposed group. Animal data showed that silicon dioxide exposure led to hepatic fat deposition and pathological damage, with the degree of injury positively correlated with exposure time. Liver sequencing identified a significant upregulation of the FMO3 (flavin monooxygenase 3) gene in mouse liver tissue following silicon dioxide exposure, accompanied by enhanced inflammatory responses. Mechanistic studies demonstrated that silicon dioxide activates Kupffer cells to secrete IL-6 (interleukin-6), which induces high expression of FMO3 in hepatocytes through the PKC/YY1 signaling pathway, thereby disrupting lipid metabolism.

Silicon dioxide exposure can promote the upregulation of FMO3 expression in hepatocytes by activating Kupffer cells to release IL-6 via the PKC/YY1 pathway, ultimately leading to lipid metabolic disorders and dyslipidemia.

Alzheimer's disease, the primary cause of dementia, is characterized by neuropathologies, such as amyloid plaques, synaptic and neuronal degeneration, and neurofibrillary tangles. Although amyloid plaques are the primary characteristic of Alzheimer's disease in the central nervous system and peripheral organs, targeting amyloid-beta clearance in the central nervous system has shown limited clinical efficacy in Alzheimer's disease treatment. Metabolic abnormalities are commonly observed in patients with Alzheimer's disease. The liver is the primary peripheral organ involved in amyloid-beta metabolism, playing a crucial role in the pathophysiology of Alzheimer's disease. Notably, impaired cholesterol metabolism in the liver may exacerbate the development of Alzheimer's disease. In this review, we explore the underlying causes of Alzheimer's disease and elucidate the role of the liver in amyloid-beta clearance and cholesterol metabolism. Furthermore, we propose that restoring normal cholesterol metabolism in the liver could represent a promising therapeutic strategy for addressing Alzheimer's disease.

Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.

Atrial cardiomyopathy is a multifaceted heart disease characterized by structural and functional abnormalities of the atria and is closely associated with atrial fibrillation and its complications. Its etiology involves a number of factors, including genetic, infectious, immunologic, and metabolic factors. Recent research has highlighted the critical role of the gut microbiota in the pathogenesis of atrial cardiomyopathy, and this is consistent with the gut-heart axis having major implications for cardiac health. The aim of this work is to bridge the knowledge gap regarding the interactions between the gut microbiota and atrial cardiomyopathy, with a particular focus on elucidating the mechanisms by which gut dysbiosis may induce atrial remodeling and dysfunction. This article provides an overview of the role of the gut microbiota in the pathogenesis of atrial cardiomyopathy, including changes in the composition of the gut microbiota and the effects of its metabolites. We also discuss how diet and exercise affect atrial cardiomyopathy by influencing the gut microbiota, as well as possible future therapeutic approaches targeting the gut-heart axis. A healthy gut microbiota can prevent disease, but ecological dysbiosis can lead to a variety of symptoms, including the induction of heart disease. We focus on the pathophysiological aspects of atrial cardiomyopathy, the impact of gut microbiota dysbiosis on atrial structure and function, and therapeutic strategies exploring modulation of the microbiota for the treatment of atrial cardiomyopathy. Finally, we discuss the role of gut microbiota in the treatment of atrial cardiomyopathy, including fecal microbiota transplantation and oral probiotics or prebiotics. Our study highlights the importance of gut microbiota homeostasis for cardiovascular health and suggests that targeted interventions on the gut microbiota may pave the way for innovative preventive and therapeutic strategies targeting atrial cardiomyopathy.

Iron overload is a common feature of alcoholic liver disease (ALD) and contributes significantly to disease progression. Quercetin, a flavonoid known for its iron-chelating properties, has emerged as a potential protective compound against ALD. However, research on quercetin's regulatory effects on iron levels in ALD is limited. To address this, we conducted a study using male C57BL/6J mice were subjected to a Lieber De Carli liquid diet containing ethanol (28% energy replacement) with or without quercetin supplementation (100 mg/kg.BW) for 12 weeks. Additionally, HepG2 cells, after transfection with the CYP2E1 plasmid, were incubated with ethanol and/or quercetin. Our findings revealed that ethanol consumption led to iron overload in both hepatocytes and lysosomes. Interestingly, despite the increase in iron levels, cells exhibited impaired iron utilization, disrupting normal iron metabolism. Further analysis identified a potential mechanism involving the Rab7-V1G1 (V-ATPase subunit) axis. Inhibition of V-ATPase by Concanamycin A caused elevated ROS levels, impaired lysosomal and mitochondria function, and increased expression of HIF1α and IRP2. Ultimately, this disruption in cellular processes led to iron overload and mitochondrial iron deficiency. Quercetin supplementation mitigated ethanol-induced hepatocyte damage by reversing iron overload through modulation of the Rab7-V1G1 axis and improving the interaction between lysosomes and mitochondria. In conclusion, this study elucidates a novel pathophysiological mechanism by which quercetin protects against ALD through its regulation of iron homeostasis.

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.

Sleep deprivation (SD) contributes to cognitive impairment. Astrocytic cholesterol biosynthesis is crucial for brain cholesterol homeostasis and cognitive function. However, the underlying mechanism of astrocytic cholesterol metabolism in SD-induced cognitive impairment has not been fully explored. Trimethylamine N-oxide (TMAO), a product of liver flavin-containing monooxygenase-3 (FMO3), has been shown to be increased in the urine of sleep-deprived humans and implicated with peripheral cholesterol metabolism. Nevertheless, how TMAO affects brain cholesterol metabolism remains unclear. In our study, increased FMO3 and brain TMAO levels were observed in the SD mice, and elevated levels of TMAO were confirmed to lead to SD-induced cognitive dysfunction. In addition, we found that the expression of sterol regulatory element-binding protein 2 (SREBP2) is decreased in the brain of SD mice, resulting in the reduction in brain cholesterol content, which in turn causes synaptic damage. Moreover, we demonstrated that TMAO inhibits the expression of SREBP2. In contrast, FMO3 inhibitor 3,3'-diindolylmethane (DIM) alleviates SD-induced cognitive impairment by targeting the liver-brain axis. In conclusion, our study revealed that the TMAO pathway is involved in memory impairment in SD mice through deregulating astrocytic cholesterol metabolism.

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.

Differences in metabolic regulation among obesity phenotypes, specifically metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) women, may lead to varied responses to interventions, which could be elucidated through metabolomics. Therefore, this study aims to investigate the differences in metabolite profiles between MHO and MUO women and the changes following a lifestyle intervention. Serum samples from 36 MHO and 34 MUO women who participated in a lifestyle intervention for weight loss were analysed using untargeted proton nuclear magnetic resonance spectroscopy (1H NMR) at baseline and 6 months post-intervention. Anthropometric, clinical, and dietary intake parameters were assessed at both time points. Both groups showed differential metabolite profiles at baseline and after six months. Seven metabolites, including trimethylamine-N-oxide (TMAO), arginine, ribose, aspartate, carnitine, choline, and tyrosine, significantly changed between groups post-intervention, which all showed a decreasing pattern in MHO. Significant reductions in body weight and body mass index (BMI) in the MUO correlated with changes in the carnitine and tyrosine levels. In conclusion, metabolite profiles differed significantly between MHO and MUO women before and after a lifestyle intervention. The changes in carnitine and tyrosine levels in MUO were correlated with weight loss, suggesting potential targets for therapeutic intervention.

Multiple studies over the last decade have established that Alzheimer's disease and related dementias (ADRD) are associated with changes in the gut microbiome. These alterations in organismal composition result in changes in the abundances of functions encoded by the microbial community, including metabolic capabilities, which likely impact host disease mechanisms. Gut microbes access dietary components and other molecules made by the host and produce metabolites that can enter circulation and cross the blood-brain barrier (BBB). In recent years, several microbial metabolites have been associated with or have been shown to influence host pathways relevant to ADRD pathology. These include short chain fatty acids, secondary bile acids, tryptophan derivatives (such as kynurenine, serotonin, tryptamine, and indoles), and trimethylamine/trimethylamine N-oxide. Notably, some of these metabolites cross the BBB and can have various effects on the brain, including modulating the release of neurotransmitters and neuronal function, inducing oxidative stress and inflammation, and impacting synaptic function. Microbial metabolites can also impact the central nervous system through immune, enteroendocrine, and enteric nervous system pathways, these perturbations in turn impact the gut barrier function and peripheral immune responses, as well as the BBB integrity, neuronal homeostasis and neurogenesis, and glial cell maturation and activation. This review examines the evidence supporting the notion that ADRD is influenced by gut microbiota and its metabolites. The potential therapeutic advantages of microbial metabolites for preventing and treating ADRD are also discussed, highlighting their potential role in developing new treatments.

The intestinal microbiome has been recently linked to several metabolic and chronic disorders, one of which is coronary artery disease (CAD). Our study aimed to analyze the intestinal microbiome of CAD patients and assess the eligibility of dysbiosis as a diagnostic marker of CAD.

PubMed, Scopus, Embase, and Web of Science were searched using terms, such as 'CAD' and 'microbiome'. Only observational controlled studies were included. R version 4.2.2 was used for the analysis.

A significant association was found between the CAD group and increased Simpson and Shannon Indices compared with the control group (MD=0.04, 95% CI=0.03-0.05, and MD=0.11, 95% CI=0.01-0.22, respectively). Our analysis yielded a statistically significant association between the CAD group and increased Prevotella genus (MD=13.27, 95% CI=4.12-22.42, P-value=0.004), Catenibacterium genus (MD=0.09, 95% CI=0.09-0.10), Pseudomonas genus (MD=0.54, 95% CI=0.29-0.78, P-value), and Subdoligranulum (MD=-0.06, 95% CI=-0.06 to -0.06) compared with the control group. Another significant association was detected between the CAD group and decreased Bacteroides vulgatus and Bacteroides dorei (MD=-10.31, 95% CI=-14.78 to -5.84, P-value <0.00001).

Dysbiosis is an acceptable diagnostic marker of CAD. Decreased B. dorei and B. vulgatus among CAD patients suggests a protective role of these bacteria. Future clinical trials are necessary to investigate the potential benefit of supplementation of these bacteria in treating or preventing CAD.

The gut microbiota metabolite trimethylamine-N-oxide (TMAO)-derived from dietary phosphatidylcholine-is mechanistically linked to cardiovascular disease (CVD) and increased cardiovascular risk. This study examined the relationship between fasting plasma TMAO levels and 5-year all-cause mortality in a cohort of patients at high risk of cardiovascular events (CORE-Thailand Registry). Of the 134 patients, 123 (92%) had established cardiovascular disease, and 11 (8%) had multiple risk factors. Fasting plasma TMAO levels were measured using nuclear magnetic resonance spectroscopy. Within this prospective cohort study, the median TMAO was 3.81 μM [interquartile range (IQR) 2.89-5.50 μM], with a mean age of 65 ± 11 years; 61% were men, and 39.6% had type II diabetes. Among 134 patients, 65 (49%) were identified as the high-TMAO group (≥ 3.8 μM), and 69 (51%) were identified as the low-TMAO group (< 3.8 μM). After a median follow-up of 58.8 months, the high-TMAO group was associated with a 2.88-fold increased mortality risk. Following adjustment for traditional risk factors, high-sensitivity cardiac troponin-T, estimated glomerular filtration rate, angiotensin-converting enzyme (ACEI), or angiotensin-receptor blocker (ARB) use, the high-TMAO group remained predictive of 5-year all-cause mortality risk (the high-TMAO vs. the low-TMAO group, adjusted hazard ratio 2.73, 95% CI 1.13-6.54; P = 0.025). Among Thai patients at high risk of cardiovascular events, increased plasma TMAO levels portended greater long-term mortality risk.

Primary prevention is the cornerstone of cardiometabolic health. In the randomized, controlled Special Turku Coronary Risk Factor Intervention Project (STRIP), dietary counseling intervention was given to children from infancy to 20 years of age and a follow-up was completed at age 26 years. We investigated the associations of age, sex, gut microbiome, and dietary intervention with the gut metabolite and the cardiac biomarker trimethylamine-N-oxide (TMAO).

Overall, 592 healthy participants (females 46%) from STRIP were investigated. Compared to the control group, the intervention group had received dietary counseling between ages 7 months and 20 years focused on low intakes of saturated fat and cholesterol and the promotion of fruit, vegetable, and whole-grain consumption. TMAO serum concentrations were measured by a liquid chromatography-tandem mass spectrometry method at ages 11, 13, 15, 17, 19, and 26 years. Microbiome composition was assessed using 16S rRNA gene sequencing at 26 years of age.

TMAO concentrations increased from age 11 to 26 years in both sexes. At all measurement time points, males showed significantly higher serum TMAO concentrations compared to females, but concentrations were similar between the intervention and control groups. A direct association between TMAO concentrations and reported fiber intake was found in females. Gut microbiome analysis did not reveal associations with TMAO.

TMAO concentration increased from childhood to early adulthood but was not affected by the given dietary intervention. In females, TMAO concentrations could be directly associated with higher fiber intake suggesting sex-specific differences in TMAO metabolism.

Trimethylamine-N-oxide (TMAO) is a gut-derived metabolite associated with cardiovascular disease (CVD). In preclinical and observational studies, resveratrol and exercise training have been suggested as potential strategies to reduce the systemic levels of TMAO. However, evidence from experimental studies in humans remains unknown. This project examined the dose-dependent effects of a combined resveratrol intervention with exercise training on circulating TMAO and other related metabolite signatures in older adults with high CVD risk.

Forty-one older adults [mean (±SD) age of 72.1 (6.8) years] participated in a 12-week supervised center-based, multi-component exercise training intervention [2×/week; 80 min/session] and were randomized to one of two resveratrol dosages [Low: 500 vs. High:1000 mg/day] or a cellulose-based placebo. Serum/plasma were collected at baseline and post-intervention and evaluated for TMAO and associated analytes.

After the 12-week intervention, TMAO concentration increased over time, regardless of treatment [mean (±SD) Placebo: 11262 (±3970); Low:13252 (±1193); High: 12661(±3359) AUC; p = 0.04]. Each resveratrol dose produced different changes in metabolite signatures. Low dose resveratrol upregulated metabolites associated with bile acids biosynthesis (i.e., glycochenodeoxycholic acid, glycoursodeoxycholic acid, and glycocholic acid). High dose resveratrol modulated metabolites enriched for glycolysis, and pyruvate, propanoate, β-alanine, and tryptophan metabolism. Different communities tightly correlated to TMAO and resveratrol metabolites were associated with the lipid and vascular inflammatory clinical markers [|r| > 0.4, p < 0.05].

These findings suggest a distinct dose-dependent adaptation response to resveratrol supplementation on circulating metabolite signatures but not on TMAO among high-risk CVD older adults when combined with an exercise training intervention.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The gut microbiome has been implicated in outcomes for HCC, and gut microbe-derived products may serve as potential non-invasive indices for early HCC detection. This study evaluated differences in plasma concentrations of gut microbiota-derived metabolites.

Forty-one patients with HCC and 96 healthy controls were enrolled from surgical clinics at the Cleveland Clinic from 2016 to 2020. Gut microbiota-derived circulating metabolites detectable in plasma were compared between patients with HCC and healthy controls. Hierarchical clustering was performed for generating heatmaps based on circulating metabolite concentrations using ClustVis, with Euclidean and Ward settings and significant differences between metabolite concentrations were tested using a binary logistic regression model.

In patients with HCC, 25 (61%) had histologically confirmed cirrhosis. Trimethylamine (TMA)-related metabolites were found at higher concentrations in those with HCC, including choline (p < 0.001), betaine (p < 0.001), carnitine (p = 0.007), TMA (p < 0.001) and trimethylamine N-oxide (TMAO, p < 0.001). Notably, concentrations of P-cresol glucuronide (p < 0.001), indole-lactic acid (p = 0.038), 5-hydroxyindoleacetic acid (p < 0.0001) and 4-hydroxyphenyllactic acid (p < 0.001) were also increased in those with HCC compared to healthy controls. Hierarchical clustering of the metabolite panel separated patients based on the presence of HCC (p < 0.001), but was not able to distinguish between patients with HCC based on the presence of cirrhosis (p = 0.42).

Gut microbiota-derived metabolites were differentially abundant in patients with HCC versus healthy controls. The observed perturbations of the TMAO pathway in HCC seem particularly promising as a target of future research and may have both diagnostic and therapeutic implications.

Tissue fibrosis is a common pathway to failure in many organ systems and is the cellular and molecular driver of myriad chronic diseases that are incompletely understood and lack effective treatment. Recent studies suggest that gut microbe-dependent metabolites might be involved in the initiation and progression of fibrosis in multiple organ systems.

In a meta-organismal pathway that begins in the gut, gut microbiota convert dietary precursors such as choline, phosphatidylcholine, and L-carnitine into trimethylamine (TMA), which is absorbed and subsequently converted to trimethylamine N-oxide (TMAO) via the host enzyme flavin-containing monooxygenase 3 (FMO3) in the liver. Chronic exposure to elevated TMAO appears to be associated with vascular injury and enhanced fibrosis propensity in diverse conditions, including chronic kidney disease, heart failure, metabolic dysfunction-associated steatotic liver disease, and systemic sclerosis.

Despite the high prevalence of fibrosis, little is known to date about the role of gut dysbiosis and of microbe-dependent metabolites in its pathogenesis. This review summarizes recent important advances in the understanding of the complex metabolism and functional role of TMAO in pathologic fibrosis and highlights unanswered questions.

Since its discovery, numerous studies have shown the role of the microbiota in well-being and disease. The gut microbiota represents an essential factor that plays a multidirectional role that affects not just the gut but also other parts of the body, including the brain, endocrine system, humoral system, immune system, and metabolic pathways, as well as host-microbiome interactions. Through a comprehensive analysis of existing literature using the desktop research methodology, this review elucidates the mechanisms by which gut microbiota dysbiosis contributes to metabolic dysfunction, including obesity, dyslipidaemia, hypertension, atherosclerosis, hyperuricemia, and hyperglycaemia. Furthermore, it examines the bidirectional communication pathways between gut microbiota and host metabolism, highlighting the role of microbial-derived metabolites, immune modulation, and gut barrier integrity in shaping metabolic homeostasis. Importantly, the review identifies promising therapeutic strategies targeting the gut microbiota as potential interventions for metabolic syndrome, including probiotics, prebiotics, symbiotics, dietary modifications, and faecal microbiota transplantation. By delineating the bidirectional interactions between gut microbiota and metabolic syndrome, the review not only advances our understanding of disease pathophysiology but also underscores the potential for innovative microbiota-based interventions to mitigate the global burden of metabolic syndrome and its associated complications.

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

The incidence of gallbladder cholesterol stones (GCS) increases rapidly among people living in high-altitude hypoxic environments compared to those in normoxic areas. Upregulation of hepatic hypoxia inducible factor 1α (Hif-1α) plays a key role in the formation of GCS. High plasma trimethylamine-N-oxide (TMAO) levels are positively correlated with the occurrence of GCS. We hypothesized that HIF-1α may upregulate TMAO levels by promoting the transcription of flavin-containing monooxygenase 3 (Fmo3), which eventually leads to GCS formation. Our study shows that in women, high plasma total cholesterol and apolipoprotein B were positively correlated with cholecystolithiasis and hypoxia. Hif-1α binds to the Fmo3 promoter and promotes Fmo3 expression. Hypoxia and lithogenic diet induce the expression of Hif-1α, Fmo3, TMAO and cholesterol tube transporters in the livers of mice, disturb the proportion of bile and plasma components, and induce the formation of GCS. In cell experiments, silencing Hif-1α downregulates the expression of Fmo3, TMAO and cholesterol tube transporters. In a mouse model of hypoxic cholecystolithiasis, silencing Hif-1α downregulates the expression of related genes, restores the proportion of bile and plasma lipid components, and reduces the formation of GCS. Our study shows that Hif-1α binds to the promoter region of Fmo3 and promotes Fmo3 transcription. Thus, it mediates the transcriptional activation of the TMA/Fmo3/TMAO pathway, upregulates the expression of ATP-binding cassettes (Abc) g5 and g8, and participates in the regulation of the occurrence of GCS in the plateau region.

Recent genome-wide association studies (GWAS) have identified a link between single-nucleotide polymorphisms (SNPs) near the MBOAT7 gene and advanced liver diseases. Specifically, the common MBOAT7 variant (rs641738) associated with reduced MBOAT7 expression is implicated in non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis. However, the precise mechanism underlying MBOAT7-driven liver disease progression remains elusive. Previously, we identified MBOAT7-driven acylation of lysophosphatidylinositol lipids as key mechanism suppressing the progression of NAFLD (Gwag et al., 2019). Here, we show that MBOAT7 loss of function promotes ALD via reorganization of lysosomal lipid homeostasis. Circulating levels of MBOAT7 metabolic products are significantly reduced in heavy drinkers compared to healthy controls. Hepatocyte- (Mboat7-HSKO), but not myeloid-specific (Mboat7-MSKO), deletion of Mboat7 exacerbates ethanol-induced liver injury. Lipidomic profiling reveals a reorganization of the hepatic lipidome in Mboat7-HSKO mice, characterized by increased endosomal/lysosomal lipids. Ethanol-exposed Mboat7-HSKO mice exhibit dysregulated autophagic flux and lysosomal biogenesis, associated with impaired transcription factor EB-mediated lysosomal biogenesis and autophagosome accumulation. This study provides mechanistic insights into how MBOAT7 influences ALD progression through dysregulation of lysosomal biogenesis and autophagic flux, highlighting hepatocyte-specific MBOAT7 loss as a key driver of ethanol-induced liver injury.

Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy and mechanism of disulfiram's antiatherosclerotic activity is yet to be explored.

We used human/mouse macrophages, endothelial cells, and smooth muscle cells and a hyperlipidemic mouse model of atherosclerosis to determine disulfiram antiatherosclerotic efficacy and mechanism. The effects of disulfiram on several atheroprotective pathways such as autophagy, efferocytosis, phagocytosis, and gut microbiota were determined. Atomic force microscopy was used to determine the effects of disulfiram on the biophysical properties of the plasma membrane of macrophages. Disulfiram-fed hyperlipidemic apolipoprotein E-/- mice showed significantly reduced interleukin-1β release upon in vivo Nlrp3 (NLR family pyrin domain containing 3) inflammasome activation. Disulfiram-fed mice showed smaller atherosclerotic lesions (~27% and 29% reduction in males and females, respectively) and necrotic core areas (~50% and 46% reduction in males and females, respectively). Disulfiram induced autophagy in macrophages, smooth muscle cells, endothelial cells, hepatocytes/liver, and atherosclerotic plaques. Disulfiram modulated other atheroprotective pathways (eg, efferocytosis, phagocytosis) and gut microbiota. Disulfiram-treated macrophages showed enhanced phagocytosis/efferocytosis, with the mechanism being a marked increase in cell-surface expression of efferocytic receptor MerTK. Atomic force microscopy analysis revealed altered biophysical properties of disulfiram-treated macrophages, showing increased order-state of plasma membrane and increased adhesion strength. Furthermore, 16sRNA sequencing of disulfiram-fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota Akkermansia and a reduction in atherogenic Romboutsia species.

Taken together, our data show that disulfiram can simultaneously modulate several atheroprotective pathways in a GsdmD-dependent as well as GsdmD-independent manner.

Metabolic syndrome (MS) is defined by the outcome of interconnected metabolic factors that directly increase the prevalence of obesity and other metabolic diseases. Currently, obesity is considered one of the most relevant topics of discussion because an epidemic heave of the incidence of obesity in both developing and underdeveloped countries has been reached. According to the World Obesity Atlas 2023 report, 38% of the world population are presently either obese or overweight. One of the causes of obesity is an imbalance of energy intake and energy expenditure, where nutritional imbalance due to consumption of high-calorie fast foods play a pivotal role. The dynamic interactions among different risk factors of obesity are highly complex; however, the underpinnings of hyperglycemia and dyslipidemia for obesity incidence are recognized. Fast foods, primarily composed of soluble carbohydrates, non-nutritive artificial sweeteners, saturated fats, and complexes of macronutrients (protein-carbohydrate, starch-lipid, starch-lipid-protein) provide high metabolic calories. Several experimental studies have pointed out that dairy proteins and peptides may modulate the activities of risk factors of obesity. To justify the results precisely, peptides from dairy milk proteins were synthesized under in vitro conditions and their contributions to biomarkers of obesity were assessed. Comprehensive information about the impact of proteins and peptides from dairy milks on fast food-induced obesity is presented in this narrative review article.

Cardiovascular diseases are the leading cause of death worldwide, significantly impacting public health. Atherosclerotic cardiovascular diseases account for the majority of these deaths, with atherosclerosis marking the initial and most critical phase of their pathophysiological progression. There is a complex relationship between atherosclerosis, the gut microbiome's composition and function, and the potential mediating role of exercise. The adaptability of the gut microbiome and the feasibility of exercise interventions present novel opportunities for therapeutic and preventative approaches.

We conducted a comprehensive literature review using professional databases such as PubMed and Web of Science. This review focuses on the application of meta-omics techniques, particularly metagenomics and metabolomics, in studying the effects of exercise interventions on the gut microbiome and atherosclerosis.

Meta-omics technologies offer unparalleled capabilities to explore the intricate connections between exercise, the microbiome, the metabolome, and cardiometabolic health. This review highlights the advancements in metagenomics and metabolomics, their applications in research, and examines how exercise influences the gut microbiome. We delve into the mechanisms connecting these elements from a metabolic perspective. Metagenomics provides insight into changes in microbial strains post-exercise, while metabolomics sheds light on the shifts in metabolites. Together, these approaches offer a comprehensive understanding of how exercise impacts atherosclerosis through specific mechanisms.

Exercise significantly influences atherosclerosis, with the gut microbiome serving as a critical intermediary. Meta-omics technology holds substantial promise for investigating the gut microbiome; however, its methodologies require further refinement. Additionally, there is a pressing need for more extensive cohort studies to enhance our comprehension of the connection among these element.

Curcumin (CUR) is a lipophilic natural polyphenol that can be isolated from the rhizome of turmeric. Studies have proposed that CUR possesses a variety of biological activities. Due to its anti-inflammatory and antioxidant properties, CUR shows promise in the treatment of inflammatory bowel disease, while its anti-obesity effects make it a potential therapeutic agent in the management of obesity. In addition, curcumin's ability to prevent atherosclerosis and its cardiovascular benefits further expand its potential application in the treatment of cardiovascular disease. Nevertheless, owing to the limited bioavailability of CUR, it is difficult to validate its specific mechanism of action in the treatment of diseases. However, the restricted bioavailability of CUR makes it challenging to confirm its precise mode of action in disease treatment. Recent research indicates that the oral intake of curcumin may lead to elevated levels of residual curcumin in the gastrointestinal system, hinting at curcumin's potential to directly influence gut microbiota. Furthermore, the ecological dysregulation of the gut microbiota has been shown to be critical in the pathogenesis of human diseases. This review summarizes the impact of gut dysbiosis on host health and the various ways in which curcumin modulates dysbiosis and ameliorates various diseases caused by it through the administration of curcumin.

This study investigated the effects of dietary energy level on the antioxidant capability, immune function, and rectal microbiota in donkey jennets during the last 60 days of gestation.

Fifteen pregnant DeZhou donkeys with age of 6.0 ± 0.1 years, body weight of 292 ± 33 kg, parity of 2.7 ± 0.1 parities and similar expected date of confinement (74 ± 4 days) were randomly allocated to three groups and feed three diets: high energy (10.92 MJ/kg, H), medium energy (10.49 MJ/kg, M), and low energy (9.94 MJ/kg, L).

The serum activity of catalase (CAT), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC) in group M was significantly higher, whereas the concentrations of malondialdehyde (MDA), interleukin 1 (IL-1), IL-2, and IL-6 were lower than those recorded for groups H and L (p ≤ 0.05). The dietary energy level significantly affected rectal microbial community structure in the jennet donkeys 35 days and 7 days before the parturition (p ≤ 0.05). The abundances of norank_f_norank_o_Coriobacteriales genus was significantly higher (p ≤ 0.05) in group H, and the abundances of norank_f_norank_o_Mollicutes_RF39 and the Candidatus_Saccharimonas were higher in group L (p ≤ 0.05). The abundance of Fibrobacter in group M was significantly increased (p ≤ 0.05). The abundance of norank_f_norank_o_Coriobacteriales was positively correlated with average daily gain (ADG) and tumor necrosis factor-α (TNF-α) concentrations (p ≤ 0.05). The abundance of norank_f_norank_o_Mollicutes_RF39 was positively correlated with IL-2 and IL-6 concentrations. The abundance of Candidatus_Saccharimonas was positively correlated with CAT, T-SOD and GSH-Px activities (p ≤ 0.05). The abundance of Fibrobacter was positively correlated with CAT and T-SOD activities (p ≤ 0.05), but negatively correlated with IL-2 concentration (p ≤ 0.05). In conclusion, an appropriate dietary with an energy content of 10.49 MJ/kg for jennet donkeys during late gestation increased the prenatal antioxidant capacity, reduced inflammatory cytokines, and promoted fetal growth, and these changes were related to diet-induced changes in rectal microbiota compositions.

Obesity, a chronic condition marked by the excessive accumulation of adipose tissue, not only affects individual well-being but also significantly inflates healthcare costs. The physiological excess of fat manifests as triglyceride (TG) deposition within adipose tissue, with white adipose tissue (WAT) expansion via adipocyte hyperplasia being a key adipogenesis mechanism. As efforts intensify to address this global health crisis, understanding the complex interplay of contributing factors becomes critical for effective public health interventions and improved patient outcomes. In this context, gut microbiota-derived metabolites play an important role in orchestrating obesity modulation. Microbial lipopolysaccharides (LPS), secondary bile acids (BA), short-chain fatty acids (SCFAs), and trimethylamine (TMA) are the main intestinal metabolites in dyslipidemic states. Emerging evidence highlights the microbiota's substantial role in influencing host metabolism and subsequent health outcomes, presenting new avenues for therapeutic strategies, including polyphenol-based manipulations of these microbial populations. Among various agents, caffeine emerges as a potent modulator of metabolic pathways, exhibiting anti-inflammatory, antioxidant, and obesity-mitigating properties. Notably, caffeine's anti-adipogenic potential, attributed to the downregulation of key adipogenesis regulators, has been established. Recent findings further indicate that caffeine's influence on obesity may be mediated through alterations in the gut microbiota and its metabolic byproducts. Therefore, the present review summarizes the anti-adipogenic effect of caffeine in modulating obesity through the intestinal microbiota and its metabolites.

The onset and progression of cardiovascular diseases with the major underlying cause being atherosclerosis, occur during chronic inflammatory persistence in the vascular system, especially within the arterial wall. Such prolonged maladaptive inflammation is driven by macrophages and their key mediators are generally attributed to a disparity in lipid metabolism. Macrophages are the primary cells of innate immunity, endowed with expansive membrane domains involved in immune responses with their signalling systems. During atherosclerosis, the membrane domains and receptors control various active organisations of macrophages. Their scavenger/endocytic receptors regulate the trafficking of intracellular and extracellular cargo. Corresponding influence on lipid metabolism is mediated by their dynamic interaction with scavenger membrane receptors and their integrated mechanisms such as pinocytosis, phagocytosis, cholesterol export/import, etc. This interaction not only results in the functional differentiation of macrophages but also modifies their structural configurations. Here, we reviewed the association of macrophage membrane biomechanics and their scavenger receptor families with lipid metabolites during the event of atherogenesis. In addition, the membrane structure of macrophages and the signalling pathways involved in endocytosis integrated with lipid metabolism are detailed. This article establishes future insights into the scavenger receptors as potential targets for cardiovascular disease prevention and treatment.

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

The gut microbiome interacts with the brain bidirectionally through the microbiome-gutbrain axis, which plays a key role in regulating various nervous system pathophysiological processes. Trimethylamine N-oxide (TMAO) is produced by choline metabolism through intestinal microorganisms, which can cross the blood-brain barrier to act on the central nervous system. Previous studies have shown that elevated plasma TMAO concentrations increase the risk of major adverse cardiovascular events, but there are few studies on TMAO in cerebrovascular disease and vascular cognitive impairment. This review summarized a decade of research on the impact of TMAO on stroke and related cognitive impairment, with particular attention to the effects on vascular cognitive disorders. We demonstrated that TMAO has a marked impact on the occurrence, development, and prognosis of stroke by regulating cholesterol metabolism, foam cell formation, platelet hyperresponsiveness and thrombosis, and promoting inflammation and oxidative stress. TMAO can also influence the cognitive impairment caused by Alzheimer's disease and Parkinson's disease via inducing abnormal aggregation of key proteins, affecting inflammation and thrombosis. However, although clinical studies have confirmed the association between the microbiome-gut-brain axis and vascular cognitive impairment (cerebral small vessel disease and post-stroke cognitive impairment), the molecular mechanism of TMAO has not been clarified, and TMAO precursors seem to play the opposite role in the process of poststroke cognitive impairment. In addition, several studies have also reported the possible neuroprotective effects of TMAO. Existing therapies for these diseases targeted to regulate intestinal flora and its metabolites have shown good efficacy. TMAO is probably a new target for early prediction and treatment of stroke and vascular cognitive impairment.

Spasticity is one of the most prevalent ischemic stroke sequelae and the leading cause of disability after stroke. Although electroacupuncture pretreatment has been shown to be effective in the treatment of ischemic stroke, its therapeutic effect and mechanism on post-stroke spasm remain unknown. The purpose of this study was to look into the potential mechanism of electroacupuncture pretreatment in inducing the NF-κB/NLRP3 signaling pathway and the gut-brain axis in the therapy of spasm after stroke.

After electroacupuncture treatment at Baihui (DU20) and Qubin (G87), the rat model of middle cerebral artery occlusion (MCAO) was first established. HE, Nissl, and TUNEL staining were used to detect pathological alterations in the rat brain. The relative levels of IL-4, IL-6, TNF-α, and TMAO were determined by ELISA. qRT-PCR and Western blot were used to evaluate the mRNA and protein levels of NF-κB p65, NLRP3, caspase3 and caspase9. Gas chromatography-mass spectrometry (GC-MS) was used to determine the levels of short-chain fatty acids (SCFAs) in rat gut.

Hippocampal cells from rats with spasticity following stroke in the MCAO group were chaotic and loosely distributed with an unclear border, a blurred nucleolus, and vanished cytoplasm when compared to those from the sham operation group. Furthermore, the number of surviving neurons decreased while the number of apoptotic cells increased. In the I/R group, relative levels of IL-6, TNF-α, and TMAO increased considerably, while NF-κB p65, NLRP3, caspase3, and caspase9 were dramatically downregulated. The intestinal contents of n-propyl acetate and propyl butyrate were lowered in rats with spasticity following stroke. Electroacupuncture treatments miraculously remedied all of the foregoing pathogenic alterations.

Pretreatment with electroacupuncture relieves spasticity after stroke by decreasing the inflammatory response, suppressing the NF-κB/NLRP3 signaling pathway, and modulating the gut-brain axis by increasing n-propyl acetate and propyl butyrate levels in the bowel. Our findings establish a new molecular mechanism and theoretical foundation for electroacupuncture therapy of ischemic stroke.

The continuous development of antitumor therapy has significantly reduced the mortality of patients with malignancies. However, the antitumor-related cardiotoxicity has become the leading cause of long-term mortality in patients with malignancies. Besides, the pathogenesis of antitumor-related cardiotoxicity is still unclear, and practical means of prevention and treatment are lacking in clinical practice. Therefore, the major challenge is how to combat the cardiotoxicity of antitumor therapy effectively. More and more studies have shown that antitumor therapy kills tumor cells while causing damage to sensitive tissues such as the intestinal mucosa, leading to the increased permeability of the intestine and the dysbiosis of intestinal microecology. In addition, the dysbiosis of intestinal microecology contributes to the development and progression of cardiovascular diseases through multiple pathways. Thus, the dysbiosis of intestinal microecology may be a potential mechanism and target for antitumor-related cardiotoxicity. We summarized the characteristics of intestinal microecology disorders induced by antitumor therapy and the association between intestinal microecological dysbiosis and CVD. And on this basis, we hypothesized the potential mechanisms of intestinal microecology mediating the occurrence of antitumor-related cardiotoxicity. Then we reviewed the previous studies targeting intestinal microecology against antitumor-associated cardiotoxicity, aiming to provide a reference for future studies on the occurrence and prevention of antitumor-related cardiotoxicity by intestinal microecology.

Diabetes and its complications are serious medical and global burdens, often manifesting as postprandial hyperglycemia. In recent years, considerable research attention has focused on relationships between the gut microbiota and circulating postprandial glucose (PPG). Different population studies have suggested that PPG is closely related to the gut microbiota which may impact PPG via short-chain fatty acids (SCFAs), bile acids (BAs) and trimethylamine N-oxide (TMAO). Studies now show that gut microbiota models can predict PPG, with individualized nutrition intervention strategies used to regulate gut microbiota and improve glucose metabolism to facilitate the precision treatment of diabetes. However, few studies have been conducted in patients with diabetes. Therefore, little is known about the relationships between the gut microbiota and PPG in this cohort. Thus, more research is required to identify key gut microbiota and associated metabolites and pathways impacting PPG to provide potential therapeutic targets for PPG.