Several systematic reviews/meta-analyses of observational studies have demonstrated associations between circulating trimethylamine-N-oxide (TMAO) and cardiovascular, cerebral, and renal diseases, including mortality. However, causal roles for TMAO in these diseases are controversial. Interventions are lacking to show whether lowering TMAO in clinical trials could reduce the risks of these diseases. TMAO could still serve as a prognostic marker for the mentioned outcomes, but investigating this potential role requires robust methodologies. We conducted a systematic search and critical evaluation of published systematic reviews/meta-analyses in the field.

We identified 27 systematic reviews/meta-analyses on the association between TMAO and stroke (n = 7), cardiovascular disease including cause-specific and/or all-cause mortality (n = 14), and other related outcomes (n = 6). The majority of the systematic reviews/meta-analyses found higher blood TMAO concentrations in patients who were positive for the outcomes. Primary studies included populations with multiple risk factors for the given outcomes and did not sufficiently account for potential confounders. Prospective studies examining associations between baseline TMAO and subsequent disease outcomes in healthy populations were entirely absent. Furthermore, we identified serious flaws in methods, conduct and reporting in the majority of the published systematic reviews/meta-analyses, thus leading to critically low confidence in the results.

High quality systematic reviews/meta-analyses examining the associations between TMAO and cardiovascular or cerebral disease are needed to examine potential causal and/or predictive roles of TMAO in these diseases. This study is registered at the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024534940).

The association between the microbiota and obstructive sleep apnea (OSA) remains understudied. In this study, we conducted a comprehensive systematic review and meta-analysis of studies investigating the diversity and relative abundance of microbiota in the gut, respiratory tracts and oral cavity of patients with OSA, aiming to provide an in-depth characterization of the microbial communities associated with OSA.

A comprehensive literature search across PubMed, the Cochrane Library, Web of Science, and Embase databases were conducted to include studies published prior to Dec 2024 that compared the gut, respiratory and oral microbiota between individuals with and without OSA. The findings regarding alpha-diversity, beta-diversity, and relative abundance of microbiota extracted from the included studies were summarized. This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the study protocol was registered with PROSPERO (CRD42024525114).

We identified a total of 753 articles, out of which 27 studies were ultimately included in the systematic review, involving 1,381 patients with OSA and 692 non-OSA populations, including 1,215 OSA patients and 537 non-OSA populations in adults and 166 OSA patients and 155 non-OSA populations in children. The results of alpha diversity revealed a reduction in the Chao1 index (SMD = -0.40, 95% CI = -0.76 to -0.05), Observed species (SMD = -0.50, 95% CI = -0.89 to -0.12) and Shannon index (SMD = -0.27, 95% CI = -0.47 to -0.08) of the gut microbiota in patients with OSA. Beta diversity analysis indicated significant differences in the gut, respiratory and oral microbial community structure between individuals with OSA and those without in more than half of the included studies. Furthermore, in comparison to the non-OSA individuals, the gut environment of patients with OSA exhibited an increased relative abundance of phylum Firmicutes, along with elevated levels of genera Lachnospira; conversely, there was a decreased relative abundance of phylum Bacteroidetes and genus Ruminococcus and Faecalibacterium. Similarly, within the oral environment of OSA patients, there was an elevated relative abundance of phylum Actinobacteria and genera Neisseria, Rothia, and Actinomyces.

Patients with OSA exhibit reduced diversity, changes in bacterial abundance, and altered structure in the microbiota, especially in the gut microbiota. The results of this study provide basic evidence for further exploration of microbiome diagnostic markers and potential intervention strategies for OSA.

Dysbiosis, which refers to an imbalance in the composition of the gut microbiome, has been associated with a range of metabolic disorders, including type 2 diabetes, obesity, and metabolic syndrome. Although the exact mechanisms connecting gut dysbiosis to these conditions are not fully understood, various lines of evidence strongly suggest a substantial role for the interaction between the gut microbiome, mitochondria, and epigenetics. Current studies suggest that the gut microbiome has the potential to affect mitochondrial function and biogenesis through the production of metabolites. A well-balanced microbiota plays a pivotal role in supporting normal mitochondrial and cellular functions by providing metabolites that are essential for mitochondrial bioenergetics and signaling pathways. Conversely, in the context of illnesses, an unbalanced microbiota can impact mitochondrial function, leading to increased aerobic glycolysis, reduced oxidative phosphorylation and fatty acid oxidation, alterations in mitochondrial membrane permeability, and heightened resistance to cellular apoptosis. Mitochondrial activity can also influence the composition and function of the gut microbiota. Because of the intricate interplay between nuclear and mitochondrial communication, the nuclear epigenome can regulate mitochondrial function, and conversely, mitochondria can produce metabolic signals that initiate epigenetic changes within the nucleus. Given the epigenetic modifications triggered by metabolic signals from mitochondria in response to stress or damage, targeting an imbalanced microbiota through interventions could offer a promising strategy to alleviate the epigenetic alterations arising from disrupted mitochondrial signaling.

The gut microbiota and its metabolites are bi-directionally associated with various human illnesses, which has received extensive attention. Trimethylamine N-oxide (TMAO) is a gut microbiota metabolite produced in the liver, which may serve the role of an "axis" connecting the gut and host organs. TMAO levels are significantly higher in the blood of individuals with cardiovascular, renal, neurological, and metabolic diseases. Endothelial cells are crucial for regulating microcirculation and maintaining tissue and organ barriers and are widely recognized as target cells for TMAO. TMAO not only induces endothelial dysfunction but also acts on various cell types, such as endothelial cells, epithelial cells, vascular smooth muscle cells, nerve cells, and pancreatic cells, triggering multiple cell death mechanisms, including necrosis and programmed cell death, thereby influencing host health. This paper thoroughly covers the origins, production, and metabolic pathways of TMAO, emphasizing its importance in the early detection and prognosis of human diseases in the "Gut-Organ" axis, as well as its mechanisms of influence on human diseases, particularly the cross-talk with cell death. Furthermore, we cover recent advances in treating human diseases by regulating gut microbiota structure and enzyme activity to influence TMAO metabolism and reduce TMAO levels, including the use of probiotics, prebiotics, antibiotics, anti-inflammatory drugs, antiplatelet drugs, hypoglycemic drugs, lipid-lowering drugs, and natural products.

Abnormal component changes of gut microbiota are related to the pathogenesis and progression of coronary heart disease (CHD), and gut microbiota-derived metabolites are key factors in host-microbiome interactions. This study aimed to explore the key gut microbiota and metabolites, as well as their relationships in CHD.

Feces samples and blood samples were collected from CHD patients and healthy controls. Then, the obtained feces samples were sent for 16s rRNA gene sequencing, and the blood samples were submitted for metabolomics analysis. Finally, conjoint analysis of 16s rRNA gene sequencing and metabolomics data was performed.

After sequencing, there were no significant differences in Chao 1, observed species, Simpson, Shannon, Pielou's evenness and Faith's PD between the CHD patients and controls. At phylum level, the dominant phyla were Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. At genus level, the abundance of Sphingomonas, Prevotella, Streptococcus, Desulfovibrio, and Shigella was relatively higher in CHD patients; whereas Roseburia, Corprococcus, and Bifidobacterium was relatively lower. Randomforest analysis showed that Sphingomonas was more important for CHD. Through metabolomic analysis, a total of 155 differential metabolites were identified, and were enriched in many signaling pathways. Additionally, the AUC of the conjoint analysis (0.908) was higher than that of gut microbiota species (0.742).

In CHD patients, the intestinal flora was disordered, as well as Sphingomonas and the identified differential metabolites may serve as was candidate biomarkers for CHD occurrence and progression.

The intestinal microbiota, hosting trillions of microorganisms that inhabit the gastrointestinal tract, functions as a symbiotic organism that plays a crucial role in regulating health by producing biologically active molecules that can enter systemic circulation. Among them, trimethylamine-N-oxide (TMAO), an organic compound derived from dietary sources and microbial metabolism, has emerged as a critical biomarker linking diet, the gut microbiota, and the host metabolism to various pathological conditions. This comprehensive review highlights TMAO's biosynthesis, physiological functions, and clinical significance, focusing on its mechanistic contributions to cardiovascular and neurodegenerative diseases. Notably, TMAO-mediated pathways include endothelial dysfunction, inflammation via NLRP3 inflammasome activation, and cholesterol metabolism disruption, which collectively accelerate atherosclerosis and disease progression. Nonetheless, this work underscores the innovative potential of targeting TMAO through dietary, nutraceutical, and microbiota-modulating strategies to mitigate its pathological effects, marking a transformative approach in the prevention and management of TMAO-related disorders.

Trimethylamine N-oxide (TMAO) is suggested as a biomarker for inflammatory and cardiovascular diseases which are identified as risk factors for severe cases of coronavirus disease 2019 (COVID-19). Our primary aim was to assess prognostic potential of serum TMAO levels in predicting COVID-19-related mortality. The secondary aim was to examine the potential of various biochemical parameters, particularly those associated with inflammation or thrombosis, as predictors of mortality.

In this prospective and single-centre study, COVID-19 patients were categorized as death (group 1) or discharged (group 2) based on their in-hospital mortality status. The characteristics of participants were documented, and clinical data, including TMAO, angiotensin-converting enzyme-2 (ACE2), and neutrophil to lymphocyte ratio (NLR), were determined. The association of these independent variables with the COVID-19-related mortality, was assessed by calculation of crude odds ratios (OR) in bivariate and logistic regression analysis. Receiver operation characteristic (ROC) analysis was used for cut-off values.

The serum levels of TMAO, ACE2 and NLR were markedly higher in group 1 on the days of hospital admission (p ​< ​0.05, p ​< ​0.05, and p ​< ​0.01, respectively). Serum TMAO levels (OR 1.422; 95 ​% CI [1.067-1.894]; p ​= ​0.016) and NLR (OR 1.166; 95 ​% CI [1.012-1.343]; p ​= ​0.033) were determined as independent predictors for COVID-19-related mortality with after multivariate logistic regression analysis. The optimal cut-off values were detected as 7.9 ​ng/ml for TMAO (71 ​% sensitivity, 68 ​% specificity, AUC ​= ​0.701).

The findings of this initial study indicate that serum TMAO levels and NLR may be useful in predicting mortality in the early stages of COVID-19.

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.

The dietary components choline, betaine, and L-carnitine are converted by intestinal microbiota into the molecule trimethylamine (TMA). In the human liver, hepatic flavin-containing monooxygenase 3 oxidizes TMA to trimethylamine-N-oxide (TMAO). TMAO is considered a candidate marker for the risk of cardiovascular disease.

The Healthy Lifestyle Community Program cohort 3 (HLCP-3) intervention was conducted with participants recruited from the general population in Germany (intervention: n = 99; control: n = 48). The intervention included intensive educational workshops, seminars, and coaching activities. The assessment was conducted using a complete case analysis (CCA) of the participants. The intervention was carried out for a ten-week intensive phase and an alumni phase. The interventional program emphasizes adopting a healthy plant-based diet and reducing meat consumption, as adherence to such a diet may lead to lowering TMAO levels. Additionally, it provides general recommendations about physical activity, stress management, and community support. The control group did not receive any intervention. TMAO was evaluated using stable isotope dilution liquid chromatography, and tandem mass spectrometry was used to measure fasting plasma levels of TMAO.

The present study aimed to determine the impact of the Healthy Lifestyle Community Program (HLCP-3) on risk profiles for lifestyle-related diseases and TMAO plasma levels.

Significant decreases in most risk profile parameters were detected, and a non-significant decrease in plasma TMAO levels was observed in the intervention group (0.37 (-1.33; 0.59) µmol/L). Furthermore, for the intervention group, after a six-month follow-up period, there was a significant negative correlation between higher healthy plant diet index (hPDI) scores and a decrease in plasma TMAO (ß = -0.200, p = 0.027). Additionally, a significant negative correlation was observed between the TMAO level and the scores for adherence to the plant diet index (PDI) (r = -0.195; p = 0.023).

HLCP-3 is effective at improving adherence to a plant-based diet and improving risk profile parameters. However, long-term interventions involving stricter dietary programs in the sense of a plant-based diet are recommended if significant decreases in TMAO levels are to be obtained.

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

Cardiovascular diseases are one of the leading causes of mortality and morbidity worldwide, with the total number of cases increasing to 523 million in 2019. Despite the advent of new drugs, cardiovascular mortality has increased at an alarming rate of 53.7 % from 12.1 million deaths in 1990. Recently, the role of gut microbiome metabolites, such as Trimethylamine N-Oxide (TMAO), in the pathogenesis of cardiovascular disease (CVD) has attracted significant attention. The gut microbiome is critical in various physiological processes including metabolism, immune function, and inflammation. Elevated TMAO levels are associated with atherosclerosis, heart failure, arrhythmia, and atrial fibrillation. TMAO accelerates atherosclerosis by promoting vascular inflammation and reducing reverse cholesterol transport, which leads to lipid accumulation and vessel narrowing. Previous research has indicated that a Mediterranean diet rich in fiber and phytochemicals can reduce TMAO levels by limiting precursors and fostering beneficial gut microbiota. Prebiotics and probiotics also decrease TMAO, while drugs such as meldonium, aspirin, and antibiotics have shown promise. However, recent studies have demonstrated major potential for the use of statins in reducing TMAO levels. Statin therapy can significantly reduce TMAO levels independent of their cholesterol-lowering effects. This reduction may involve direct interactions with the gut microbiome, changes in cholesterol metabolism, and changes in bile acid composition. This review aims to comprehensively evaluate the therapeutic potential of statins in reducing TMAO levels to improve CV outcomes.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, with the gut microbiota and its metabolites are important regulators of its progression. Trimethylamine N-oxide (TMAO), a metabolite of the gut microbiota, has been closely associated with various metabolic diseases, but its relationship with NAFLD remains to be elucidated. In this study, we found that fecal TMAO levels correlated with NAFLD severity. Moreover, TMAO promoted lipid deposition in HepG2 fatty liver cells and exacerbated hepatic steatosis in NAFLD rats. In the colon, TMAO undermined the structure and function of the intestinal barrier at various levels, further activated the TLR4/MyD88/NF-κB pathway, and inhibited the WNT/β-catenin pathway. In the liver, TMAO induced endothelial dysfunction with capillarization of liver sinusoidal endothelial cells, while modulating macrophage polarization. In conclusion, our study suggests that gut microbiota metabolite TMAO promotes NAFLD progression by impairing the gut and liver and that targeting TMAO could be an alternative therapeutic strategy for NAFLD.

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.

Background/Objectives: Alterations in fecal microbial communities in patients with systemic sclerosis (SSc) are common, but the clinical significance of this observation is poorly understood. Gut microbial production of trimethylamine (TMA), and its conversion by the host to trimethylamine N-oxide (TMAO), has clinical and mechanistic links to cardiovascular and renal diseases. Direct provision of TMAO has been shown to promote fibrosis and vascular injury, hallmarks of SSc. We sought to determine levels of TMAO and related metabolites in SSc patients and investigate associations between the metabolite levels with disease features. Methods: This is an observational case:control study. Adults with SSc (n = 200) and non-SSc controls (n = 400) were matched for age, sex, indices of renal function, diabetes mellitus, and cardiovascular disease. Serum TMAO, choline, betaine, carnitine, γ-butyrobetaine, and crotonobetaine were measured using stable isotope dilution liquid chromatography tandem mass spectrometry. Results: Median TMAO concentration was higher (p = 0.020) in SSc patients (3.31 [interquartile range 2.18, 5.23] µM) relative to controls (2.85 [IQR 1.88, 4.54] µM). TMAO was highest among obese and male SSc participants compared to all other groups. Following adjustment for sex, BMI, age, race, and eGFR in a quantile regression model, elevated TMAO levels remained associated with SSc at each quantile of TMAO. Conclusions: Patients with SSc have increased circulating levels of TMAO independent of comorbidities including age, sex, renal function, diabetes mellitus, and cardiovascular disease. As a potentially modifiable factor, further studies examining the link between TMAO and SSc disease severity and course are warranted.

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.

To evaluate the association between trimethylamine N-oxide (TMAO) and related metabolites with adverse cardiovascular events in a multiethnic urban primary prevention population.

We performed a case-control study of 361 participants of the Dallas Heart Study, including 88 participants with an incident atherosclerotic cardiovascular disease (ASCVD) event and 273 controls matched for age, sex, and body mass index without an ASCVD event during 12 years of follow-up (January 1, 2000, through December 31, 2015). Plasma levels of TMAO, choline, carnitine, betaine, and butyrobetaine were measured by mass spectrometry. The differential odds for incident ASCVD by metabolite levels between cases and controls were compared by a conditional logistic regression model adjusted for cardiovascular risk factors.

Participants with incident ASCVD had higher levels of TMAO and related metabolites compared with those without ASCVD (P<.05 for all). Those with plasma TMAO concentrations in quartile 4 had a more than 2-fold higher odds of ASCVD compared with those in quartile 1 (odds ratio, 2.77 [95% CI, 1.05 to 7.7; P=.04] for hard ASCVD and 2.41 [95% CI, 1.049 to 5.709; P=.04]). Similar trends were seen with the related metabolites choline, betaine, carnitine, and butyrobetaine.

Our results suggest that TMAO and related metabolites are independently associated with ASCVD events. Although further studies are needed, measurement of TMAO and related metabolites may have a role in ASCVD risk stratification for primary prevention.

Significance: Aging is a complex process associated with an increased risk of many diseases, including thrombosis. This review summarizes age-related prothrombotic mechanisms in clinical settings of thromboembolism, focusing on the role of fibrin structure and function modified by oxidative stress. Recent Advances: Aging affects blood coagulation and fibrinolysis via multiple mechanisms, including enhanced oxidative stress, with an imbalance in the oxidant/antioxidant mechanisms, leading to loss of function and accumulation of oxidized proteins, including fibrinogen. Age-related prothrombotic alterations are multifactorial involving enhanced platelet activation, endothelial dysfunction, and changes in coagulation factors and inhibitors. Formation of more compact fibrin clot networks displaying impaired susceptibility to fibrinolysis represents a novel mechanism, which might contribute to atherothrombosis and venous thrombosis. Alterations to fibrin clot structure/function are at least in part modulated by post-translational modifications of fibrinogen and other proteins involved in thrombus formation, with a major impact of carbonylation. Fibrin clot properties are also involved in the efficacy and safety of therapy with oral anticoagulants, statins, and/or aspirin. Critical Issues: Since a prothrombotic state is observed in very elderly individuals free of diseases associated with thromboembolism, the actual role of activated blood coagulation in health remains elusive. It is unclear to what extent oxidative modifications of coagulation and fibrinolytic proteins, in particular fibrinogen, contribute to a prothrombotic state in healthy aging. Future Directions: Ongoing studies will show whether novel therapies that may alter oxidative stress and fibrin characteristics are beneficial to prevent atherosclerosis and thromboembolic events associated with aging.

Monosodium glutamate (MSG) is used as a common food additive in some foods. However, based on our search and knowledge, no comprehensive study discussed the effect of MSG on the human gut microbiome. In this study, the effects of MSG on the gut microbiome, liver, and kidney were performed. Data were collected from databases including PubMed, Scopus, Web of Science, and ScienceDirect using the search strategy and keywords. Finally, 14 eligible studies were selected for systematic review. This study provides a new perspective on the effects of MSG on the gut flora, shedding light on the potential relationship between MSG intake and human health.

Obesity causes metabolic changes, such as the development of cardiovascular diseases. Moreover, physical exercise promotes protection against these diseases. Thus, the objective of the present study was to evaluate whether combined physical training can improve the metabolic system of women with obesity, reducing plasma concentrations of trimethylamine N-oxide (TMAO) and sphingolipids, regardless of weight loss. Fourteen obese women (BMI 30-40 kg/m2), aged 20-40 years, sedentary, were submitted to 8 weeks of combined physical training (strength and aerobic exercises). The training was performed three times/week, 55 min/session, at 75-90% maximum heart rate. All participants were evaluated pre- and post-exercise intervention, and their body composition, plasma TMAO, creatinine, lipid profile, and sphingolipid concentrations were recorded. Maximum oxygen consumption (VO2max), Speed lactate threshold 1 (SpeedLT1), and Speed lactate threshold 2 (SpeedLT2) evaluated physical performance. Results: After combined exercise, it did not change body composition, but TMAO, total cholesterol, and sphingolipid concentrations significantly decreased (p < 0.05). There was an increase in physical performance by improving VO2max, SpeedLT1, and SpeedLT2 (p < 0.05). The combined physical exercise could induce cardiovascular risk protection by decreasing TMAO in obese women, parallel to physical performance improvement, independent of weight loss.

Trimethylamine-N-oxide (TMAO) is linked with obesity, while limited evidence on its relationship with body fat distribution. Herein, we investigated the associations between serum TMAO and longitudinal change of fat distribution in this prospective cohort study.

Data of 1964 participants (40-75y old) from Guangzhou Nutrition and Health Study (GNHS) during 2008-2014 was analyzed. Serum TMAO concentration was quantified by HPLC-MS/MS at baseline. The body composition was assessed by dual-energy X-ray absorptiometry at each 3-y follow-up. Fat distribution parameters were fat-to-lean mass ratio (FLR) and trunk-to-leg fat ratio (TLR). Fat distribution changes were derived from the coefficient of linear regression between their parameters and follow-up duration.

After an average of 6.2-y follow-up, analysis of covariance (ANCOVA) and linear regression displayed women with higher serum TMAO level had greater increments in trunk FLR (mean ± SD: 1.47 ± 4.39, P-trend = 0.006) and TLR (mean ± SD: 0.06 ± 0.24, P-trend = 0.011). Meanwhile, for women in the highest TMAO tertile, linear mixed-effects model (LMEM) analysis demonstrated the annual estimated increments (95% CI) were 0.03 (95% CI: 0.003 - 0.06, P = 0.032) in trunk FLR and 1.28 (95% CI: -0.17 - 2.73, P = 0.083) in TLR, respectively. In men, there were no similar significant observations. Sensitivity analysis yielded consistent results.

Serum TMAO displayed a more profound correlation with increment of FLR and TLR in middle-aged and older community-dwelling women in current study. More and further studies are still warranted in the future.

NCT03179657.

People are living longer and rates of age-related diseases such as age-related macular degeneration (AMD) are accelerating, placing enormous burdens on patients and health care systems. The quality of carbohydrate foods consumed by an individual impacts health. The glycemic index (GI) is a kinetic measure of the rate at which glucose arrives in the blood stream after consuming various carbohydrates. Consuming diets that favor slowly digested carbohydrates releases sugar into the bloodstream gradually after consuming a meal (low glycemic index). This is associated with reduced risk for major age-related diseases including AMD, cardiovascular disease, and diabetes. In comparison, consuming the same amounts of different carbohydrates in higher GI diets, releases glucose into the blood rapidly, causing glycative stress as well as accumulation of advanced glycation end products (AGEs). Such AGEs are cytotoxic by virtue of their forming abnormal proteins and protein aggregates, as well as inhibiting proteolytic and other protective pathways that might otherwise selectively recognize and remove toxic species. Using in vitro and animal models of glycative stress, we observed that consuming higher GI diets perturbs metabolism and the microbiome, resulting in a shift to more lipid-rich metabolomic profiles. Interactions between aging, diet, eye phenotypes and physiology were observed. A large body of laboratory animal and human clinical epidemiologic data indicates that consuming lower GI diets, or lower glycemia diets, is protective against features of early AMD (AMDf) in mice and AMD prevalence or AMD progression in humans. Drugs may be optimized to diminish the ravages of higher glycemic diets. Human trials are indicated to determine if AMD progression can be retarded using lower GI diets. Here we summarized the current knowledge regarding the pathological role of glycative stress in retinal dysfunction and how dietary strategies might diminish retinal disease.

Trimethyl-N-oxide (TMAO) has been linked to peripheral artery disease (PAD). TaurisoloⓇ is a natural, balanced phytocomplex containing resveratrol, quercetin, catechins, procianidins, gallic acid, and caffeic acid. Numerous studies have shown that TaurisoloⓇ reduces the damage of TMAO and exerts a protective effect on endothelial cells (ECs). The aim of this randomized, double-blind, single-center study was to evaluate the effects of TaurisoloⓇ on claudication in patients with PAD (Rutheford grade I, category II, Fontaine Classification: Stage IIA, American Medical Association Whole Person Impairment Classification: Class 0-WPI 0%) in two parallel groups of 31 patients. The primary outcomes were an increase in the pain-free walking distance and the ankle/brachial pressure index at the beginning and at the end of the treatment with Taurisolo. The secondary endpoint was the serum TMAO changes. The claudication distance improved by 14.1% in the Taurisolo group and by 2.0% in the placebo group, while the maximal distance increased by 15.8% and 0.6% only, respectively (both p < 0.05). The TMAO plasma levels decreased from 3.97 ± 2.13 micromole/L to 0.87 ± 0.48 (p < 0.0001) in the treated group. All these changes were highly significant both in univariate mixed models as well as in the adjusted model. Ultimately, TaurisoloⓇ might be an effective intervention to ameliorate intermittent claudication.

The human system's secret organ, the gut microbiome, has received considerable attention. Emerging research has yielded substantial scientific evidence indicating that changes in gut microbial composition and microbial metabolites may contribute to the development of atherosclerotic cardiovascular disease. The burden of cardiovascular disease on healthcare systems is exacerbated by atherosclerotic cardiovascular disease, which continues to be the leading cause of mortality globally. Reverse cholesterol transport is a powerful protective mechanism that effectively prevents excessive accumulation of cholesterol for atherosclerotic cardiovascular disease. It has been revealed how the gut microbiota modulates reverse cholesterol transport in patients with atherosclerotic risk. In this review, we highlight the complex interactions between microbes, their metabolites, and their potential impacts in reverse cholesterol transport. We also explore the feasibility of modulating gut microbes and metabolites to facilitate reverse cholesterol transport as a novel therapy for atherosclerosis.

Trimethylamine N-oxide (TMAO) is synthesized by the intestinal microbiota and is an independent predictor of cardiovascular disease (CVD). However, its underlying mechanisms remain unclear. We investigated TMAO levels across different CVD-risk patient groups, and evaluated associations between TMAO and vascular alterations (e.g., arterial stiffness, intima-media thickness [IMT], and the presence and grade of carotid artery plaques [CAPs]).

We examined 95 patients (58.5 ± 7.3 years): 40 with clinical atherosclerotic cardiovascular disease (ASCVD), 40 with atherosclerosis risk factors (RF), and 15 controls. Arterial stiffness was measured by Carotid-Femoral Pulse Wave Velocity (C-F PWV). B-mode ultrasound was used to evaluate the presence and grade of CAPs and carotid IMT (CIMT). TMAO was measured by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) and results were presented as the median (interquartile range).

TMAO levels were higher in patients with ASCVD (251.5 [164.5] µg/l) when compared with patients with RFs (194.0 [174] µg/l, P=0.04) and controls (122.0 (77) µg/l, P<0.001). A significant correlation was observed between TMAO and PWV (r = 0.31, P=0.003), which was not confirmed after adjustment for RFs. TMAO levels were significantly correlated with plaque score (r = 0.46, P<0.001) and plaque height (r=0.41, P=0.003), and were independent predictors for grade III plaques (odds ratio [OR] = 1.002, confidence interval (CI) 95%: 1.000047-1.003, P=0.044).

TMAO levels are increased with expanded CVD risk. Across different types of vascular damage, TMAO is associated with atherosclerotic changes.

Chronic diseases (CD) may result from a combination of genetic factors, lifestyle and social behaviours, healthcare system influences, community factors, and environmental determinants of health. These risk factors frequently coexist and interact with one another. Ongoing research and a focus on personalized interventions are pivotal strategies for preventing and managing chronic disease outcomes. A wealth of literature suggests the potential involvement of gut microbiota in influencing host metabolism, thereby impacting various risk factors associated with chronic diseases. Dysbiosis, the perturbation of the composition and activity of the gut microbiota, is crucial in the etiopathogenesis of multiple CD. Recent studies indicate that specific microorganism-derived metabolites, including trimethylamine N-oxide, lipopolysaccharide and uremic toxins, contribute to subclinical inflammatory processes implicated in CD. Various factors, including diet, lifestyle, and medications, can alter the taxonomic species or abundance of gut microbiota. Researchers are currently dedicating efforts to understanding how the natural progression of microbiome development in humans affects health outcomes. Simultaneously, there is a focus on enhancing the understanding of microbiome-host molecular interactions. These endeavours ultimately aim to devise practical approaches for rehabilitating dysregulated human microbial ecosystems, intending to restore health and prevent diseases. This review investigates how the gut microbiome contributes to CD and explains ways to modulate it for managing or preventing chronic conditions.

An elevated triglyceride-glucose (TyG) level is associated with increased risk of mortality in patients with CAD. Trimethylamine N-oxide (TMAO) has mechanistic links to atherosclerotic coronary artery disease (CAD) pathogenesis and is correlated with adverse outcomes. However, the incremental prognostic value of TMAO and TyG in the cohort of optical coherence tomography (OCT)-defined high-risk ST-segment elevation myocardial infarction (STEMI) patients is unknown.

We studied 274 consecutive aged ≥18 years patients with evidence of STEMI and detected on pre-intervention OCT imaging of culprit lesions between March 2017 and March 2019.

There were 22 (22.68%), 27 (27.84%), 26 (26.80%), and 22 (22.68%) patients in groups A-D, respectively. The baseline characteristics according to the level of TMAO and TyG showed that patients with higher level in both indicators were more likely to have higher triglycerides (p < 0.001), fasting glucose (p < 0.001) and higher incidence of diabetes (p = 0.008). The group with TMAO > median and TyG ≤ median was associated with higher rates of MACEs significantly (p = 0.009) in fully adjusted analyses. During a median follow-up of 2.027 years, 20 (20.6%) patients experienced MACEs. To evaluate the diagnostic value of the TyG index combined with TMAO, the area under the receiver operating characteristic curve for predicting MACEs after full adjustment was 0.815 (95% confidence interval, 0.723-0.887; sensitivity, 85.00%; specificity, 72.73%; cut-off level, 0.577). Among the group of patients with TMAO > median and TyG ≤ median, there was a significantly higher incidence of MACEs (p=0.033). A similar tendency was found in the cohort with hyperlipidemia (p=0.016) and diabetes mellitus (p=0.036).

This study demonstrated the usefulness of combined measures of the TyG index and TMAO in enhancing risk stratification in STEMI patients with OCT-defined high-risk plaque characteristics.

This study was registered at ClinicalTrials.gov as NCT03593928.

Ischemic stroke (IS) is a severe cerebrovascular disease that seriously endangers human health. Gut microbiota plays a key role as an intermediate mediator in bidirectional regulation between the brain and the intestine. In recent years, trimethylamine N-oxide (TMAO) as a gut microbiota metabolite has received widespread attention in cardiovascular diseases. Elevated levels of TMAO may increase the risk of IS by affecting IS risk factors such as atherosclerosis, atrial fibrillation, hypertension, and type 2 diabetes. TMAO exacerbates neurological damage in IS patients, increases the risk of IS recurrence, and is an independent predictor of post-stroke cognitive impairment (PSCI) in patients. Current research suggests that the mechanisms of TMAO action include endothelial dysfunction, promoting of foam cell formation, influence on cholesterol metabolism, and enhancement of platelet reactivity. Lowering plasma TMAO levels through the rational use of traditional Chinese medicine, dietary management, vitamins, and probiotics can prevent and treat IS.

Hereditary hemochromatosis with the homozygous C282Y HFE mutation (HH-282H) is a genetic condition which causes iron overload (IO) and elevated reactive oxygen species (ROS) secondary to the IO. Interestingly, even after successful iron removal therapy, HH-282H subjects demonstrate chronically elevated ROS. Raised ROS are also associated with the development of multiple cardiovascular diseases and HH-282H subjects may be at risk to develop these complications. In this narrative review, we consider HH-282H subjects as a clinical model for assessing the contribution of elevated ROS to the development of cardiovascular diseases in subjects with fewer confounding clinical risk factors as compared to other disease conditions with high ROS. We identify HH-282H subjects as a potentially unique clinical model to assess the impact of chronically elevated ROS on the development of cardiovascular disease and to serve as a clinical model to detect effective interventions for anti-ROS therapy.

Recently, trimethylamine N-oxide (TMAO) has been considered a risk factor for cardiovascular disease and has a proatherogenic effect. Many studies have found that TMAO is involved in plaque oxidative stress and lipid metabolism, but the specific mechanism is still unclear. In our study, meta-analysis and bioinformatic analysis were firstly conducted in the database, and found that the effect of high plasma TMAO levels on promoting atherosclerotic plaque may be related to the expression of key antioxidant genes nuclear factor erytheroid-derived-2-like 2 (NFE2L2/Nrf2) decreased. Next, we assessed the role of Nrf2-mediated signaling pathway in TMAO-treated foam cells. Our results showed that TMAO can inhibit the expression of Nrf2 and its downstream antioxidant response element such as heme oxygenase-1 (HO-1) and glutathione peroxidase4 (GPX4), resulting in increased production of reactive oxygen species and decreased activity of superoxide dismutase, promoting oxidative stress. And TMAO can also promote lipid accumulation in foam cells by inhibiting cholesterol efflux protein expression. In addition, upregulation of Nrf2 expression partially rescues TMAO-induced oxidative stress and reduces ATP-binding cassette A1 (ABCA1)-mediated lipid accumulation. Therefore, TMAO promotes oxidative stress and lipid accumulation in macrophage foam cells through the Nrf2/ABCA1 pathway, which may provide a potential mechanism for the proatherogenic effect of TMAO.

The gut microbiome is a heterogeneous population of microbes comprising viruses, bacteria, fungi, and protozoa. Such a microbiome is essential for sustaining host equilibrium, and its impact on human health can be altered by a variety of factors such as external variables, social behavior, age, nutrition, and genetics. Gut microbes' imbalances are related to a variety of chronic diseases including cancer, obesity, and digestive disorders. Globally, recent findings show that intestinal microbes have a significant role in the formation of cardiovascular disease (CVD), which is still the primary cause of fatalities. Atherosclerosis, hypertension, diabetes, inflammation, and some inherited variables are all cardiovascular risk variables. However, studies found correlations between metabolism, intestinal flora, and dietary intake. Variations in the diversity of gut microbes and changes in their activity are thought to influence CVD etiology. Furthermore, the gut microbiota acts as an endocrine organ, producing bioactive metabolites such as TMA (trimethylamine)/TMAO (trimethylamine N-oxide), SCFA (short-chain fatty acids), and bile acids, which have a substantial impact on host wellness and disease by multiple mechanisms. The purpose of this overview is to compile current evidence highlighting the intricate links between gut microbiota, metabolites, and the development of CVD. It focuses on how intestinal dysbiosis promotes CVD risk factors such as heart failure, hypertension, and atherosclerosis. This review explores the normal physiology of intestinal microbes and potential techniques for targeting gut bacteria for CVD treatment using various microbial metabolites. It also examines the significance of gut bacteria in disease treatment, including supplements, prebiotics, probiotics, antibiotic therapies, and fecal transplantation, which is an innovative approach to the management of CVD. As a result, gut bacteria and metabolic pathways become increasingly attractive as potential targets for CVD intervention.

Gestational diabetes mellitus (GDM) is a complex metabolic condition during pregnancy with an intricate link to gut microbiota alterations. Throughout gestation, notable shifts in the gut microbial component occur. GDM is marked by significant dysbiosis, with a decline in beneficial taxa like Bifidobacterium and Lactobacillus and a surge in opportunistic taxa such as Enterococcus. These changes, detectable in the first trimester, hint as the potential early markers for GDM risk. Alongside these taxa shifts, microbial metabolic outputs, especially short-chain fatty acids and bile acids, are perturbed in GDM. These metabolites play pivotal roles in host glucose regulation, insulin responsiveness, and inflammation modulation, which are the key pathways disrupted in GDM. Moreover, maternal GDM status influences neonatal gut microbiota, indicating potential intergenerational health implications. With the advance of multi-omics approaches, a deeper understanding of the nuanced microbiota-host interactions via metabolites in GDM is emerging. The reviewed knowledge offers avenues for targeted microbiota-based interventions, holding promise for innovative strategies in GDM diagnosis, management, and prevention.

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.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The gut microbiota and its associated metabolites may be involved in the development and progression of CVD, although the mechanisms and impact on clinical outcomes are not fully understood. This study investigated the gut microbiome profile and associated metabolites in patients with chronic stable angina (CSA) and acute coronary syndrome (ACS) compared with healthy controls. Bacterial alpha diversity in stool from patients with ACS or CSA was comparable to healthy controls at both baseline and follow-up visits. Differential abundance analysis identified operational taxonomic units (OTUs) assigned to commensal taxa differentiating patients with ACS from healthy controls at both baseline and follow-up. Patients with CSA and ACS had significantly higher levels of trimethylamine N-oxide compared with healthy controls (CSA: 0.032 ± 0.023 mmol/L, P < 0.01 vs. healthy, and ACS: 0.032 ± 0.023 mmol/L, P = 0.02 vs. healthy, respectively). Patients with ACS had reduced levels of propionate and butyrate (119 ± 4 vs. 139 ± 5.1 µM, P = 0.001, and 14 ± 4.3 vs. 23.5 ± 8.1 µM, P < 0.001, respectively), as well as elevated serum sCD14 (2245 ± 75.1 vs. 1834 ± 45.8 ng/mL, P < 0.0001) and sCD163 levels (457.3 ± 31.8 vs. 326.8 ± 20.7 ng/mL, P = 0.001), compared with healthy controls at baseline. Furthermore, a modified small molecule metabolomic and lipidomic signature was observed in patients with CSA and ACS compared with healthy controls. These findings provide evidence of a link between gut microbiome composition and gut bacterial metabolites with CVD. Future time course studies in patients to observe temporal changes and subsequent associations with gut microbiome composition are required to provide insight into how these are affected by transient changes following an acute coronary event.NEW & NOTEWORTHY The study found discriminative microorganisms differentiating patients with acute coronary syndrome (ACS) from healthy controls. In addition, reduced levels of certain bacterial metabolites and elevated sCD14 and sCD163 were observed in patients with ACS compared with healthy controls. Furthermore, modified small molecule metabolomic and lipidomic signatures were found in both patient groups. Although it is not known whether these differences in profiles are associated with disease development and/or progression, the findings provide exciting options for potential new disease-related mechanism(s) and associated therapeutic target(s).

Endothelial dysfunction is a critical initiating factor contributing to cardiovascular diseases, involving the gut microbiome-derived metabolite trimethylamine N-oxide (TMAO). This study aims to clarify the time-dependent molecular pathways by which TMAO mediates endothelial dysfunction through transcriptomics and metabolomics analyses in human microvascular endothelial cells (HMEC-1). Cell viability and reactive oxygen species (ROS) generation were also evaluated. TMAO treatment for either 24H or 48H induces reduced cell viability and enhanced oxidative stress. Interestingly, the molecular signatures were distinct between the two time-points. Specifically, few Gene Ontology biological processes (BPs) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were modulated after a short (24H) compared to a long (48H) treatment. However, the KEGG signalling pathways namely "tumour necrosis factor (TNF)" and "cytokine-cytokine receptor interaction" were downregulated at 24H but activated at 48H. In addition, at 48H, BPs linked to inflammatory phenotypes were activated (confirming KEGG results), while BPs linked to extracellular matrix (ECM) structural organisation, endothelial cell proliferation, and collagen metabolism were repressed. Lastly, metabolic profiling showed that arachidonic acid, prostaglandins, and palmitic acid were enriched at 48H. This study demonstrates that TMAO induces distinct time-dependent molecular signatures involving inflammation and remodelling pathways, while pathways such as oxidative stress are also modulated, but in a non-time-dependent manner.

Atherosclerosis (AS) is a metabolic disorder and the pre-stage of several cardiovascular diseases, including myocardial infarction, stroke, and angina pectoris. Early detection of AS can provide the opportunity for effective management and better clinical results, along with the prevention of further progression of the disease. In the current study, an untargeted and targeted metabolomic approach was used to identify possible metabolic signatures that have altered levels in AS patients. A total of 200 serum samples from individuals with AS and normal were analyzed via liquid chromatography-high-resolution mass spectrometry. Univariate and multivariate analysis approaches were used to identify differential metabolites. A group of metabolites associated with bile acids, amino acids, steroid hormones, and purine metabolism were identified that are capable of distinguishing AS-risk sera from normal. Further, the targeted metabolomics approach confirmed that six metabolites, namely taurocholic acid, cholic acid, cortisol, hypoxanthine, trimethylamine N-oxide (TMAO), and isoleucine, were found to be significantly upregulated, while the concentrations of glycoursodeoxycholic acid, glycocholic acid, testosterone, leucine, methionine, phenylalanine, tyrosine, and valine were found to be significantly downregulated in the AS-risk sera. The receiver operating characteristic curves of three metabolites, including cortisol, hypoxanthine, and isoleucine, showed high sensitivity and specificity. Taken together, these findings suggest cortisol, hypoxanthine, and isoleucine as novel biomarkers for the early and non-invasive detection of AS. Thus, this study provides new insights for further investigations into the prevention and management of AS.

The microbiota represents a key factor in determining health and disease. Its role in inflammation and immunological disorders is well known, but it is also involved in several complex conditions, ranging from neurological to psychiatric, from gastrointestinal to cardiovascular diseases. It has recently been hypothesized that the gut microbiota may act as an intermediary in the close interaction between kidneys and the cardiovascular system, leading to the conceptualization of the "gut-kidney-heart" axis. In this narrative review, we will discuss the impact of the gut microbiota on each system while also reviewing the available data regarding the axis itself. We will also describe the role of gut metabolites in this complex interplay, as well as potential therapeutical perspectives.

Childhood obesity leads to early subclinical atherosclerosis and arterial stiffness. Studying biomarkers like trimethylamine N-oxide (TMAO), linked to cardio-metabolic disorders in adults, is crucial to prevent long-term cardiovascular issues.

The study involved 70 children aged 4 to 18 (50 obese, 20 normal-weight). Clinical examination included BMI, waist measurements, puberty stage, the presence of acanthosis nigricans, and irregular menstrual cycles. Subclinical atherosclerosis was assessed by measuring the carotid intima-media thickness (CIMT), and the arterial stiffness was evaluated through surrogate markers like the pulse wave velocity (PWV), augmentation index (AIx), and peripheral and central blood pressures. The blood biomarkers included determining the values of TMAO, HOMA-IR, and other usual biomarkers investigating metabolism.

The study detected significantly elevated levels of TMAO in obese children compared to controls. TMAO presented positive correlations to BMI, waist circumference and waist-to-height ratio and was also observed as an independent predictor of all three parameters. Significant correlations were observed between TMAO and vascular markers such as CIMT, PWV, and peripheral BP levels. TMAO independently predicts CIMT, PWV, peripheral BP, and central SBP levels, even after adding BMI, waist circumference, waist-to-height ratio, puberty development and age in the regression model. Obese children with high HOMA-IR presented a greater weight excess and significantly higher vascular markers, but TMAO levels did not differ significantly from the obese with HOMA-IR

Conclusion

Our study provides compelling evidence supporting the link between serum TMAO, obesity, and vascular damage in children. These findings highlight the importance of further research to unravel the underlying mechanisms of this connection.

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