ABSTRACT
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is associated with systemic inflammation, obesity, metabolic syndrome, and gut microbiome changes. Increased trimethylamine-N-oxide (TMAO) levels are predictive for mortality in HFpEF. The TMAO precursor trimethylamine (TMA) is synthesized by the intestinal microbiome, crosses the intestinal barrier and is metabolized to TMAO by hepatic flavin-containing monooxygenases (FMO). The intricate interactions of microbiome alterations and TMAO in relation to HFpEF manifestation and progression are analyzed here. METHODS: Healthy lean (L-ZSF1, n = 12) and obese ZSF1 rats with HFpEF (O-ZSF1, n = 12) were studied. HFpEF was confirmed by transthoracic echocardiography, invasive hemodynamic measurements, and detection of N-terminal pro-brain natriuretic peptide (NT-proBNP). TMAO, carnitine, symmetric dimethylarginine (SDMA), and amino acids were measured using mass-spectrometry. The intestinal epithelial barrier was analyzed by immunohistochemistry, in-vitro impedance measurements and determination of plasma lipopolysaccharide via ELISA. Hepatic FMO3 quantity was determined by Western blot. The fecal microbiome at the age of 8, 13 and 20 weeks was assessed using 16s rRNA amplicon sequencing. RESULTS: Increased levels of TMAO (+ 54%), carnitine (+ 46%) and the cardiac stress marker NT-proBNP (+ 25%) as well as a pronounced amino acid imbalance were observed in obese rats with HFpEF. SDMA levels in O-ZSF1 were comparable to L-ZSF1, indicating stable kidney function. Anatomy and zonula occludens protein density in the intestinal epithelium remained unchanged, but both impedance measurements and increased levels of LPS indicated an impaired epithelial barrier function. FMO3 was decreased (- 20%) in the enlarged, but histologically normal livers of O-ZSF1. Alpha diversity, as indicated by the Shannon diversity index, was comparable at 8 weeks of age, but decreased by 13 weeks of age, when HFpEF manifests in O-ZSF1. Bray-Curtis dissimilarity (Beta-Diversity) was shown to be effective in differentiating L-ZSF1 from O-ZSF1 at 20 weeks of age. Members of the microbial families Lactobacillaceae, Ruminococcaceae, Erysipelotrichaceae and Lachnospiraceae were significantly differentially abundant in O-ZSF1 and L-ZSF1 rats. CONCLUSIONS: In the ZSF1 HFpEF rat model, increased dietary intake is associated with alterations in gut microbiome composition and bacterial metabolites, an impaired intestinal barrier, and changes in pro-inflammatory and health-predictive metabolic profiles. HFpEF as well as its most common comorbidities obesity and metabolic syndrome and the alterations described here evolve in parallel and are likely to be interrelated and mutually reinforcing. Dietary adaption may have a positive impact on all entities.
Subject(s)
Disease Models, Animal , Disease Progression , Gastrointestinal Microbiome , Heart Failure , Methylamines , Stroke Volume , Ventricular Function, Left , Animals , Heart Failure/physiopathology , Heart Failure/microbiology , Heart Failure/metabolism , Methylamines/metabolism , Methylamines/blood , Male , Obesity/microbiology , Obesity/physiopathology , Obesity/metabolism , Oxygenases/metabolism , Oxygenases/genetics , Liver/metabolism , Biomarkers/blood , Feces/microbiology , Rats , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Bacteria/metabolism , DysbiosisABSTRACT
Heart failure (HF) is a clinical syndrome characterizing by typical physical signs and symptomatology resulting from reduced cardiac output and/or intracardiac pressure at rest or under stress due to structural and/or functional abnormalities of the heart. HF is often the final stage of all cardiovascular diseases and a significant risk factor for sudden cardiac arrest, death, and liver or kidney failure. Current pharmacological treatments can only slow the progression and recurrence of HF. With advancing research into the gut microbiome and its metabolites, one such trimethylamine N-oxide (TMAO)-has been implicated in the advancement of HF and is correlated with poor prognosis in patients with HF. However, the precise role of TMAO in HF has not yet been clarified. This review highlights and concludes the available evidence and potential mechanisms associated with HF, with the hope of contributing new insights into the diagnosis and prevention of HF.
ABSTRACT
Pacific spiny dogfish, Squalus suckleyi, move to shallow coastal waters during critical reproductive life stages and are thus at risk of encountering hypoxic events which occur more frequently in these areas. For effective conservation management, we need to fully understand the consequences of hypoxia on marine key species such as elasmobranchs. Because of their benthic life style, we hypothesized that S. suckleyi are hypoxia tolerant and able to efficiently regulate oxygen consumption, and that anaerobic metabolism is supported by a broad range of metabolites including ketones, fatty acids and amino acids. Therefore, we studied oxygen consumption rates, ventilation frequency and amplitude, blood gasses, acid-base regulation, and changes in plasma and tissue metabolites during progressive hypoxia. Our results show that critical oxygen levels (P crit) where oxyregulation is lost were indeed low (18.1% air saturation or 28.5 Torr at 13°C). However, many dogfish behaved as oxyconformers rather than oxyregulators. Arterial blood PO2 levels mostly decreased linearly with decreasing environmental PO2. Blood gases and acid-base status were dependent on open versus closed respirometry but in both set-ups ventilation frequency increased. Hypoxia below Pcrit resulted in an up-regulation of anaerobic glycolysis, as evidenced by increased lactate levels in all tissues except brain. Elasmobranchs typically rely on ketone bodies as oxidative substrates, and decreased concentrations of acetoacetate and ß-hydroxybutyrate were observed in white muscle of hypoxic and/or recovering fish. Furthermore, reductions in isoleucine, glutamate, glutamine and other amino acids were observed. After 6 hours of normoxic recovery, changes persisted and only lactate returned to normal in most tissues. This emphasizes the importance of using suitable bioindicators adjusted to preferred metabolic pathways of the target species in conservation physiology. We conclude that Pacific spiny dogfish can tolerate severe transient hypoxic events, but recovery is slow and negative impacts can be expected when hypoxia persists.
ABSTRACT
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a growing health concern due to its increasing prevalence worldwide. Metabolic homeostasis encompasses the stable internal conditions vital for efficient metabolism. This equilibrium extends to the intestinal microbiota, whose metabolic activities profoundly influence overall metabolic balance and organ health. The metabolites derived from the gut microbiota metabolism can be defined as microbiota-related co-metabolites. They serve as mediators between the gut microbiota and the host, influencing various physiological processes. The recent redefinition of the term MASLD has highlighted the metabolic dysfunction that characterize the disease. Metabolic dysfunction encompasses a spectrum of abnormalities, including impaired glucose regulation, dyslipidemia, mitochondrial dysfunction, inflammation, and accumulation of toxic byproducts. In addition, MASLD progression has been linked to dysregulation in the gut microbiota and associated co-metabolites. Short-chain fatty acids (SCFAs), hippurate, indole derivatives, branched-chain amino acids (BCAAs), and bile acids (BAs) are among the key co-metabolites implicated in MASLD progression. In this review, we will unravel the relationship between the microbiota-related metabolites which have been associated with MASLD and that could play an important role for developing effective therapeutic interventions for MASLD and related metabolic disorders.
ABSTRACT
Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are severe age-related disorders with complex and multifactorial causes. Recent research suggests a critical link between neurodegeneration and the gut microbiome, via the gut-brain communication pathway. This review examines the role of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, in the development of AD and PD, and investigates its interaction with microRNAs (miRNAs) along this bidirectional pathway. TMAO, which is produced from dietary metabolites like choline and carnitine, has been linked to increased neuroinflammation, protein misfolding, and cognitive decline. In AD, elevated TMAO levels are associated with amyloid-beta and tau pathologies, blood-brain barrier disruption, and neuronal death. TMAO can cross the blood-brain barrier and promote the aggregation of amyloid and tau proteins. Similarly, TMAO affects alpha-synuclein conformation and aggregation, a hallmark of PD. TMAO also activates pro-inflammatory pathways such as NF-kB signaling, exacerbating neuroinflammation further. Moreover, TMAO modulates the expression of various miRNAs that are involved in neurodegenerative processes. Thus, the gut microbiome-miRNA-brain axis represents a newly discovered mechanistic link between gut dysbiosis and neurodegeneration. MiRNAs regulate the key pathways involved in neuroinflammation, oxidative stress, and neuronal death, contributing to disease progression. As a direct consequence, specific miRNA signatures may serve as potential biomarkers for the early detection and monitoring of AD and PD progression. This review aims to elucidate the complex interrelationships between the gut microbiota, trimethylamine-N-oxide (TMAO), microRNAs (miRNAs), and the central nervous system, and the implications of these connections in neurodegenerative diseases. In this context, an overview of the current neuroradiology techniques available for studying neuroinflammation and of the animal models used to investigate these intricate pathologies will also be provided. In summary, a bulk of evidence supports the concept that modulating the gut-brain communication pathway through dietary changes, the manipulation of the microbiome, and/or miRNA-based therapies may offer novel approaches for implementing the treatment of debilitating neurological disorders.
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BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. TRIAL REGISTRATION: NCT03179657.
Subject(s)
Body Fat Distribution , Methylamines , Humans , Methylamines/blood , Female , Middle Aged , Male , Prospective Studies , Aged , Body Fat Distribution/methods , Adult , Absorptiometry, Photon/methods , Body Composition , Cohort Studies , ChinaABSTRACT
Understanding how gut flora interacts with oxidative stress has been the subject of significant research in recent years. There is much evidence demonstrating the existence of the microbiome-oxidative stress interaction. However, the biochemical basis of this interaction is still unclear. In this narrative review, possible pathways of the gut microbiota and oxidative stress interaction are presented, among which genetic underpinnings play an important role. Trimethylamine-N-oxide, mitochondria, short-chain fatty acids, and melatonin also appear to play roles. Moreover, the relationship between oxidative stress and the gut microbiome in obesity, metabolic syndrome, chronic ethanol consumption, dietary supplements, and medications is considered. An investigation of the correlation between bacterial community features and OS parameter changes under normal and pathological conditions might provide information for the determination of new research methods. Furthermore, such research could contribute to establishing a foundation for determining the linkers in the microbiome-OS association.
ABSTRACT
Trimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome-wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO-to-precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish-TMAO, meat-carnitine, and plant-based food-betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.
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BACKGROUND: A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with type 2 diabetes mellitus (T2DM). Few previous prospective studies have addressed associations between the changes in TMAO and T2DM incidence. METHODS: Data were derived from a longitudinal cohort conducted from 2019 to 2021 in rural areas of Fuxin County, Liaoning Province, China, and 1515 diabetes-free participants aged above 35 years were included. The concentrations of serum TMAO and its precursors were measured at two time points, namely in 2019 and 2021. TMAO and TMAO changes (ΔTMAO) were separately tested in a logistic regression model. For further examination, the odds ratios (ORs) for T2DM were calculated according to a combination of TMAO levels and ΔTMAO levels. RESULTS: During a median follow-up of 1.85 years, 81 incident cases of T2DM (5.35%) were identified. Baseline TMAO levels exhibited a nonlinear relationship, first decreasing and then increasing, and only at the highest quartile was it associated with the risk of T2DM. The OR for T2DM in the highest quartile of serum TMAO was 3.35 (95%CI: 1.55-7.26, p = 0.002), compared with the lowest quartile. As for its precursors, only choline level was associated with T2DM risk and the OR for T2DM in the Q3 and Q4 of serum choline was 3.37 (95%CI: 1.41-8.05, p = 0.006) and 4.72 (95%CI: 1.47-15.13, p = 0.009), respectively. When considering both baseline TMAO levels and ΔTMAO over time, participants with sustained high TMAO levels demonstrated a significantly increased risk of T2DM, with a multivariable-adjusted OR of 8.68 (95%CI: 1.97, 38.34). CONCLUSION: Both initial serum TMAO levels and long-term serum TMAO changes were collectively and significantly associated with the occurrence of subsequent T2DM events. Interventions aimed at normalizing TMAO levels, such as adopting a healthy dietary pattern, may be particularly beneficial in T2DM prevention.
Subject(s)
Diabetes Mellitus, Type 2 , Gastrointestinal Microbiome , Methylamines , Humans , Diabetes Mellitus, Type 2/prevention & control , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Methylamines/blood , Female , Male , Middle Aged , Longitudinal Studies , China/epidemiology , Adult , Risk Factors , Diet , Prospective Studies , Incidence , Aged , Choline/bloodABSTRACT
Trimethylamine N-oxide (TMAO), a characteristic nonprotein nitrogen compound, is widely present in seafood, which exhibits osmoregulatory effects for marine organisms in vivo and plays an important role in aquaculture and aquatic product preservation. However, much attention has been focused on the negative effect of TMAO since it has recently emerged as a putative promoter of chronic diseases. To get full knowledge and maximize our ability to balance the positive and negative aspects of TMAO, in this review, we comprehensively discuss the TMAO in aquatic products from the aspects of physiological functions for marine organisms, flavor, quality, the conversion of precursors, the influences on human health, and the seafood ingredients interaction consideration. Though the circulating TMAO level is inevitably enhanced after seafood consumption, dietary seafood still exhibits beneficial health effects and may provide nutraceuticals to balance the possible adverse effects of TMAO.
Subject(s)
Methylamines , Seafood , Methylamines/analysis , Methylamines/metabolism , Humans , Animals , Seafood/analysis , Aquatic Organisms/chemistry , FishesABSTRACT
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.
ABSTRACT
Trimethyl-N-oxide (TMAO) has been linked to peripheral artery disease (PAD). Taurisoloâ is a natural, balanced phytocomplex containing resveratrol, quercetin, catechins, procianidins, gallic acid, and caffeic acid. Numerous studies have shown that Taurisoloâ 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 Taurisoloâ 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, Taurisoloâ might be an effective intervention to ameliorate intermittent claudication.
ABSTRACT
The gut-immune axis is a relatively novel phenomenon that provides mechanistic links between the gut microbiome and the immune system. A growing body of evidence supports it is key in how the gut microbiome contributes to several diseases, including hypertension and cardiovascular diseases (CVDs). Evidence over the past decade supports a causal link of the gut microbiome in hypertension and its complications, including myocardial infarction, atherosclerosis, heart failure, and stroke. Perturbations in gut homeostasis such as dysbiosis (i.e., alterations in gut microbial composition) may trigger immune responses that lead to chronic low-grade inflammation and, ultimately, the development and progression of these conditions. This is unsurprising, as the gut harbors one of the largest numbers of immune cells in the body, yet is a phenomenon not entirely understood in the context of cardiometabolic disorders. In this review, we discuss the role of the gut microbiome, the immune system, and inflammation in the context of hypertension and CVD, and consolidate current evidence of this complex interplay, whilst highlighting gaps in the literature. We focus on diet as one of the major modulators of the gut microbiota, and explain key microbial-derived metabolites (e.g., short-chain fatty acids, trimethylamine N-oxide) as potential mediators of the communication between the gut and peripheral organs such as the heart, arteries, kidneys, and the brain via the immune system. Finally, we explore the dual role of both the gut microbiome and the immune system, and how they work together to not only contribute, but also mitigate hypertension and CVD.
Subject(s)
Cardiovascular Diseases , Gastrointestinal Microbiome , Hypertension , Humans , Gastrointestinal Microbiome/physiology , Hypertension/immunology , Hypertension/physiopathology , Hypertension/microbiology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/microbiology , Animals , Dysbiosis/immunology , Inflammation/immunology , Inflammation/metabolismABSTRACT
BACKGROUND: Trimethylamine N-oxide (TMAO) is a metabolite derived from the gut microbiota and has been reported to be correlated with cardiovascular diseases. Although TMAO is associated with the severity of coronary artery disease in subjects with coronary heart disease (CHD) history. However, the correlation between TMAO and the atherosclerotic burden in newly diagnosed cases of CHD is unknown. METHODS: In this hospital-based study, we enrolled 429 individuals newly diagnosed with CHD undergoing coronary angiography. Plasma TMAO was assessed before coronary angiography. SYNTAX score was computed during coronary angiography to estimate the coronary artery atherosclerotic burden. Both linear and logistic regression analyses were conducted to explore the correlation between plasma TMAO levels and SYNTAX score in newly diagnosed CHD population. RESULTS: The TMAO in patients with SYNTAX ≥ 33 and subjects with SYNTAX < 23 were 6.10 (interquartile range [IQR]: 3.53 to 9.15) µmol/L and 4.90 [IQR: 3.25 to 7.68] µmol/L, respectively. Linear regression adjusting for traditional risk factors showed TMAO level was positively correlated with SYNTAX score (ß = 0.179; p = 0.006) in CHD population. When TMAO was added to models with traditional risk factors, the predictive value improved significantly, with the receiver operating characteristic curve (AUC) increased from 0.7312 to 0.7502 (p = 0.003). Stratified analysis showed that the correlations did not hold true for subjects who were non-smoker or with histories of diabetes. None of the stratifying factors significantly altered the correlation (all p for interaction < 0.05). CONCLUSIONS: We found a positive linear correlation between plasma TMAO and SYNTAX score among newly diagnosed CHD individuals in Chinese population.
Subject(s)
Biomarkers , Coronary Angiography , Coronary Artery Disease , Methylamines , Predictive Value of Tests , Severity of Illness Index , Humans , Methylamines/blood , Male , Female , Middle Aged , Coronary Artery Disease/blood , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/diagnosis , Biomarkers/blood , Aged , Risk Factors , Up-Regulation , Plaque, Atherosclerotic/blood , Risk AssessmentABSTRACT
Objective: This study aims to explore the mechanism of action of Yixintai in treating chronic ischemic heart failure by combining bioinformatics and experimental validation. Materials and Methods: Five potential drugs for treating heart failure were obtained from Yixintai (YXT) through early mass spectrometry detection. The targets of YXT for treating heart failure were obtained by a search of online databases. Gene ontology (GO) functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were conducted on the common targets using the DAVID database. A rat heart failure model was established by ligating the anterior descending branch of the left coronary artery. A small animal color Doppler ultrasound imaging system detected cardiac function indicators. Hematoxylin-eosin (HE), Masson's, and electron microscopy were used to observe the pathological morphology of the myocardium in rats with heart failure. The network pharmacology analysis results were validated by ELISA, qPCR, and Western blotting. Results: A total of 107 effective targets were obtained by combining compound targets and eliminating duplicate values. PPI analysis showed that inflammation-related proteins (TNF and IL1B) were key targets for treating heart failure, and KEGG enrichment suggested that NF-κB signaling pathway was a key pathway for YXT treatment of heart failure. Animal model validation results indicated the following: YXT can significantly reduce the content of intestinal microbiota metabolites such as trimethylamine oxide (TMAO) and improve heart failure by improving the EF and FS values of heart ultrasound in rats and reducing the levels of serum NT-proBNP, ANP, and BNP to improve heart failure. Together, YXT can inhibit cardiac muscle hypertrophy and fibrosis in rats and improve myocardial ultrastructure and serum IL-1ß, IL-6, and TNF-α levels. These effects are achieved by inhibiting the expressions of NF-κB and PKC. Conclusion: YXT regulates the TMAO/PKC/NF-κB signaling pathway in heart failure.
Subject(s)
Drugs, Chinese Herbal , Heart Failure , Network Pharmacology , Signal Transduction , Animals , Male , Rats , Disease Models, Animal , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Heart Failure/drug therapy , Heart Failure/metabolism , Methylamines/pharmacology , NF-kappa B/metabolism , Protein Kinase C/metabolism , Protein Kinase C/antagonists & inhibitors , Rats, Sprague-Dawley , Signal Transduction/drug effectsABSTRACT
The gut microbiota is increasingly recognised as a key player in influencing human health and changes in the gut microbiota have been strongly linked with many non-communicable conditions in humans such as type 2 diabetes, obesity and cardiovascular disease. However, characterising the molecular mechanisms that underpin these associations remains an important challenge for researchers. The gut microbiota is a complex microbial community that acts as a metabolic interface to transform ingested food (and other xenobiotics) into metabolites that are detected in the host faeces, urine and blood. Many of these metabolites are only produced by microbes and there is accumulating evidence to suggest that these microbe-specific metabolites do act as effectors to influence human physiology. For example, the gut microbiota can digest dietary complex polysaccharides (such as fibre) into short-chain fatty acids (SCFA) such as acetate, propionate and butyrate that have a pervasive role in host physiology from nutrition to immune function. In this review we will outline our current understanding of the role of some key microbial metabolites, such as SCFA, indole and bile acids, in human health. Whilst many studies linking microbial metabolites with human health are correlative we will try to highlight examples where genetic evidence is available to support a specific role for a microbial metabolite in host health and well-being.
Subject(s)
Bile Acids and Salts , Fatty Acids, Volatile , Gastrointestinal Microbiome , Humans , Gastrointestinal Microbiome/physiology , Fatty Acids, Volatile/metabolism , Bile Acids and Salts/metabolism , Indoles/metabolism , Host Microbial Interactions , Bacteria/metabolism , Bacteria/genetics , AnimalsABSTRACT
Trimethylamine N-oxide (TMAO), a molecule produced by the microbiota, has been associated with human health and illness. Its early discovery in body fluids may affect our understanding of the pathophysiology and treatment of many illnesses. Therefore, our knowledge of the pathophysiology and diagnostics of disorders associated with TMAO might be enhanced by the creation of dependable and fast methods for TMAO detection. Therefore, we developed a fluorescent probe for detecting TMAO utilizing an on-off-on strategy. Bovine serum albumin (BSA)@AuNCs luminescence is effectively quenched by Mo4+ because BSA@AuNCs and Mo4+ have a strong binding relationship. Mo4+ ions can substantially decrease the emission intensity of gold nanoclusters by establishing a BSA@AuNCs-Mo system. Then, the luminescence of BSA@AuNCs was restored due to the interaction between Mo4+ and TMAO. A significant linear relationship was seen between the emission intensity and TMAO concentration within the 0-201 µM range, with a detection limit of 1.532 µM. Additionally, the method can measure TMAO in blood and urine samples.
Subject(s)
Fluorescent Dyes , Gold , Metal Nanoparticles , Methylamines , Serum Albumin, Bovine , Animals , Cattle , Humans , Biocompatible Materials/chemistry , Fluorescence , Fluorescent Dyes/chemistry , Gold/chemistry , Materials Testing , Metal Nanoparticles/chemistry , Methylamines/chemistry , Molecular Structure , Particle Size , Serum Albumin, Bovine/chemistry , Spectrometry, FluorescenceABSTRACT
Trimethylamine N-oxide (TMAO) is a gut metabolite that acts as a biomarker for chronic diseases, and is generated by the oxidation of trimethylamine (TMA) produced by gut microflora. Since, microbial degradation of TMA is predicted to be used to restrict the production of TMAO, we aimed to isolate bacterial strains that could effectively degrade TMA before being oxidized to TMAO. As marine fish is considered to have a rich content of TMAO, we have isolated TMA degrading isolates from fish skin. Out of the fourteen isolates, depending on their rapid TMA utilization capability in mineral salt medium supplemented with TMA as a sole carbon and nitrogen source, isolate PS1 was selected as our desired isolate. Its TMA degrading capacity was further confirmed through spectrophotometric, Electrospray Ionization Time-of-Flight Mass Spectrometry (ESI TOF-MS) and High performance liquid chromatography (HPLC) analysis and in silico analysis of whole genome (WG) gave further insights of protein into its TMA degradation pathways. PS1 was taxonomically identified as Paracoccus sp. based on its 16S rRNA and whole genome sequence analysis. As PS1 possesses the enzymes required for degradation of TMA, clinical use of this isolate has the potential to reduce TMAO generation in the human gut.
Subject(s)
Genomics , Methylamines , Paracoccus , Animals , Humans , RNA, Ribosomal, 16S/genetics , Paracoccus/geneticsABSTRACT
Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite and TNF-α is proinflammatory cytokine, both known to be associated with renal inflammation, fibrosis and chronic kidney disease. However, today there are no data showing the combined effect of TMAO and TNF-α on renal fibrosis-and inflammation. The aim of this study was to investigate whether TMAO can enhance the inflammatory and fibrotic effects of TNF-α on renal fibroblasts. We found that the combination of TNF-α and TMAO synergistically increased fibronectin release and total collagen production from renal fibroblasts. The combination of TMAO and TNF-α also promoted increased cell proliferation. Both renal proliferation and collagen production were mediated through Akt/mTOR/ERK signaling. We also found that TMAO enhanced TNF-α mediated renal inflammation by inducing the release of several cytokines (IL-6, LAP TGF-beta-1), chemokines (CXCL-6, MCP-3), inflammatory-and growth mediators (VEGFA, CD40, HGF) from renal fibroblasts. In conclusion, we showed that TMAO can enhance TNF-α mediated renal fibrosis and release of inflammatory mediators from renal fibroblasts in vitro. Our results can promote further research evaluating the combined effect of TMAO and inflammatory mediators on the development of kidney disease.
Subject(s)
Methylamines , Renal Insufficiency, Chronic , Tumor Necrosis Factor-alpha , Humans , Inflammation Mediators , Fibrosis , Renal Insufficiency, Chronic/metabolism , Cytokines , Fibroblasts/metabolism , Inflammation/metabolism , CollagenABSTRACT
Background: Flavin monooxygenases (FMOs) are enzymes responsible for the oxidation of a broad spectrum of exogenous and endogenous amines. There is increasing evidence that trimethylamine (TMA), a compound produced by gut bacteria and also recognized as an industrial pollutant, contributes to cardiovascular diseases. FMOs convert TMA into trimethylamine oxide (TMAO), which is an emerging marker of cardiovascular risk. This study hypothesized that blood pressure phenotypes in rats might be associated with variations in the expression of FMOs. Methods: The expression of FMO1, FMO3, and FMO5 was evaluated in the kidneys, liver, lungs, small intestine, and large intestine of normotensive male Wistar-Kyoto rats (WKY) and two distinct hypertensive rat models: spontaneously hypertensive rats (SHRs) and WKY rats with angiotensin II-induced hypertension (WKY-ANG). Plasma concentrations of TMA and TMAO were measured at baseline and after intravenous administration of TMA using liquid chromatography-mass spectrometry (LC-MS). Results: We found that the expression of FMOs in WKY, SHR, and WKY-ANG rats was in the descending order of FMO3 > FMO1 >> FMO5. The highest expression of FMOs was observed in the liver. Notably, SHRs exhibited a significantly elevated expression of FMO3 in the liver compared to WKY and WKY-ANG rats. Additionally, the plasma TMAO/TMA ratio was significantly higher in SHRs than in WKY rats. Conclusion: SHRs demonstrate enhanced expression of FMO3 and a higher plasma TMAO/TMA ratio. The variability in the expression of FMOs and the metabolism of amines might contribute to the hypertensive phenotype observed in SHRs.