Trimethylamine N-oxide and kidney diseases: what do we know? / N-óxido de trimetilamina e doenças renais: o que sabemos?

Abstract In the human gut, there is a metabolically active microbiome whose metabolic products reach various organs and are used in the physiological activities of the body. When dysbiosis of intestinal microbial homeostasis occurs, pathogenic metabolites may increase and one of them is trimethyl amine-N-oxide (TMAO). TMAO is thought to have a role in the pathogenesis of insulin resistance, diabetes, hyperlipidemia, atherosclerotic heart diseases, and cerebrovascular events. TMAO level is also associated with renal inflammation, fibrosis, acute kidney injury, diabetic kidney disease, and chronic kidney disease. In this review, the effect of TMAO on various kidney diseases is discussed.

Resumo No intestino humano, existe um microbioma metabolicamente ativo cujos produtos metabólicos alcançam diversos órgãos e são utilizados nas atividades fisiológicas do corpo. Quando ocorre disbiose da homeostase microbiana intestinal, os metabólitos patogênicos podem aumentar, e um deles é o N-óxido de trimetilamina (TMAO). Acredita-se que o TMAO tenha um papel na patogênese da resistência à insulina, diabetes, hiperlipidemia, doenças cardíacas ateroscleróticas e eventos cerebrovasculares. O nível de TMAO também está associado à inflamação renal, fibrose, lesão renal aguda, doença renal diabética e doença renal crônica. Nesta revisão, discute-se o efeito do TMAO em diversas doenças renais.

Role and mechanism of intestinal flora metabolites in obesity regulation / 中国组织工程研究

BACKGROUND:Gut microbiota is closely related to host energy balance and metabolism.The metabolites of intestinal flora can regulate the occurrence and development of obesity and can be a new target for the prevention and treatment of obesity. OBJECTIVE:To summarize the interaction between the intestinal flora and obesity,as well as the specific mechanism underlying regulation of obesity by metabolites of intestinal flora,thereby providing a new reference and basis for the prevention and treatment of obesity. METHODS:"Intestinal microbiota,intestinal bacteria,intestinal microbiota metabolites,short-chain fatty acids,bile acids,ipopolysaccharide,trimethylamine N-oxide,medium-chain fatty acids,tryptophan derivatives,obesity"were used as search terms in Chinese and English.Literature related to obesity from 1990 to 2022 was retrieved in PubMed and CNKI databases.According to inclusion and exclusion criteria,88 articles were finally selected. RESULTS AND CONCLUSION:Intestinal flora is closely related to the occurrence and development of obesity.For example,changes in the Firmicutes to Bacteroidetes ratio can be used as a biomarker for the diagnosis of obesity,and the occurrence of obesity can be delayed by the colonization of probiotics such as Bifidobacterium breve,Lactobacillus and Akkermansia.Intestinal flora is mainly mediated by the metabolites of intestinal flora to participate in the regulation of obesity.For example,short-chain fatty acid can regulate adipogenesis by regulating signaling pathways such as G protein-coupled receptors 41,43 and peroxisome proliferator-activated receptor γ,thus delaying the occurrence and development of obesity.Bile acids can increase insulin sensitivity and body energy expenditure by promoting the activation of G protein-coupled receptor 5 and farnesol X receptor.In addition,lipopolysaccharide,trimethylamine oxide,medium-chain fatty acids and tryptophan derivatives are also widely involved in the occurrence and development of obesity through various signaling pathways.Further studies have found that metabolites of the same bacterial community exert heterogeneous effects in the specific process of regulating obesity via different signaling pathways.For example,under the influence of high-fat diet,acetic acids can activate the parasympathetic nervous system,leading to hyperphagia and liver insulin resistance and thus accelerating the physiological course of obesity.

Clinical Research Progress of L-carnitine in the Treatment of Primary Carnitine Deficiency / 医药导报

L-carnitine is a carrier that assist in transport of long-chain fatty acids into mitochondria and an effective drug for treating primary carnitine deficiency(PCD).Starting supplementation as early as possible before irreversible organ damage oc-cured can alleviate organ damage,reduce the risk of sudden death,and improve the quality of life.However,in recent years,some studies have suggested that long-term oral L-carnitine has potential risks,the metabolism of L-carnitine through intestinal flora re-sults in the production of trimethylamine oxide(TMAO),which can increase the risk of cardiovascular disease(CVD).There-fore,this paper summarizes the clinical research progress of L-carnitine in treating PCD to provide a theoretical basis for the clini-cal application of L-carnitine in PCD.

Research progress of the effect of TMAO on coronary heart disease and the efficacy of antiplatelet drugs / 中国临床药理学与治疗学

Coronary heart disease is still one of the most common cardiovascular disease and causes of death worldwide(including China).Anti-platelet drugs are fundamental in the treatment of coronary heart disease.In recent years,more and more studies have found that trimethylamine N-ox-ide(TMAO),a major metabolite of intestinal flora,can promote atherosclerosis through various mech-anisms,affecting the prognosis of patients with cor-onary heart disease and the efficacy of antiplatelet drugs.This article reviews the effect of TMAO on coronary heart disease and the efficacy of anti-platelet drugs.

The role of trimethylamine-N-oxide level in the diagnosis of diabetic retinopathy and the differential diagnosis of diabetic and nondiabetic retinopathy / Papel do nível de N-óxido de trimetilamina no diagnóstico da retinopatia diabética e no diagnóstico diferencial da retinopatia diabética e não-diabética

ABSTRACT Purpose: Trimethylamine N-oxide serum levels have been associated with type 2 diabetes mellitus and its complications. The current study aimed to find out if plasma trimethylamine N-oxide level may be a novel marker in the diagnosis of diabetic retinopathy and if it can be used in the differential diagnosis of diabetic and nondiabetic retinopathy. Methods: The study included 30 patients with diabetic retinopathy, 30 patients with nondiabetic retinopathy, 30 patients with type 2 diabetes mellitus without retinopathy, and 30 healthy control participants. Biochemical parameters, serum IL-6, TNF-α, and trimethylamine N-oxide levels were measured in all participants. Results: Trimethylamine N-oxide level was significantly higher in diabetic retinopathy than in the other groups (p<0.001). There was no significant difference in trimethylamine N-oxide levels between nondiabetic retinopathy and control or type 2 diabetes mellitus Groups. There was a significant positive correlation between trimethylamine N-oxide level and elevated FPG, BMI, HOMA-IR score, BUN, IL-6, and TNF-α levels. Conclusion: The current study showed that the trimethylamine N-oxide level is elevated in diabetic retinopathy. These findings suggest that serum trimethylamine N-oxide level might be a novel marker for diabetic retinopathy, and it might be used in the differential diagnosis of diabetic and nondiabetic retinopathy.

RESUMO Objetivo: Os níveis séricos de N-óxido de trimetilamina têm sido associados ao diabetes mellitus tipo 2 e suas complicações. O presente estudo tem como objetivo responder a duas questões, entre elas: O nível plasmático de N-óxido de trimetilamina poderia ser um novo marcador no diagnóstico de retinopatia diabética? e Ele poderia ser utilizado no diagnóstico diferencial de retinopatia diabética e não diabética? Métodos: Trinta pacientes com retinopatia diabética, 30 pacientes com retinopatia não diabética, 30 pacientes com diabetes mellitus tipo 2 sem retinopatia e 30 participantes saudáveis do grupo controle foram incluídos no estudo. Parâmetros bioquímicos, níveis séricos de IL-6, de TNF-α e de N-óxido de trimetilamina foram medidos em todos os participantes. Resultados: O nível de N-óxido de trimetilamina foi significativamente maior na retinopatia diabética do que nos outros grupos (p<0,001). Não houve diferença significativa no nível de N-óxido de trimetilamina entre o grupo de retinopatia não diabética, do grupo controle ou do grupo de diabetes mellitus tipo 2. Houve uma correlação positiva significativa entre o nível de N-óxido de trimetilamina e os níveis elevados de FPG, IMC, HOMA-IR, BUN, IL-6 e TNF-α. Conclusão: O estudo atual mostrou que o nível de N-óxido de trimetilamina encontra-se elevado na retinopatia diabética. Esses achados sugerem que o nível sérico de N-óxido de trimetilamina pode ser um novo marcador na retinopatia diabética, podendo ser usado no diagnóstico diferencial de retinopatia diabética e não diabética.

The effects and mechanisms of trimethylamine-N-oxide on insulin sensitivity in insulin target cells / 药学学报

Gut microbial metabolite trimethylamine-N-oxide (TMAO) is associated with type 2 diabetes (T2DM). Decreased insulin sensitivity is a significant etiological factor of T2DM. Adipocytes, myocytes, and hepatocytes are the three major target cells for insulin. This study aims to investigate the effects and mechanisms of TMAO on the insulin sensitivity of these target cells. Research results indicate that in different ages of db/db diabetic mice, plasma TMAO levels were increased. TMAO significantly inhibits the insulin signaling pathways in these three major insulin target cells, reduces glucose uptake in 3T3-L1 adipocytes and L6 myocytes and downregulates genes related to gluconeogenesis in primary mouse hepatocytes. Furthermore, in mice with normal insulin sensitivity, elevating plasma TMAO levels to those seen in db/db mice using a minipump results in impaired glucose tolerance and hyperinsulinemia. All animal experiments were carried out with approval of the Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica (Chinese Academy of Medical Sciences and Peking Union Medical College). Mechanistic studies suggest that TMAO exposure increases the levels of endoplasmic reticulum stress-related proteins in these three major insulin target cells. In summary, TMAO directly attenuates insulin sensitivity in insulin target cells, and its mechanism of action may involve enhancing endoplasmic reticulum stress.

Effect of traditional Chinese medicine in attenuating chronic kidney disease and its complications by regulating gut microbiota-derived metabolite trimethylamine N-oxide: a review / 中国中药杂志

Trimethylamine N-oxide(TMAO), a metabolite of gut microbiota, is closely associated with chronic kidney disease(CKD). It can aggravate the kidney injury and promote the occurrence of complications of CKD mainly by inducing renal fibroblast activation, vascular endothelial inflammation, macrophage foaming, platelet hyperreactivity, and inhibition of reverse cholesterol transport. Thus it is of great significance for clinical treatment of CKD to regulate circulating TMAO and alleviate its induced body damage. Currently, therapeutic strategies for TMAO regulation include dietary structure adjustment, lifestyle intervention, intestinal microflora regulation, and inhibition of intestinal trimethylamine synthesis and liver trimethylamine oxidation. Chinese medicinal herbs have the clinical advantage of multi-component and multi-target effects, and application of traditional Chinese medicine(TCM) to synergistically regulating TMAO and improving CKD via multiple pathways has broad prospects. This study systematically reviewed the clinical relevance and mechanism of TMAO in aggravating CKD renal function deterioration and complication progression. In addition, the effect and mechanism of TCM in improving TMAO-induced kidney injury, cardiovascular disease, hyperlipidemia, thrombosis and osteoporosis were summarized. The results provided a theoretical basis for TCM in attenuating gut microbiota-derived metabolite TMAO and improving CKD, as well as a basis and direction for in-depth clinical development and mechanism research in the future.

Mechanism of gut microbiota metabolite TMAO activating inflammatory pathway HMGB1/NLRP3 to promote cerebral ischemic penumbra damage in mice / 中风与神经疾病杂志

@#Objective To explore the mechanism of the gut microbiota metabolite trimethylamine-N-oxide （TMAO） acting on high mobility group box 1 （HMGB1）/NOD-like receptor protein 3 （NLRP3） to regulate inflammatory response after cerebral ischemia/reperfusion （I/R） injury in mice. Methods A mouse atherosclerosis model was established by feeding on TMAO and high-fat diet.A mouse model of middle cerebral artery occlusion （MCAO） was prepared using the suture method.Mice were randomly divided into sham group，2-week-TMAO-feeding group，and 6-week-TMAO-feeding group.After I/R injury，we measured the protein levels of NLRP3，HMGB1，cleaved interleukin-1β （Cle-IL-1β），and zonula occludens-1 （ZO-1） by Western blotting.After six weeks of TMAO feeding，mice were randomly divided into sham group，I/R group，TMAO+I/R group，and TMAO+DMB+I/R group.For each group，we scored neurological function，determined NLRP3，HMGB1，Cle-IL-1β，and ZO-1 protein expression by Western blot，measured brain infarct volume with TTC staining，and measured the water content of brain tissue. Results Compared with those of the sham group，NLRP3，HMGB1，and Cle-IL-1β protein expression increased significantly and ZO-1 decreased significantly with the length of TMAO feeding （all P<0.05）.Compared with the I/R group，the TMAO+I/R group showed a significant decline in neurological scores，significantly increased NLRP3，HMGB1，and Cle-IL-1β expression，significantly decreased ZO-1 expression，a significant increase in brain infarct volume，and a significant decrease in the water content of brain tissue （all P<0.05）.With DMB lowering TMAO，the TMAO+DMB+I/R group had significantly better neurological scores，significantly lower NLRP3，HMGB1，and Cle-IL-1β levels，a significantly increased ZO-1 level，and significantly reduced brain infarct volume and brain tissue water content，as compared with the TMAO+I/R group （all P<0.05）. Conclusion The gut microbiota metabolite TMAO can upregulate HMGB1/NLRP3-mediated inflammatory response in mice with cerebral I/R injury，worsening the breakdown of the blood-brain barrier to exacerbate brain tissue damage.

Influence of gut microbiota-derived trimethylamine N-oxide on early neurological deterioration in diabetic patients with acute ischemic stroke / 中华老年医学杂志

Objective:To investigate the influence of trimethylamine N-oxide(TMAO)on the development of early neurological deterioration(END)in diabetic patients with acute ischemic stroke.Methods:In this cross-sectional study, 108 type 2 diabetes patients with acute ischemic stroke treated at the Department of Neurology in the Affiliated Wuxi People’s Hospital of Nanjing Medical University between October 2019 and November 2020 were consecutively recruited.END was defined as an increase in the National Institutes of Health Stroke Scale(NIHSS)≥ 2 points and exclusion of intracranial hemorrhage or bleeding transformation in cranial imaging evaluation within 5 days of initial deterioration of neurological dysfunction.The patients were divided into 2 groups, an END(n=36)group and a non-END group(n=72). Fasting plasma TMAO was measured using isotope dilution liquid chromatography coupled to tandem mass spectrometry.Results:Of the 108 patients, 36(33.3%)were diagnosed with END, and their plasma TMAO levels were significantly higher compared with patients without END( Z=-3.500, P<0.001). For prediction of END, the area under the ROC curve for plasma TMAO levels was 0.707(95% CI: 0.603-0.811, P<0.001). The frequencies of END in subjects grouped via tertiles of TMAO were 22.2%, 19.4% and 58.3%, respectively, with significant differences between the 3 groups( χ2=14.979, P=0.001). Univariate analysis showed that elevated TMAO( OR=1.160, 95% CI: 1.050-1.282, P=0.004)was associated with END.A multivariate logistic regression model further confirmed the association between TMAO and END( OR=1.145, 95% CI: 1.033-1.269, P=0.010). Conclusions:Increased plasma TMAO levels are associated with END in diabetic patients with acute ischemic stroke.

Advancement in the relationship between gut microbiota and coronary artery disease / 中国胸心血管外科临床杂志

@#Including gut microbiota and oral microbiota, various microorganisms in different human ecosystem constitute the human microbiota, which play an important role in human metabolism, immunity and maintaining microecological homeostasis. Abnormal changes in gut microbiota known as dysbiosis may lead to metabolic abnormalities and inflammatory changes, which are closely related to disease states including hypertension, diabetes, inflammatory bowel disease, and autoimmune diseases. The main cause of coronary artery disease is coronary atherosclerosis, a chronic and progressive inflammatory disease. Many evidences have shown that there is a correlation between gut microbiota and coronary artery disease. Therefore, we aim to review the relationship between gut microbiota and coronary artery disease, and discuss the possible research directions and application prospects.

Research progress of effect of gut microbiota and its metabolites on coronary artery diseases / 中国胸心血管外科临床杂志

@#Gut microbiota and its metabolites in various human diseases have gradually become a research hotspot in the current medical community. And coronary artery disease is currently one of the most threatening clinical cardiovascular diseases in the world, so the use of gut microbiota and its metabolites in the development of its pathophysiology has also received more and more attention. Therefore, this paper reviews the effects of gut microbiota and its metabolites on coronary artery disease, as well as the research progress of intervening gut microbiota and its metabolites as therapeutic targets, hoping to expand the future research direction in this field and provide new ideas with treating coronary artery disease.

Trimethylamine N-oxide: a potential target for osteoporosis treatment / 中国临床药理学与治疗学

Trimethylamine N-oxide (TMAO) is an intestinal flora metabolite produced in the liver by the oxidation of trimethylamine (TMA) by hepatic enzymes. Recently, it has been found that plasma TMAO levels play an important role in the development and progression of osteoporosis. This review has presented the physiological functions and metabolic processes of TMAO, and its effects on the development and progression of osteoporosis through oxidative stress and inflammation. Plasma TMAO levels are influenced by diet as well as medications, which provides a new perspective and target for the treatment and prevention of osteoporosis.

Consumo de Castanha-do-Brasil reduz o N-óxido de trimetilamina (TMAO) e a inflamação em um paciente com síndrome cardiorrenal: uma comunicação breve / Brazil nut consumption reduces trimethylamine-n-oxide (TMAO) and inflammation in a patient with cardiorenal syndrome: a brief communication

Introdução: A disbiose intestinal é uma característica comum na síndrome cardiorrenal e está associada ao aumento de toxinas urêmicas, como o N-óxido de trimetilamina (TMAO), que estão envolvidas com a inflamação e mortalidade cardiovascular. A castanha-do-Brasil (semente típica brasileira) possui propriedades anti-inflamatórias e antioxidantes, mas não há evidências dos seus efeitos na modulação da microbiota intestinal e redução de toxinas urêmicas. Objetivo: Avaliar o impacto do consumo de castanha-do-Brasil nos níveis de TMAO e marcadores de inflamação em um paciente com síndrome cardiorrenal. Métodos: Um paciente com doença arterial coronariana (66 anos e IMC, 26 kg/m2), estágio 3 da DRC (TFGe 36 mL/min), recebeu uma castanha-do-Brasil por dia durante três meses. Resultados: Os níveis plasmáticos de TMAO e a expressão de mRNA de NF-κB foram reduzidos e a atividade da glutationa peroxidase (GPx) aumentou após esta intervenção. Conclusão: A prescrição de castanha-do-Brasil pode ser uma estratégia promissora para mitigar as complicações relacionadas à síndrome cardiorrenal. Este caso apoia o conceito de "alimento como remédio" visando o fenótipo urêmico na síndrome cardiorrenal.

Introduction: Gut dysbiosis is a common feature in cardiorenal syndrome, and it is linked to increased uremic toxins, like trimethylamine-n-oxide (TMAO), which are involved with inflammation and cardiovascular mortality. Brazil nut (typical Brazilian seed) has anti-inflammatory and antioxidant properties, but there is no evidence of the effects of gut microbiota modulation and reduction of uremic toxins. Objective: To assess the impact of Brazil nut consumption on TMAO levels and inflammation markers in a patient with cardiorenal syndrome. Methods: Acoronary artery disease patient(66 years and BMI, 26 kg/m2),stage-3 of CKD (eGFR 36 mL/min), receivedone Brazil nut per day for three months. Results: TMAO plasma levels and NF-κB mRNA expression were reduced, and glutathione peroxidase (GPx) activity increased after this intervention. Conclusion: Brazil nut prescription may be a promising strategy to mitigate complications related tothe cardiorenal syndrome. This case supports the concept of "Food as medicine" targeting the uremic phenotype in cardiorenal syndrome.

The interplay between oat beta glucan, gut microbiota and gut-liver axis in treatment of obesity associated non-alcoholic steatohepatitis and Type II diabetes mellitus

Dietary fibers regulate host health through various mechanisms related to their physicochemical structure and physiological properties in the gut. The interplay between diet, gut microbiota and human host appear to play a significant role in pathogenesis of obesity associated complications. This study was designed to unravel oat beta glucan modulatory effect on non-alcoholic steatohepatitis and type II diabetes mellitus in high fat fed rats and to explain possible pathomechanics involving gut microbiota and gut liver axis. Sixty male albino rats were included and randomly divided into four equal groups: control group; positive control group; diet induced obesity group; oat beta glucan treated group. All were subjected to assessment of glycemic profile; liver enzymes; serum trimethylamine-N-oxide levels; hepatic G-protein coupled receptor 43 relative gene expression. Histopathological examination of hepatic tissue was performed. Results revealed that oat beta glucan administration improved the biochemical changes. The histopathological findings confirmed the biochemical changes. Gut microbiota appeared to be highly implicated via its metabolites short chain fatty acids and trimethylamine. Our conclusion was that oat beta glucan was a successful compliance in the management strategy of hepatic steatosis and diabetes mellitus via modulating a number of gut microbial products.

FMO3-TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction: evidence from an Asian population / 医学前沿

The association among plasma trimethylamine-N-oxide (TMAO), FMO3 polymorphisms, and chronic heart failure (CHF) remains to be elucidated. TMAO is a microbiota-dependent metabolite from dietary choline and carnitine. A prospective study was performed including 955 consecutively diagnosed CHF patients with reduced ejection fraction, with the longest follow-up of 7 years. The concentrations of plasma TMAO and its precursors, namely, choline and carnitine, were determined by liquid chromatography-mass spectrometry, and the FMO3 E158K polymorphisms (rs2266782) were genotyped. The top tertile of plasma TMAO was associated with a significant increment in hazard ratio (HR) for the composite outcome of cardiovascular death or heart transplantation (HR = 1.47, 95% CI = 1.13-1.91, P = 0.004) compared with the lowest tertile. After adjustments of the potential confounders, higher TMAO could still be used to predict the risk of the primary endpoint (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). This result was also obtained after further adjustment for carnitine (adjusted HR = 1.33, 95% CI = 1.01-1.74, P = 0.039). The FMO3 rs2266782 polymorphism was associated with the plasma TMAO concentrations in our cohort, and lower TMAO levels were found in the AA-genotype. Thus, higher plasma TMAO levels indicated increased risk of the composite outcome of cardiovascular death or heart transplantation independent of potential confounders, and the FMO3 AA-genotype in rs2266782 was related to lower plasma TMAO levels.

Association between plasma trimethylamine-N-oxide level and premature coronary heart disease / 中华全科医师杂志

Objective:To investigate the associations between plasma trimethylamine-N-oxide (TMAO) level and premature coronary heart disease (PCHD).Methods:From July 2018 to July 2020, total of 166 patients with suspected coronary heart disease were enrolled from the Heart Center of Shenzhen Bao′an Hospital affiliated to Southern Medical University. According to the coronary imaging results and age of onset, they were divided into young control group ( n=30), PCHD group ( n=49), middle-aged and elderly control group ( n=30) and the middle-aged and elderly coronary heart disease group ( n=57). Plasma TMAO concentration in each group was determined by stable isotope liquid chromatography/mass spectrometry, and the correlation of plasma TMAO level with PCHD and SYNTAX score was analyzed. Results:The plasma TMAO level in PCHD group was significantly higher than that in young control group [(7.54±2.10) μmol/L vs. (4.60±1.89) μmol/L; t=6.73, P?0.001] and middle-aged and elderly coronary heart disease group [(3.90±1.75) μmol/L; t=2.45, P=0.015]. The plasma TMAO level was positively correlated with SYNTAX score in PCHD group ( r=0.66, P?0.001) and in middle-aged and elderly coronary heart disease group ( r=0.27, P=0.042). Multivariate logistic regression analysis showed that plasma TMAO level was an independent risk factor for PCHD ( OR=2.30, P?0.001). Receiver operating characteristic (ROC) curve analysis showed that when the cutoff level of plasma TMAO was 6.08 μmol/L, the sensitivity and specificity for diagnosis of PCHD were 73.5% and 76.7%, respectively. Conclusion:The plasma TMAO level is significantly correlated with PCHD and had certain predictive value for PCHD.

Macrophage Activation Induced by TMAO through CD147 / MMPs / 中国生物化学与分子生物学报

Trimethylamine N-oxide (TMAO), a metabolite of intestinal flora, can promote Atherosclerosis (AS) in various ways. Current studies have found that it has a close relationship with plaque stability in clinical practice, but its molecular mechanism remains unclear at present. Extracellular matrix metalloproteinase inducers (CD147) / matrix metalloproteinases (MMPs) regulate a signal pathway highly related to plaque stability, which can promote plaque instability and lead to cardiovascular adverse events by weakening the thickness of the fibrous cap. Therefore, in this study, the mouse macrophageRAW264. 7 was stimulated by TMAO to establish a cell model to observe the effects on CD147, MMP2, and MMP9, and the CD147 gene silencing model was further constructed by using the siRNA transfection method to explore the interaction between CD147 and MMP2 and MMP9. Rt-qPCR and Western blotting results showed that there was no significant change in the gene expression level of CD147 in mouse macrophage RAW264. 7, but significantly increased in protein levels (P < 0. 05), while MMP2 andMMP9 were increased in mRNA and protein levels (P<0. 05). The expression of CD147, MMP2, andMMP9 was significantly inhibited in CD147 siRNA transfected cells (P<0. 05). In conclusion, TMAO significantly increases the expression of MMP2 and MMP9 in mouse macrophages RAW264. 7, and this effect may be partially realized through the CD147/ MMP pathway.

Prognostic values of the plasma trimethylamine N-oxide in sepsis / 中国医师杂志

Objective:To investigate the value of serum trimethylamine N-oxide (TMAO) level in evaluating the severity and short-term clinical prognosis of patients with sepsis.Methods:A prospective case-control study was conducted. Patients in the case group were admitted to the emergency intensive care unit of Shanghai Putuo District People′s Hospital Affiliated to Tongji University from March 2018 to December 2019. According to the diagnosis criteria of sepsis 3.0 in 2016, the patients in the case group were divided into sepsis non shock group (33 cases) and septic shock group (12 cases). They were divided into survival group and death group according to 28 day outcome; Healthy volunteers were selected as control group (30 cases). The levels of C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), Acute Physiology And Chronic Health Evaluation Ⅱ (APACHE Ⅱ) and the sequential organ failure assessment (SOFA), serum TMAO were compared. The relationship between serum TMAO, sepsis severity and short-term clinical prognosis were analyzed.Results:The serum IL-6, CRP, PCT, scores of SOFA and APACHE Ⅱ in septic shock group were significantly higher than those in normal sepsis group ( P<0.01). The serum IL-6, PCT, scores of SOFA and APACHE Ⅱ in the death group of sepsis patients were significantly higher than those in the survival group ( P<0.01). The serum TMAO level of the sepsis group on 1st day was significantly higher than that of the healthy control group ( P<0.01). The serum TMAO level in the septic shock group on the 1st, 3rd and 7 th day was higher than that in the normal sepsis group, with statistically significant difference ( P<0.01). The serum TMAO level in the septic shock group and normal sepsis group on the third day were significant different with the first day ( P<0.01). The serum TMAO level in the death group on the 1st, 3rd and 7th day was higher than that in the survival group, with statistically significant difference ( P<0.05). And the serum TMAO level in the death group and survival group on the third day were significant different with the first day ( P<0.01). The serum TMAO level of sepsis patients was positively correlated with APACHE Ⅱ score ( r=0.848, P<0.01). The level of TMAO was positively correlated with serum IL-6 ( r=0.956, P<0.01). Conclusions:Serum TMAO is closely related to the severity and recent clinical prognosis of patients with sepsis, and is a risk factor for the death of patients with sepsis.

Gut microbiota and its metabolite trimethylamine-N-oxide (TMAO): a novel regulator in coronary artery disease / 生物工程学报

Coronary artery disease (CAD) is a chronic disease but causes the highest mortality and morbidity among the cardiovascular diseases worldwide. Correlations between CAD and gut microbiota have been observed. This suggests that the gut microbiota could become a vital diagnostic marker of CAD, and restoring the gut habitat may become a promising strategy for CAD therapy. The elevated level of trimethylamine-N-oxide (TMAO), a gut microbiota-derived metabolite, was found to be associated with the increased risk of cardiovascular disease and the all-cause mortality. Preclinical studies have shown that it has pro-arteriosclerosis properties. It is likely that regulating the production of TMAO by gut microbiota may become a promising strategy for anti-atherosclerosis therapy. This review summarizes the clinical and preclinical researches on the intervention of CAD by regulating the gut microbiota and the microbiota-derived metabolite TMAO, with the aim to provide new target for the therapy of CAD.

Distinct Urinary Metabolic Profile in Rheumatoid Arthritis Patients: A Possible Link between Diet and Arthritis Phenotype

OBJECTIVE: We undertook this study to investigate the discriminant metabolites in urine from patients with established rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and from healthy individuals. METHODS: Urine samples were collected from 148 RA patients, 41 SLE patients and 104 healthy participants. The urinary metabolomic profiles were assessed using 1H nuclear magnetic resonance spectroscopy. The relationships between discriminant metabolites and clinical variables were assessed. Collagen-induced arthritis was induced in mice to determine if a choline-rich diet reduces arthritis progression. RESULTS: The urinary metabolic fingerprint of patients with established RA differs from that of healthy controls and SLE patients. Markers of altered gut microbiota (trimethylamine-N-oxide, TMAO), and oxidative stress (dimethylamine) were upregulated in patients with RA. In contrast, markers of mitochondrial dysfunction (citrate and succinate) and metabolic waste products (p-cresol sulfate, p-CS) were downregulated in patients with RA. TMAO and dimethylamine were negatively associated with serum inflammatory markers in RA patients. In particular, patients with lower p-CS levels exhibited a more rapid radiographic progression over two years than did those with higher p-CS levels. The in vivo functional study demonstrated that mice fed with 1% choline, a source of TMAO experienced a less severe form of collagen-induced arthritis than did those fed a control diet. CONCLUSION: Patients with RA showed a distinct urinary metabolomics pattern. Urinary metabolites can reflect a pattern indicative of inflammation and accelerated radiographic progression of RA. A choline-rich diet reduces experimentally-induced arthritis. This finding suggests that the interaction between diet and the intestinal microbiota contributes to the RA phenotype.