Metabolomics studies identify novel diagnostic and prognostic indicators in patients with alcoholic hepatitis

AIM: To identify plasma analytes using metabolomics that correlate with the diagnosis and severity of liver disease in patients with alcoholic hepatitis(AH).METHODS: We prospectively recruited patients with cirrhosis from AH(n = 23) and those with cirrhosis with acute decompensation(AD) from etiologies other than alcohol(n = 25). We used mass spectrometry to identify 29 metabolic compounds in plasma samples from fasted subjects. A receiver operating characteristics analysis was performed to assess the utility of biomarkers in distinguishing acute AH from alcoholic cirrhosis. Logistic regression analysis was performed to build a predictive model for AH based on clinical characteristics. A survival analysis was used to construct Kaplan Meier curves evaluating transplant-free survival.RESULTS: A comparison of model for end-stage liver disease(MELD)-adjusted metabolomics levels between cirrhosis patients who had AD or AH showed that patients with AH had significantly higher levels of betaine, and lower creatinine, phenylalanine, homocitrulline, citrulline, tyrosine, octenoyl-carnitine, and symmetric dimethylarginine. When considering combined levels, betaine and citrulline were highly accurate predictors for differentiation between AH and AD(area under receiver operating characteristics curve = 0.84). The plasma levels of carnitine [0.54(0.18, 0.91); P = 0.005], homocitrulline [0.66(0.34, 0.99); P < 0.001] and pentanoyl-carnitine [0.53(0.16, 0.90); P = 0.007] correlated with MELD scores in patients diagnosed with AH. Increased levels of many biomarkers(carnitine P = 0.005, butyrobetaine P = 0.32, homocitrulline P = 0.002, leucine P = 0.027, valine P = 0.024, phenylalanine P = 0.037, tyrosine P = 0.012, acetyl-carnitine P = 0.006, propionyl-carnitine P = 0.03, butyryl-carnitine P = 0.03, trimethyl-lisine P = 0.034, pentanoyl-carnitine P = 0.03, hexanoyl-carnitine P = 0.026) were associated with increased mortality in patients with AH. CONCLUSION: Metabolomics plasma analyte levels might be used to diagnose of AH or help predict patient prognoses.

Gut Microbiota Community Shift with Severity of Coronary Artery Disease

Gut microbiota community shift with coronary artery disease(CAD)has been reported in several limited cohorts during the past several years.However,whether the enriched or decreased microbiota taxa with CAD can be reproducible deserves further investigation and validation.In this study,78 human subjects were recruited.Of these,19 were diagnosed without stenosis in coronary artery(control group,referred to herein as Ctrl),14 with stenosis less than 50%(LT50),and 45 with stenosis greater than 50%(GT50).Fecal samples were collected and DNA was extracted to perform 16S ribosomal RNA(rRNA)gene sequencing.The operational taxonomic units(OTUs)were analyzed to identify taxa specific to different groups;next,multivariate logistic regression was employed to test whether the defined taxa could independently predict CAD risk.We found that Deltaproteobacteria,Fusobacterium,Bilophila,Actinomyces,and Clostridium XIX were enriched in Ctrl;Prevotellaceae,Parabacteriodes,and Butyricicoccus were enriched in LT50;and Roseburia and Butyricimonas were enriched in GT50.Further analysis revealed that increased populations of Deltaproteobacteria,Fusobacterium,Bilophila,and Desulfovibrionaceae were associated with a 0.26-fold,0.21-fold,0.18-fold,and 0.26-fold decreased risk of CAD,respectively(p<0.05),and an increased Prevotellaceae population was associated with a 5.63-fold increased risk of CAD(p<0.01).A combination of the 20 microbial taxa achieved an area under the receiver operating characteristic(ROC)curve of higher than 0.88 for all discriminations between LT50 vs Ctrl,GT50 vs Ctrl,LT50+GT50 vs Ctrl,and GT50 vs Ctrl+LT50.However,the microbial taxa previously reported as enriched in CAD patients or healthy controls could not be observed in our cohort except for Bacteroides.In conclusion,CAD patients showed a different microbial taxa signature than the healthy controls.However,the non-reproducibility of the microbiota taxa enriched in CAD across different cohorts limits the use of this signature in early diagnosis and prevention.Only decreased Bacteroides abundance was found to be a reliable marker to indicate CAD progression.

Gut microbiota derived metabolites in cardiovascular health and disease

Trillions of microbes inhabit the human gut, not only providing nutrients and energy to the host from the ingested food, but also producing metabolic bioactive signaling molecules to maintain health and elicit dis- ease, such as cardiovascular disease （CVD）. CVD is the leading cause of mortality worldwide. In this review, we presented gut microbiota derived metabolites involved in cardiovascular health and disease, including trimethylamine-N-oxide （TMAO）, uremic toxins, short chain fatty acids （SCFAs）, phytoestrogens, antho- cyanins, bile acids and lipopolysaccharide. These gut microbiota derived metabolites play critical roles in maintaining a healthy cardiovascular function, and if dysregulated, potentially causally linked to CVD. A bet- ter understanding of the function and dynamics of gut microbiota derived metabolites holds great promise toward mechanistic predicative CVD biomarker discoveries and precise interventions.

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

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 FM03 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.