4-cresol-sulfate and phenylacetylglutamine

Diets including red meat and other animal-sourced foods may increase proteolytic fermentation and microbial-generated trimethylamine (TMA) and, subsequently, trimethylamine-N-oxide (TMAO), a metabolite associated with increased risk of cardiovascular disease and dementia. It was hypothesized that compared to usual dietary intake, a maintenance-energy high-protein diet (HPD) would increase products of proteolytic fermentation, whereas adjunctive prebiotic, probiotic, and synbiotic supplementation may mitigate these effects. An exploratory aim was to determine the association of the relative abundance of the TMA-generating taxon, Emergencia timonensis, with serum and urinary TMAO. At 5 time points (usual dietary intake, HPD diet, HPD + prebiotic, HPD + probiotic, and HPD + synbiotic), urinary (24-hour) and serum metabolites and fecal microbiota profile of healthy older women (n = 20) were measured by liquid chromatography-tandem mass spectrometry and 16S rRNA gene amplicon sequencing analyses, respectively. The HPD induced increases in serum levels of l-carnitine, indoxyl sulfate, and phenylacetylglutamine but not TMAO or p-cresyl sulfate. Urinary excretion of l-carnitine, indoxyl sulfate, phenylacetylglutamine, and TMA increased with the HPD but not TMAO or p-cresyl sulfate. Most participants had undetectable levels of E.timonensis at baseline and only 50% during the HPD interventions, suggesting other taxa are responsible for the microbial generation of TMA in these individuals. An HPD diet with or without a prebiotic, probiotic, or synbiotic elicited an increase in products of proteolytic fermentation. The urinary l-carnitine response suggests that the additional dietary l-carnitine provided was primarily bioavailable, providing little substrate for microbial conversion to TMA and subsequent TMAO formation.

Topics: Aged; Carnitine; Clostridiales; Cresols; Cross-Over Studies; Diet, High-Protein; Feces; Female; Gastrointestinal Microbiome; Glutamine; Humans; Indican; Meat; Methylamines; Prebiotics; Probiotics; Sulfuric Acid Esters; Synbiotics

Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors, we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine, and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dl), a twofold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98-1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06-1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin.

Topics: Adult; Aged; Cardiovascular Diseases; Cresols; Female; Glutamine; Hippurates; Humans; Indican; Kidney Failure, Chronic; Longitudinal Studies; Male; Middle Aged; Renal Dialysis; Risk Factors; Serum Albumin; Sulfuric Acid Esters; Uremia

Due to the global increase in obesity rates and success of bariatric surgery in weight reduction, an increasing number of women now present pregnant with a previous bariatric procedure. This study investigates the extent of bariatric-associated metabolic and gut microbial alterations during pregnancy and their impact on fetal development.. A parallel metabonomic (molecular phenotyping based on proton nuclear magnetic resonance spectroscopy) and gut bacterial (16S ribosomal RNA gene amplicon sequencing) profiling approach was used to determine maternal longitudinal phenotypes associated with malabsorptive/mixed (n=25) or restrictive (n=16) procedures, compared with women with similar early pregnancy body mass index but without bariatric surgery (n=70). Metabolic profiles of offspring at birth were also analysed.. Metabolism is altered in pregnant women with a previous malabsorptive bariatric surgery. These alterations may be beneficial for maternal outcomes, but the effect of elevated levels of phenolic and indolic compounds on fetal and infant health should be investigated further.

Topics: 3-Hydroxybutyric Acid; Adult; Amino Acids; Birth Weight; Body Mass Index; Clostridiales; Creatinine; Cresols; Enterococcus; Escherichia; Feces; Female; Fetal Development; Gastric Bypass; Gastrointestinal Microbiome; Gastroplasty; Glutamine; Hemiterpenes; Humans; Indican; Infant, Newborn; Insulin Resistance; Isobutyrates; Isoleucine; Keto Acids; Leucine; Metabolomics; Micrococcaceae; Phenotype; Phenylacetates; Pregnancy; Streptococcus; Sulfuric Acid Esters; Young Adult

Numerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline free levels of four organic solutes that are secreted in the native kidney - p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine - with outcomes in hemodialysis patients.. We measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/VUREA.. Mean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17-2.25; p=0.004) and first cardiovascular event (1.60; 1.23-2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18-1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05-3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12-2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses.. Free levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Cause of Death; Cresols; Female; Glutamine; Hippurates; Humans; Indican; Kidney Failure, Chronic; Male; Middle Aged; Morbidity; Mortality; Patient Outcome Assessment; Renal Dialysis; Sulfuric Acid Esters; United States

Several circulating metabolites derived from bacterial protein fermentation have been found to be inversely associated with renal function but the timing and disease severity is unclear. The aim of this study is to explore the relationship between indoxyl-sulfate, p-cresyl-sulfate, phenylacetylglutamine and gut-microbial profiles in early renal function decline.. Indoxyl-sulfate (Beta(SE) = -2.74(0.24); P = 8.8x10-29), p-cresyl-sulfate (-1.99(0.24), P = 4.6x10-16), and phenylacetylglutamine(-2.73 (0.25), P = 1.2x10-25) were inversely associated with eGFR in a large population base cohort (TwinsUK, n = 4439) with minimal renal function decline. In a sub-sample of 855 individuals, we analysed metabolite associations with 16S gut microbiome profiles (909 profiles, QIIME 1.7.0). Three Operational Taxonomic Units (OTUs) were significantly associated with indoxyl-sulfate and 52 with phenylacetylglutamine after multiple testing; while one OTU was nominally associated with p-cresyl sulfate. All 56 microbial members belong to the order Clostridiales and are represented by anaerobic Gram-positive families Christensenellaceae, Ruminococcaceae and Lachnospiraceae. Within these, three microbes were also associated with eGFR.. Our data suggest that indoxyl-sulfate, p-cresyl-sulfate and phenylacetylglutamine are early markers of renal function decline. Changes in the intestinal flora associated with these metabolites are detectable in early kidney disease. Future efforts should dissect this relationship to improve early diagnostics and therapeutics strategies.

Topics: Adult; Aged; Aged, 80 and over; Body Mass Index; Clostridiales; Cresols; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diseases in Twins; Feces; Female; Fermentation; Gastrointestinal Microbiome; Glomerular Filtration Rate; Glutamine; Humans; Indican; Kidney Diseases; Male; Metabolome; Microbiota; Middle Aged; Ribotyping; Sulfuric Acid Esters

Understanding the metabolic processes associated with aging is key to developing effective management and treatment strategies for age-related diseases. We investigated the metabolic profiles associated with age in a Taiwanese and an American population. ¹H NMR spectral profiles were generated for urine specimens collected from the Taiwanese Social Environment and Biomarkers of Aging Study (SEBAS; n = 857; age 54-91 years) and the Mid-Life in the USA study (MIDUS II; n = 1148; age 35-86 years). Multivariate and univariate linear projection methods revealed some common age-related characteristics in urinary metabolite profiles in the American and Taiwanese populations, as well as some distinctive features. In both cases, two metabolites--4-cresyl sulfate (4CS) and phenylacetylglutamine (PAG)--were positively associated with age. In addition, creatine and β-hydroxy-β-methylbutyrate (HMB) were negatively correlated with age in both populations (p < 4 × 10⁻⁶). These age-associated gradients in creatine and HMB reflect decreasing muscle mass with age. The systematic increase in PAG and 4CS was confirmed using ultraperformance liquid chromatography-mass spectrometry (UPLC-MS). Both are products of concerted microbial-mammalian host cometabolism and indicate an age-related association with the balance of host-microbiome metabolism.

Topics: Aged; Aging; Cresols; Glutamine; Humans; Magnetic Resonance Spectroscopy; Male; Metabolome; Middle Aged; Sex Characteristics; Sulfuric Acid Esters; Taiwan; United States