4-cresol-sulfate and trimethyloxamine

The gut microbiome recently has emerged as a novel risk factor that impacts health and disease. Our gut microbiota can function as an endocrine organ through its unique ability to metabolize various dietary precursors, and can fuel the systemic inflammation observed in chronic disease. This is especially important in the setting of chronic kidney disease, in which microbial metabolism can contribute directly to accumulation of circulating toxins that then can alter and shift the balance of microbiota composition and downstream functions. To study this process, advances in -omics technologies are providing opportunities to understand not only the taxonomy, but also the functional diversity of our microbiome. We also reliably can quantify en masse a wide range of uremic byproducts of microbial metabolism. Herein, we examine the bidirectional relationship between the gut microbiome and the failing kidneys. We describe potential approaches targeting gut microbiota for cardiovascular risk reduction in chronic kidney disease using an illustrative example of a novel gut-generated metabolite, trimethylamine N-oxide.

Topics: Animals; Cardiovascular Diseases; Cresols; Diet Therapy; Dietary Supplements; Dysbiosis; Enzyme Inhibitors; Fatty Acids, Volatile; Gastrointestinal Microbiome; Humans; Indican; Inflammation; Methylamines; Renal Insufficiency, Chronic; Sulfuric Acid Esters; Toxins, Biological

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

Endoplasmic reticulum (ER) stress is a cellular state that results from the overload of unfolded/misfolded protein in the ER that, if not resolved properly, can lead to cell death. Both acute lung infections and chronic lung diseases have been found related to ER stress. Yet no study has been presented integrating metabolomic and transcriptomic data from total lung in interpreting the pathogenic state of ER stress. Total mouse lungs were used to perform LC-MS and RNA sequencing in relevance to ER stress. Untargeted metabolomics revealed 16 metabolites of aberrant levels with statistical significance while transcriptomics revealed 1593 genes abnormally expressed. Enrichment results demonstrated the injury ER stress inflicted upon lung through the alteration of multiple critical pathways involving energy expenditure, signal transduction, and redox homeostasis. Ultimately, we have presented p-cresol sulfate (PCS) and trimethylamine N-oxide (TMAO) as two potential ER stress biomarkers. Glutathione metabolism stood out in both omics as a notably altered pathway that believed to take important roles in maintaining the redox homeostasis in the cells critical for the development and relief of ER stress, in consistence with the existing reports.

Topics: Animals; Biomarkers; Cresols; Endoplasmic Reticulum Stress; Gene Expression Profiling; Glutathione; Lung; Lung Injury; Male; Metabolomics; Methylamines; Mice; Mice, Inbred C57BL; Oxidative Stress; Sulfuric Acid Esters; Unfolded Protein Response

Equine grass sickness (EGS) is a frequently fatal disease of horses, responsible for the death of 1 to 2% of the U.K. horse population annually. The etiology of this disease is currently uncharacterized, although there is evidence it is associated with Clostridium botulinum neurotoxin in the gut. Prevention is currently not possible, and ileal biopsy diagnosis is invasive. The aim of this study was to characterize the fecal microbiota and biofluid metabolic profiles of EGS horses, to further understand the mechanisms underlying this disease, and to identify metabolic biomarkers to aid in diagnosis. Urine, plasma, and feces were collected from horses with EGS, matched controls, and hospital controls. Sequencing the16S rRNA gene of the fecal bacterial population of the study horses found a severe dysbiosis in EGS horses, with an increase in Bacteroidetes and a decrease in Firmicutes bacteria. Metabolic profiling by

Topics: Acetylcarnitine; Animals; Bacteroidetes; Biomarkers; Clostridium botulinum; Cresols; Dysbiosis; Feces; Firmicutes; Gastrointestinal Microbiome; Hippurates; Horse Diseases; Horses; Magnetic Resonance Spectroscopy; Methylamines; RNA, Ribosomal, 16S; Sulfuric Acid Esters

In-center, extended duration nocturnal hemodialysis has been associated with variable clinical benefits, but the effect of extended duration hemodialysis on many established uremic solutes and other components of the metabolome is unknown. We determined the magnitude of change in metabolite profiles for patients on extended duration nocturnal hemodialysis.. In a 52-week prospective, observational study, we followed 33 patients receiving conventional thrice weekly hemodialysis who converted to nocturnal hemodialysis (7-8 hours per session, three times per week). A separate group of 20 patients who remained on conventional hemodialysis (3-4 hours per session, three times per week) served as a control group. For both groups, we applied liquid chromatography-mass spectrometry-based metabolite profiling on stored plasma samples collected from all participants at baseline and after 1 year. We examined longitudinal changes in 164 metabolites among those who remained on conventional hemodialysis and those who converted to nocturnal hemodialysis using Wilcoxon rank sum tests adjusted for multiple comparisons (false discovery rate <0.05).. On average, the nocturnal group had 9.6 hours more dialysis per week than the conventional group. Among 164 metabolites, none changed significantly from baseline to study end in the conventional group. Twenty-nine metabolites changed in the nocturnal group, 21 of which increased from baseline to study end (including all branched-chain amino acids). Eight metabolites decreased after conversion to nocturnal dialysis, including l-carnitine and acetylcarnitine. By contrast, several established uremic retention solutes, including. Across a wide array of metabolites examined, extended duration hemodialysis was associated with modest changes in the plasma metabolome, with most differences relating to metabolite increases, despite increased dialysis time. Few metabolites showed reduction with more dialysis, and no change in several established uremic toxins was observed.

Topics: Acetylcarnitine; Adult; Aged; Amino Acids, Branched-Chain; Case-Control Studies; Cresols; Female; Humans; Indican; Longitudinal Studies; Male; Metabolome; Methylamines; Middle Aged; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Sulfuric Acid Esters; Time Factors