The impact of alterations in intestinal microbiota on microbial metabolites and on disease processes, such as graft-versus-host disease (GVHD), is not known. Here we performed unbiased analysis to identify novel alterations in gastrointestinal microbiota-derived short chain fatty acids (SCFA) after allogeneic bone marrow transplant (allo-BMT). Alterations in the amounts of only one SCFA, butyrate, were observed only within the intestinal tissue. The reduced butyrate in CD326+ intestinal epithelial cells (IECs) after allo-BMT resulted in decreased histone acetylation, which was restored upon local administration of exogenous butyrate. Butyrate restoration improved IEC junctional integrity, decreased apoptosis, and mitigated GVHD. Furthermore, alteration of the indigenous microbiota with 17 rationally selected strains of high butyrate producing Clostridia also decreased GVHD. These data demonstrate a heretofore unrecognized role of microbial metabolites and suggest that local and specific alteration of microbial metabolites has direct salutary effects on GVHD target tissues and can mitigate its severity.
Diabetic kidney disease is the leading cause of ESRD, but few biomarkers of diabetic kidney disease are available. This study used gas chromatography-mass spectrometry to quantify 94 urine metabolites in screening and validation cohorts of patients with diabetes mellitus (DM) and CKD(DM+CKD), in patients with DM without CKD (DM-CKD), and in healthy controls. Compared with levels in healthy controls, 13 metabolites were significantly reduced in the DM+CKD cohorts (P#0.001), and 12 of the 13 remained significant when compared with the DM-CKD cohort. Many of the differentially expressed metabolites were water-soluble organic anions. Notably, organic anion transporter-1 (OAT1) knockout mice expressed a similar pattern of reduced levels of urinary organic acids, and human kidney tissue from patients with diabetic nephropathy demonstrated lower gene expression of OAT1 and OAT3. Analysis of bioinformatics data indicated that 12 of the 13 differentially expressed metabolites are linked to mitochondrial metabolism and suggested global suppression of mitochondrial activity in diabetic kidney disease. Supporting this analysis, human diabetic kidney sections expressed less mitochondrial protein, urine exosomes from patients with diabetes and CKD had less mitochondrial DNA, and kidney tissues from patients with diabetic kidney disease had lower gene expression of PGC1a (a master regulator of mitochondrial biogenesis). We conclude that urine metabolomics is a reliable source for biomarkers of diabetic complications, and our data suggest that renal organic ion transport and mitochondrial function are dysregulated in diabetic kidney disease.
Evidence for a link between gut microbiota and hypertension in the Dahl rat. Physiol Genomics 47: 187-197, 2015. First published March 31, 2015 doi:10.1152/physiolgenomics.00136.2014.-The gut microbiota plays a critical role in maintaining physiological homeostasis. This study was designed to evaluate whether gut microbial composition affects hypertension. 16S rRNA genes obtained from cecal samples of Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats were sequenced. Bacteria of the phylum Bacteroidetes were higher in the S rats compared with the R rats. Furthermore, the family S24-7 of the phylum Bacteroidetes and the family Veillonellaceae of the phylum Firmicutes were higher in the S rats compared with the R rats. Analyses of the various phylogenetic groups of cecal microbiota revealed significant differences between S and R rats. Both strains were maintained on a high-salt diet, administered antibiotics for ablation of microbiota, transplanted with S or R rat cecal contents, and monitored for blood pressure (BP). Systolic BP of the R rats remained unaltered irrespective of S or R rat cecal transplantation. Surprisingly, compared with the S rats given S rat cecal content, systolic BP of the S rats given a single bolus of cecal content from R rats was consistently and significantly elevated during the rest of their life, and they had a shorter lifespan. A lower level of fecal bacteria of the family Veillonellaceae and increased plasma acetate and heptanoate were features associated with the increased BP observed in the S rats given R rat microbiota compared with the S rats given S rat microbiota. These data demonstrate a link between microbial content and BP regulation and, because the S and R rats differ in their genomic composition, provide the necessary basis to further examine the relationship between the host genome and microbiome in the context of BP regulation in the Dahl rats. gut; microbial; SCFA; metabolic; metabolomics THE MAINTENANCE OF blood pressure (BP) homeostasis is a complex process that is carefully orchestrated by a variety of genetic and environmental factors and studied extensively in rat models (2, 5, 11, 15-17, 19, 21-23, 26, 42-44, 50). Dietary salt is one of the prominent environmental factors influencing the development and progression of salt-sensitive hypertension (13,14,24,57). As the consumed salt is transported through the gastrointestinal tract, one of the anatomical sites through which it is absorbed, in addition to the small intestine and the colon, is the cecum. The functions of the cecum are to absorb fluids and salts that remain after completion of intestinal digestion and absorption and to mix its contents with a lubricating substance, mucus. The cecum is also an "anerobic fermentor" as it houses a large number of bacteria that aid in digestion of undigested material in the stomach and small intestine. This is accomplished by a fermentative process that helps in breaking down fibers for their survival (33).In recent years, there is ample evidence in the literature ...
The mechanisms underlying the association between obesity and progressive renal disease are not well understood. Exposure to a high-fat diet decreases levels of the cellular energy sensor AMPK in many organs, including the kidney, but whether AMPK contributes to the pathophysiology of kidney disease induced by a high-fat diet is unknown. In this study, we randomly assigned C57BL/6J mice to a standard or high-fat diet. After 1 week, mice fed a high-fat diet exhibited an increase in body weight, renal hypertrophy, an increase in urine H 2 O 2 and urine MCP-1, and a decrease in circulating adiponectin levels and renal AMPK activity. Urine ACR progressively increased after 4 weeks of a high-fat diet. After 12 weeks, kidneys of mice fed a high-fat diet demonstrated a marked increase in markers of fibrosis and inflammation, and AMPK activity remained significantly suppressed. To determine whether inhibition of AMPK activity explained these renal effects, we administered an AMPK activator along with a high-fat diet for 1 week. Although AMPK activation did not abrogate the weight gain, it reduced the renal hypertrophy, urine H 2 O 2 , and urine and renal MCP-1. In vitro, AMPK activation completely inhibited the induction of MCP-1 by palmitic acid in mesangial cells. In conclusion, these data suggest that the energy sensor AMPK mediates the early renal effects of a high-fat diet. Obesity has been dramatically increasing in the United States and worldwide. Between 1999 and 2004, 32.2% of all adults in the United States were obese (body mass index Ͼ 30 kg/m 2 ) 1 and the prevalence of obesity is expected to reach 50% by 2030. Obesity is the major risk factor for the metabolic syndrome, characterized by insulin resistance, dyslipidemia, and hypertension. 2 Obesity in association with insulin resistance contribute to the development of cardiovascular disease and diabetes. Furthermore, obesity is now being increasingly recognized as a major and independent risk factor for the development of kidney disease. [3][4][5] In the general population, obesity was the second most highly predictive factor to predict ESRD, even independent of diabetes and hypertension. 6 Clinical and experimental studies have demonstrated that the characteristic features of obesity-induced kidney injury include glomerular hypertrophy, thickening of the glomerular basement membrane, mesangial matrix expansion, and increased renal inflammation. [7][8][9][10] These alterations likely contribute to albuminuria, a progressive decline in renal function and ultimately glomerulosclerosis and tubulointerstitial fibrosis. 7-10 Despite the public health and clinical implications of the relationships between obesity and kidney injury, the signaling pathways leading to renal pathology with obesity are not well understood.
Here we studied plasma metabolomic profiles as determinants of progression to ESRD in patients with Type 2 diabetes (T2D). This nested case-control study evaluated 40 cases who progressed to ESRD during 8-12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics; although controls had slightly higher eGFR and lower levels of urinary albumin excretion than T2D cases. Plasma metabolites at baseline were measured by mass spectrometry-based global metabolomic profiling. Of the named metabolites in the library, 262 were detected in at least 80% of the study patients. The metabolomic platform recognized 78 metabolites previously reported to be elevated in ESRD (uremic solutes). Sixteen were already elevated in the baseline plasma of our cases years before ESRD developed. Other uremic solutes were either not different or not commonly detectable. Essential amino acids and their derivatives were significantly depleted in the cases, whereas certain amino acid-derived acylcarnitines were increased. All findings remained statistically significant after adjustment for differences between study groups in albumin excretion rate, eGFR or HbA1c. Uremic solute differences were confirmed by quantitative measurements. Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D.
Objective Oxidative stress and oxidized high-density lipoprotein (oxHDL) are implicated as risk factors for cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Yet, how HDL is oxidized and rendered dysfunctional in SLE remains unclear. Neutrophil extracellular traps (NETs), which are elevated in lupus, possess oxidant-generating enzymes including myeloperoxidase (MPO), NADPH oxidase (NOX) and nitric oxide synthase (NOS). We hypothesized that NETs mediate HDL oxidation, impairing cholesterol efflux capacity (CEC). Methods Control and lupus plasma MPO levels and CEC activity were examined; 3-chlorotyrosine (MPO-specific) and 3-nitrotyrosine (derived from reactive nitrogen species) were quantified in human HDL. Multivariable linear models estimated and tested differences between groups. HDL was exposed to NETs from control and lupus neutrophils in the presence or absence of MPO, NOX, NOS inhibitors and chloroquine. Murine HDL oxidation was quantified after NET inhibition in vivo. Results SLE subjects displayed higher MPO levels and diminished CEC. SLE HDL had higher 3-nitrotyrosine and 3-chlorotyrosine content, with site-specific oxidation signatures on apoA1. Experiments with human and murine NETs confirmed that chlorination is mediated by MPO and NOX, and nitration by NOS and NOX. Lupus mice treated with the NET-inhibitor Cl-amidine displayed significantly decreased oxHDL. Chloroquine inhibited NET formation in vitro. Conclusion Active NOS, NOX and MPO within NETs significantly modify HDL, rendering the lipoprotein proatherogenic. As NET formation is enhanced in SLE, these findings support a novel role for NET-derived lipoprotein oxidation in SLE-associated CVD and identify additional proatherogenic roles of neutrophils and putative protective roles of antimalarials in autoimmunity.
Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebocontrolled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m 2 ). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (ϩ3.3 Ϯ 8.5 ml/min per 1.73 m 2 ) whereas the mean eGFR decreased in the placebo group (Ϫ2.2 Ϯ 4.8 ml/min per 1.73 m 2 ; P ϭ 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (Ϫ1.9 Ϯ 6.7 ml/min per 1.73 m 2 ). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P ϭ 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.
OBJECTIVEPatients with type 1 diabetes (T1D) with impaired renal function are at increased risk for end-stage renal disease (ESRD). Although the rate of progression varies, determinants and mechanisms of this variation are unknown.RESEARCH DESIGN AND METHODSWe examined serum metabolomic profiles associated with variation in renal function decline in participants with T1D (the Joslin Kidney Study prospective cohort). One hundred fifty-eight patients with proteinuria and chronic kidney disease stage 3 were followed for a median of 11 years to determine estimated glomerular filtration rate slopes from serial measurements of serum creatinine and to ascertain time to onset of ESRD. Baseline serum samples were subjected to global metabolomic profiling.RESULTSOne hundred ten amino acids and purine and pyrimidine metabolites were detected in at least 80% of participants. Serum levels of seven modified metabolites (C-glycosyltryptophan, pseudouridine, O-sulfotyrosine, N-acetylthreonine, N-acetylserine, N6-carbamoylthreonyladenosine, and N6-acetyllysine) were associated with renal function decline and time to ESRD (P < 0.001) independent of the relevant clinical covariates. The significant metabolites correlated with one another and with the indices of tubular injury.CONCLUSIONSThis prospective cohort study in participants with T1D, proteinuria, and impaired renal function at baseline demonstrated that patients with increased circulating levels of certain modified metabolites experience faster renal function decline, leading to ESRD. Whether some of these candidate metabolites are risk factors or just prognostic biomarkers of progression to ESRD in T1D needs to be determined.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.