Gut Microbiota and Uremic Retention Solutes in Adults With Moderate CKD: A 6-Day Controlled Feeding Study.

To determine serum and urine concentrations of the uremic retention solutes (URSs), indoxyl sulfate (IS), p-cresol sulfate (PCS), and trimethylamine N-oxide (TMAO), and gut microbiota composition in individuals with moderate chronic kidney disease (CKD) compared with matched adults without CKD in a 6-day controlled feeding study. This study was a secondary analysis in which 8 adults with moderate CKD were matched for age, sex, and race with 8 adults without CKD in a parallel-arm, 6-day controlled feeding study. IS, PCS, and TMAO were quantified using liquid chromatography-mass spectrometry in fecal samples, fasting serum, and fasting spot urine samples collected at the end of the feeding period. Fasting serum URS concentrations were 2.8 to 4.9x higher in CKD compared to controls (all P < .05). No differences were found in the composition of the gut microbiota between patients with and without CKD when analyzing samples for α-diversity, β-diversity, and only minor abundance differences across taxa were apparent. Estimated glomerular filtration rate (eGFR) was inversely related to each serum URS in the whole cohort (all P < .01). However, within groups the relationships between eGFR and serum URS remained strong for CKD patients for IS and TMAO (both P < .05) but weakened for PCS (P = .10). eGFR was only correlated with urine PCS in the whole cohort (P = .03); within groups, no correlation for eGFR with any urine URS was observed. Only urine TMAO was higher in CKD compared to controls (P < .05). Serum URS concentrations are elevated in adults with CKD compared to matched non-CKD adults without differences in gut microbiota composition after consuming the same controlled study diet for 6 days. Future studies are needed to determine if specific dietary components may differentially alter the microbiota and URS.

Wiese GN ，Biruete A ，Stremke ER ，Lindemann SR ，Jannasch A ，Moorthi RN ，Moe SM ，Swanson KS ，Cross TW ，Hill Gallant KM ... -  《-》

Altered gut microbiota and gut-derived p-cresyl sulfate serum levels in peritoneal dialysis patients.

Peritoneal dialysis (PD) is a renal replacement therapy for end-stage renal disease. Gut microbiota-derived uremic solutes, indoxyl sulfate (IS), p-cresyl sulfate (PCS), and trimethylamine-N-oxide (TMAO) accumulate in PD patients. The objective was to explore the gut microbiota and their influence on uremic toxins in PD patients and healthy controls (HC). Fecal samples were collected from PD patients (n = 105) and HC (n = 102). 16S rRNA gene regions were sequenced for gut microbiota analysis. IS, PCS, and TMAO levels were measured using HPLC-MS. PD patients exhibited lower alpha diversity and altered gut microbiota composition compared to HC. At the genus level, PD patients showed increased abundance of opportunistic pathogenic bacteria, and decreased abundance of beneficial bacteria. Three Operational Taxonomic Units discriminated PD patients from HC. Phenylalanine metabolism increased in PD, whereas tryptophan metabolism was unaltered. Low serum PCS did not necessarily mean healthier due to the loss of alpha diversity, increased Proteobacteria and opportunistic pathogenic bacteria. High serum PCS was mainly caused by elevated p-cresol-producing bacteria, enriched amino acid related enzymes, and enhanced sulfur metabolism, rather than declined residual renal function. In patients with different urine volumes, the gut microbiota alpha diversity and composition were unaltered, but serum IS and TMAO were significantly elevated in anuric patients. In conclusion, the gut microbiota abundance, composition, and function were altered in PD patients, which increased the PCS levels. We provided a better understanding of the microbiota-metabolite-kidney axis in PD patients. Targeting certain bacteria could decrease the PCS levels, whereas preserving the residual renal function could reduce the IS and TMAO levels.

Bao M ，Zhang P ，Guo S ，Zou J ，Ji J ，Ding X ，Yu X ... -  《Frontiers in Cellular and Infection Microbiology》

The associations between nutrition and circulating gut microbiota-derived uremic toxins in patients undergoing kidney replacement therapy: An observational, cross-sectional study.

Gut microbiota generates a series of bioactive metabolites that can be converted into uremic toxins such as trimethylamine-N-oxide (TMAO), p-cresyl sulfate (pCS), and indoxyl sulfate (IS). The aim of the study was to examine the association between diet and the concentrations of the mentioned gut microbiota-derived uremic toxins. An observational cross-sectional study was conducted involving 210 participants: 84 hemodialysis (HD) patients, 44 peritoneal dialysis (PD) patients, 52 kidney transplant recipients (KTR), and 30 healthy controls. Dietary intake was assessed using a 3-day food diary and a food frequency questionnaire with 6 answers (FFQ-6). The alternate Mediterranean diet (aMED) score was calculated based on data obtained from the 3-day food diary and FFQ-6. Blood samples were analyzed for TMAO, pCS, and IS concentrations using liquid chromatography-mass spectrometry (LC-MS/MS). Significant differences in TMAO, pCS, and IS concentrations were observed among the study groups. HD and PD patients exhibited higher levels of these metabolites compared to KTR and healthy controls. The median aMED score was 4 (3-5) points in the HD group, 4.5 (4-6) points in the PD group, 5 (4-6) points in the KTRs, and 6 (5-7) points in the control group. Higher adherence to the Mediterranean diet (aMED score) was associated with lower pCS levels in dialysis patients. Vegetable intake several times a day was found to mitigate the effects of phenylalanine and tyrosine intake on pCS concentration among dialysis patients. The diet of patients undergoing kidney replacement therapy (KRT) significantly affects the concentrations of gut microbiota-derived uremic toxins. These findings highlight the importance of dietary management in mitigating the adverse effects of these toxins in patients with chronic kidney disease (CKD).

Czaja-Stolc S ，Potrykus M ，Ruszkowski J ，Styburski D ，Dębska-Ślizień A ，Małgorzewicz S ... -  《Clinical Nutrition ESPEN》

Alterations in gut-derived uremic toxins before the onset of azotemic chronic kidney disease in cats.

Although gut-derived uremic toxins are increased in azotemic chronic kidney disease (CKD) in cats and implicated in disease progression, it remains unclear if augmented formation or retention of these toxins is associated with the development of renal azotemia. Assess the association between gut-derived toxins (ie, indoxyl-sulfate, p-cresyl-sulfate, and trimethylamine-N-oxide [TMAO]) and the onset of azotemic CKD in cats. Forty-eight client-owned cats. Nested case-control study, comparing serum and urine gut-derived uremic toxin abundance at 6-month intervals between initially healthy cats that developed azotemic CKD (n = 22) and a control group (n = 26) that remained healthy, using a targeted metabolomic approach. Cats in the CKD group had significantly higher serum indoxyl-sulfate (mean [SD], 1.44 [1.06] vs 0.83 [0.46]; P = .02) and TMAO (mean [SD], 1.82 [1.80] vs 1.60 [0.62]; P = .01) abundance 6 months before the detection of azotemic CKD. Furthermore, logistic regression analysis indicated that indoxyl-sulfate (odds ratio [OR]: 3.2; 95% confidence interval [CI]: 1.2-9.0; P = .04) and TMAO (OR: 3.9; 95% CI: 1.4-11; P = .03) were predictors for the onset of azotemia 6 months before diagnosis. However, renal function biomarkers creatinine, symmetric dimethylarginine, and urinary specific gravity were significantly correlated with indoxyl-sulfate and TMAO abundance, causing a loss in predictive significance after correction for these factors. Impaired gut-derived uremic toxin handling is apparent at least 6 months before the diagnosis of azotemia, likely reflecting an already ongoing decrease in GFR, tubular function, or both. A direct causal relationship between gut-derived uremic toxicity and the initiation of CKD in cats is still lacking.

Van Mulders L ，Vanden Broecke E ，De Paepe E ，Mortier F ，Vanhaecke L ，Daminet S ... -  《-》

Gut microbiota generation of protein-bound uremic toxins and related metabolites is not altered at different stages of chronic kidney disease.

Chronic kidney disease (CKD) is characterized by accumulation of protein-bound uremic toxins such as p-cresyl sulfate, p-cresyl glucuronide, indoxyl sulfate and indole-3-acetic acid, which originate in the gut. Intestinal bacteria metabolize aromatic amino acids into p-cresol and indole, (further conjugated in the colon mucosa and liver) and indole-3-acetic acid. Here we measured fecal, plasma and urine metabolite concentrations; the contribution of gut bacterial generation to plasma protein-bound uremic toxins accumulation; and influx into the gut of circulating protein-bound uremic toxins at different stages of CKD. Feces, blood and urine were collected from 14 control individuals and 141 patients with CKD. Solutes were quantified by ultra-high performance liquid chromatography. To assess the rate of bacterial generation of p-cresol, indole and indole-3-acetic acid, fecal samples were cultured ex vivo. With CKD progression, an increase in protein-bound uremic toxins levels was observed in plasma, whereas the levels of these toxins and their precursors remained the same in feces and urine. Anaerobic culture of fecal samples showed no difference in ex vivo p-cresol, indole and indole-3-acetic acid generation. Therefore, differences in plasma protein-bound uremic toxins levels between different CKD stages cannot be explained by differences in bacterial generation rates in the gut, suggesting retention due to impaired kidney function as the main contributor to their increased plasma levels. Thus, as fractional clearance decreased with the progression of CKD, tubular clearance appeared to be more affected than the glomerular filtration rate, and there was no net increase in protein-bound uremic toxins influx into the gut lumen with increased plasma levels.

Gryp T ，De Paepe K ，Vanholder R ，Kerckhof FM ，Van Biesen W ，Van de Wiele T ，Verbeke F ，Speeckaert M ，Joossens M ，Couttenye MM ，Vaneechoutte M ，Glorieux G ... -  《-》