Effect of dietary synbiotic supplementation on serum indoxyl sulfate in prevalent hemodialysis patients

Background Indoxyl sulfate (IS) is produced by action of the intestinal flora on tryptophan in protein diet, and it is normally excreted by the kidney. IS is a protein-bound uremic toxin, and it is difficult to be removed by conventional hemodialysis (HD) methods; so, it accumulates in HD patients and may contribute to major cardiovascular morbidity and mortality. Aim To study the effect of dietary synbiotic (prebiotic and probiotic) supplementation on IS level in prevalent HD patients. Patients and methods This single-blind, placebo-controlled trial was conducted on 80 prevalent HD patients (between January 2017 and March 2017) in Ain Shams University Hospital. Patients were divided into 2 groups: group 1 was given synbiotic (SYN) and group 2 was given placebo for 6 weeks. Blood levels of IS, CRP, creatinine, blood urea nitrogen (BUN), sodium, potassium, calcium, and phosphorus were measured at baseline and after 6 weeks. Results There was a significant reduction in serum IS level in groups 1 and 2 in comparison to their baselines (P value = 0.000 and 0.019 respectively); however, the change in IS level in group 1 after SYN supplementation (64% with IR 72.38–33.33) was more than that shown in group 2 (did not receive SYN) (18.47% with IR 26.75–26.75) with a highly significant P value, 0.000. Also, there were significant reductions in the levels of creatinine, BUN, phosphorus (P values < 0.001), and CRP (P values 0.002) in group 1 respectively with no similar changes noticed in group 2. Conclusion SYN supplementation in HD patients can reduce serum levels of IS and other uremic toxins like BUN and creatinine. Also, it may help to reduce serum phosphorus and CRP levels.

Association between Cardiac Outcomes and Indoxyl Sulfate Levels in Hemodialysis Patients: A Cross-sectional Study

Objective Indoxyl sulfate (IS) is a protein-bound uremic toxin that is associated with cardiovascular events and mortality in hemodialysis (HD) patients. However, the factors affecting the levels of IS are currently unclear. This study aimed to investigate the factors influencing serum IS concentrations in HD patients. Methods We included 100 HD patients from Guangdong Provincial People’s Hospital. Baseline characteristics, including sex, age, clinical features, duration of HD, echocardiography findings, electrocardiogram results, and biochemical indicators, were collected and analyzed in relation to serum total-form IS levels. Results Among all 100 patients, serum IS levels were significantly higher in patients aged ≥ 60 years, males, and patients with mitral regurgitation and inadequate dialysis. Among patients aged < 60 years, IS levels were significantly higher among patients with mitral regurgitation compared with those without. Furthermore, multiple linear regression analysis identified sex, age, ventricular septal thickness, and mitral regurgitation as factors independently associated with serum IS (STDβ = −0.475, 0.162, −0.153, 0.142, and 0.136, respectively; all P < 0.05) adjusted for body mass index, smoking, and fasting plasma glucose. Conclusions Male sex, age ≥ 60 years, ventricular septal thickness, and mitral regurgitation are factors associated with high total serum IS concentrations in Chinese HD patients. Elevated IS levels may play a role in the process of mitral regurgitation in HD patients < 60 years old.

Indoxyl Sulfate Contributes to mTORC1-Induced Renal Fibrosis via The OAT/NADPH Oxidase/ROS Pathway

Activation of mTORC1 (mechanistic target of rapamycin complex 1) in renal tissue has been reported in chronic kidney disease (CKD)-induced renal fibrosis. However, the molecular mechanisms responsible for activating mTORC1 in CKD pathology are not well understood. The purpose of this study was to identify the uremic toxin involved in mTORC1-induced renal fibrosis. Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS) caused significant activation of mTORC1 in human kidney 2 cells (HK-2 cells). This IS-induced mTORC1 activation was inhibited in the presence of an organic anion transporter inhibitor, a NADPH oxidase inhibitor, and an antioxidant. IS also induced epithelial–mesenchymal transition of tubular epithelial cells (HK-2 cells), differentiation of fibroblasts into myofibroblasts (NRK-49F cells), and inflammatory response of macrophages (THP-1 cells), which are associated with renal fibrosis, and these effects were inhibited in the presence of rapamycin (mTORC1 inhibitor). In in vivo experiments, IS overload was found to activate mTORC1 in the mouse kidney. The administration of AST-120 or rapamycin targeted to IS or mTORC1 ameliorated renal fibrosis in Adenine-induced CKD mice. The findings reported herein indicate that IS activates mTORC1, which then contributes to renal fibrosis. Therapeutic interventions targeting IS and mTORC1 could be effective against renal fibrosis in CKD.

Indoxyl Sulfate Elevated Lnc-SLC15A1-1 Upregulating CXCL10/CXCL8 Expression in High-Glucose Endothelial Cells by Sponging MicroRNAs

Cardiovascular disease (CVD) is the leading cause of mortality in diabetes mellitus (DM). Immunomodulatory dysfunction is a primary feature of DM, and the emergence of chronic kidney disease (CKD) in DM abruptly increases CVD mortality compared with DM alone. Endothelial injury and the accumulation of uremic toxins in the blood of DM/CKD patients are known mechanisms for the pathogenesis of CVD. However, the molecular factors that cause this disproportional increase in CVD in the DM/CKD population are still unknown. Since long non-protein-coding RNAs (lncRNAs) play an important role in regulating multiple cellular functions, we used human endothelial cells treated with high glucose to mimic DM and with the uremic toxin indoxyl sulfate (IS) to mimic the endothelial injury associated with CKD. Differentially expressed lncRNAs in these conditions were analyzed by RNA sequencing. We discovered that lnc-SLC15A1-1 expression was significantly increased upon IS treatment in comparison with high glucose alone, and then cascaded the signal of chemokines CXCL10 and CXCL8 via sponging miR-27b, miR-297, and miR-150b. This novel pathway might be responsible for the endothelial inflammation implicated in augmenting CVD in DM/CKD and could be a therapeutic target with future clinical applications.

High-coverage metabolomics uncovers microbiota-driven biochemical landscape of interorgan transport and gut-brain communication in mice

The mammalian gut harbors a complex and dynamic microbial ecosystem: the microbiota. While emerging studies support that microbiota regulates brain function with a few molecular cues suggested, the overall biochemical landscape of the “microbiota-gut-brain axis” remains largely unclear. Here we use high-coverage metabolomics to comparatively profile feces, blood sera, and cerebral cortical brain tissues of germ-free C57BL/6 mice and their age-matched conventionally raised counterparts. Results revealed for all three matrices metabolomic signatures owing to microbiota, yielding hundreds of identified metabolites including 533 altered for feces, 231 for sera, and 58 for brain with numerous significantly enriched pathways involving aromatic amino acids and neurotransmitters. Multicompartmental comparative analyses single out microbiota-derived metabolites potentially implicated in interorgan transport and the gut-brain axis, as exemplified by indoxyl sulfate and trimethylamine-N-oxide. Gender-specific characteristics of these landscapes are discussed. Our findings may be valuable for future research probing microbial influences on host metabolism and gut-brain communication.