Metabolites Potentially Derived from Gut Microbiota Associated with Podocyte, Proximal Tubule, and Renal and Cerebrovascular Endothelial Damage in Early Diabetic Kidney Disease in T2DM Patients

Abstract

Complications due to type 2 diabetes mellitus (T2DM) such as diabetic kidney disease (DKD) and cerebral small vessel disease (CSVD) have a powerful impact on mortality and morbidity. Our current diagnostic markers have become outdated as T2DM-related complications continue to develop. The aim of the investigation was to point out the relationship between previously selected metabolites which are potentially derived from gut microbiota and indicators of endothelial, proximal tubule (PT), and podocyte dysfunction, and neurosonological indices. The study participants were 20 healthy controls and 90 T2DM patients divided into three stages: normoalbuminuria, microalbuminuria, and macroalbuminuria. Serum and urine metabolites were determined by untargeted and targeted metabolomic techniques. The markers of endothelial, PT and podocyte dysfunction were assessed by ELISA technique, and the neurosonological indices were provided by an ultrasound device with high resolution (MYLAB 8-ESAOTE Italy). The descriptive statistical analysis was followed by univariable and multivariable linear regression analyses. In conclusion, in serum, arginine (sArg), butenoylcarnitine (sBCA), and indoxyl sulfate (sIS) expressed a biomarker potential in terms of renal endothelial dysfunction and carotid atherosclerosis, whereas sorbitol (sSorb) may be a potential biomarker of blood–brain barrier (BBB) dysfunction. In urine, BCA and IS were associated with markers of podocyte damage, whereas PCS correlated with markers of PT dysfunction.

Metabolome-wide Mendelian randomization reveals causal effects of betaine and N-acetylornithine on impairment of renal function

“…In the recent decade, metabolomics has been applied to explore the relationship between blood metabolomic profiling and kidney disease ( 17 ). Several metabolic studies indicated that some metabolites such as tiglylcarnitine, kynurenine, arginine metabolites and tryptophan-related metabolism identified from serum or urine samples may be related with progression of CKD ( 4 , 5 , 18 ). But it is not easy to determine the causal association using cress-sectional or longitudinal observational studies due to high costs for measurements of all blood metabolites and the difficulty in explaining the intrinsic relationships.…”

“…Metabolites, produced by upstream genes and proteins, may act as important nutrients or harmful products for human health. Previous studies indicated some gut microbiota derived metabolites such as arginine ( 4 ), butenoylcarnitine ( 5 ) and tryptophan metabolism ( 6 ) may participate in the development of chronic kidney disease, underlying the associations between blood metabolites and renal function. Identification of blood metabolites beneficial to renal function may provide novel insight into renal nutrition treatment.…”