Gut-Derived Metabolomic Biomarkers as Mediators of the Inflammatory Pathway in Early Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a major complication of type 2 diabetes mellitus (T2DM) and a leading cause of morbidity and mortality. Both metabolic and inflammatory pathways have emerged as potential sources of biomarkers that may improve DKD detection and treatment. This study investigated the relationship between gut-derived metabolites, such as acylcarnitines (ACs), uremic toxins (UTs), polyol pathway intermediates (PIs), and amino acid derivatives (AADs), and renal inflammation markers, detected in serum and urine. It included 20 healthy controls and 90 patients with T2DM, divided into normoalbuminuria, microalbuminuria, and macroalbuminuria. Serum and urine metabolites were analyzed using untargeted and targeted metabolomic assessments, whereas inflammatory markers were quantified using the ELISA technique. Statistical analysis consisted of descriptive statistics followed by univariable and multivariable linear regression analyses. Our findings revealed that serum AADs contribute to renal fibrosis progression, whereas urinary AADs indicate impaired tubular reabsorption in inflammatory conditions. Additionally, UTs and PIs are linked to inflammatory processes mediated by TNF-α but not by early renal fibrosis, whereas serum ACs appear to modulate immune responses, exerting pro-inflammatory and cytotoxic effects on tubular epithelial cells in early DKD. Thus, the metabolic and inflammatory pathways are tightly interconnected and synergistically contribute to the pathogenesis of early DKD.