Comparative analysis of renal dysfunction, immune remodeling, and gut microbiota profiles in dietary models of metabolic liver disease

Metabolic dysfunction–associated steatotic liver disease (MASLD) is increasingly recognized as a multisystem metabolic disorder accompanied by extrahepatic complications, including renal dysfunction. High-fat diet (HFD) and choline-deficient, L-amino acid–defined high-fat diet (CDAHFD) are widely used experimental models of MASLD; however, their comparative effects on hepatic and renal pathology, immune cell composition, and gut microbial profiles remain incompletely characterized. Male C57BL/6 mice were fed with a normal chow diet (NCD), HFD (16 weeks), or CDAHFD (8 weeks). Metabolic profiles, hepatic and renal histopathology, biochemical indices, and flow-cytometric immune cell analyses were performed. Parallel 16S rRNA sequencing and STAMP-based Welch’s t-tests were used to identify diet-specific alterations in microbial communities and functional pathways. Both dietary interventions induced steatosis and systemic metabolic disturbances, but CDAHFD provoked more severe hepatic inflammation, collagen deposition, and renal dysfunction. HFD-fed mice exhibited gradual hyperglycemia, dyslipidemia, and glomerular hypertrophy, whereas CDAHFD-fed mice developed acute hepatocellular injury accompanied by elevated blood urea nitrogen (BUN) and creatinine. Flow cytometric analysis revealed diet-specific differences in renal immune cell composition, with HFD favoring macrophage-dominant profiles and CDAHFD associated with increased inflammatory monocyte, dendritic cell, and T-cell proportions. Gut microbiota profiling demonstrated distinct compositional signatures between diets: HFD feeding was associated with increased relative abundance of Dubosiella newyorkensis and Faecalibaculum rodentium, whereas CDAHFD feeding was characterized by enrichment of Romboutsia ilealis and Kineothrix alysoides, accompanied by a pronounced reduction in microbial diversity. Distinct nutrient compositions elicited divergent immunometabolic and microbial responses across the gut–liver–kidney axis. HFD and CDAHFD produce disparate hepatic, renal, immune, and microbial phenotypes in mice, indicating unique metabolic injury mechanisms rather than synchronized disease stages. Although mechanistic inter-organ communication was not directly assessed, this comparative framework highlights the importance of dietary composition and injury kinetics when interpreting multi-organ outcomes in experimental MASLD models.