Diet-Specific Microbial Rewiring Governs Immune Activation Across the Gut—Liver—Kidney Axis in Experimental MASLD 2303975

Abstract Introduction Metabolic dysfunction—associated steatotic liver disease (MASLD) often advances beyond hepatosteatosis to systemic immune dysregulation and kidney injury, yet the ways in which different dietary models reprogram immunometabolic circuits remain poorly defined. To test this, we directly compared two widely used MASLD models, prolonged high-fat diet (HFD) and the rapidly injurious choline-deficient, L-amino-acid—defined high-fat diet (CDAHFD), to delineate diet-specific immunopathogenic signatures. Methods C57BL/6 mice were fed either a 16-week high-fat diet (HFD) or an 8-week choline-deficient, L-amino-acid—defined high-fat diet (CDAHFD). We assessed systemic metabolic markers (ALT, AST, BUN, creatinine), histopathologic injury (H&E, Picrosirius Red, PAS), renal immune composition (Ly6C+ monocytes, dendritic cells, and T-cell subsets), and gut microbiota structure (16S rRNA sequencing analyzed with STAMP using Welch’s test). Results The CDAHFD regimen induced a hyperacute immunometabolic profile manifesting as profound hepatocellular damage and marked renal tubular degeneration. This pathological state was associated with a robust infiltration of CD11b+Ly6C+ inflammatory monocytes and cytotoxic CD8+ T cells–an immunophenotype distinct from that observed in the HFD cohort. Microbiome profiling identified a CDAHFD-specific dysbiosis defined by the expansion of Kineothrix alysoides, a taxon linked to gut barrier disruption and endotoxemia, suggesting a mechanism driving enhanced renal immune activation. In distinct contrast, HFD favored the retention of gut taxa implicated in the preservation of epithelial integrity, the attenuation of hepatic inflammation, and the modulation of renal immune responses. Conclusion Despite its shorter duration, CDAHFD provoked a markedly more aggressive and microbiota-amplified immunopathology across the gut—liver—kidney axis than HFD. These findings reveal diet-specific immune—microbial signatures that shape the MASLD—CKD trajectory. Funding Source 111-2314-B-A49-072, NSTC 112-2314-B-A49 -028 -MY3 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)