The Gut-Kidney-GBM Axis: Emerging Evidence That Microbial Metabolites May Modify Glomerular Basement Membrane Perm-selectivity: A Systematic Review

Abstract

Introduction. The glomerular basement membrane (GBM) is the final filtration barrier in the kidney, and its dysfunction is 
central to nephrotic syndrome. Emerging evidence suggests that gut microbiota-derived metabolites directly modify GBM perm
selectivity, yet this axis remains underexplored.
Methods. We conducted a systematic review following PRISMA guidelines, searching PubMed, Scopus, Web of Science, Embase, 
and Cochrane Library from January 2000 to April 2026. Studies examining relationships between gut microbiota or microbial 
metabolites (indoxyl sulfate, TMAO, p-cresyl sulfate, SCFAs) and GBM structure/function were included.
Results. Mendelian randomization studies provide causal evidence linking Alistipes putredinis, Veillonellaceae, and 
RuminococcaceaeUCG002 to CKD risk. Indoxyl sulfate upregulates heparanase, degrading GBM heparan sulfate and disrupting charge selectivity. TMAO and p-cresyl sulfate activate AhR signaling, inducing aberrant sulfation patterns. Conversely, short-chain fatty acids (particularly butyrate) protect GBM via HDAC inhibition and Treg modulation. A novel gut-lymphatic-renal feedback loop involving Th17 cells explains treatment resistance in chronic nephrosis. Clinical studies suggest that AST-120 and probiotic supplementation may reduce proteinuria and improve eGFR, although heterogeneity across studies limits definitive conclusions.
Conclusions. The gut-kidney-GBM axis represents a bona fide pathophysiological pathway in nephrotic syndrome. Microbiome
targeted interventions represent promising but still investigational adjunctive strategies that require confirmatory human trials for preserving GBM integrity. Screening for gut dysbiosis and uremic toxins should guide personalized therapy in steroid-resistant nephrosis.