Microbiota-Associated Metabolites as Immunometabolic Regulators of Glomerular Inflammation: Disease-Specific Mechanisms and Therapeutic Opportunities

Background

Immunoglobulin A nephropathy (IgAN), membranous nephropathy (MN), and lupus nephritis (LN) are immune-mediated glomerular diseases in which dysregulated adaptive immunity converges with innate inflammatory and filtration-barrier injury. Clinical relapse and incomplete recovery despite upstream immune control motivate investigation of additional injury modifiers. Main body: This review evaluates five microbiota-associated metabolite families-short-chain fatty acids (SCFAs), tryptophan-derived metabolites, aromatic amino acid-derived uremic solutes, trimethylamine N-oxide (TMAO), and bile acids-across three modules: immune-tolerance failure, innate inflammatory amplification, and filtration-barrier disruption. In IgAN, multi-omics data showing preserved or elevated systemic acetate with reduced glomerular free fatty acid receptor 2/3 (FFAR2/FFAR3)-associated signaling suggest impaired renal SCFA sensing, but do not establish receptor competence as the dominant target. In MN, disease-specific studies support podocyte injury mediated by complement C3a and its receptor (C3a/C3aR) and complement-associated NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-caspase-1-gasdermin D (GSDMD) pyroptosis as related injury processes, whereas proposed SCFA-regulatory T cell (Treg)-B-cell and SCFA-inflammasome interactions remain largely hypothesis-generating; experimental Lactobacillus-indole-aryl hydrocarbon receptor (AhR) data provide preliminary evidence. In LN, microbiota-dependent tryptophan pathway perturbation and treatment-associated metabolomic changes support the kynurenine-to-tryptophan ratio as a readily measurable candidate biomarker requiring prospective validation. Across diseases, interpretation requires separating microbial production from renal retention, metabolite abundance from receptor signaling competence, and total from unbound exposure for protein-bound solutes.