Altered acetate metabolism and signaling in IgA nephropathy: an integrated gut microbiome and glomerular spatial transcriptome analysis

Introduction: IgA nephropathy (IgAN) is the most common primary glomerulonephritis, and emerging evidence implicates the gut microbiome in its pathogenesis. Additional studies focusing on the molecular mechanisms linking gut microbial signals to intraglomerular changes are warranted. Methods: We performed 16S rRNA-based microbial profiling of fecal samples of 172 IgAN patients, 51 healthy controls, and other glomerular disease controls including 15 diabetic nephropathy, 35 minimal change disease, and 63 membranous nephropathy cases. Serum and fecal acetate levels were measured by liquid chromatography–mass spectrometry. Glomerular spatial transcriptomic profiling was performed with the GeoMx Digital Spatial Profiler. DESeq2 analysis was performed to identify differentially expressed genes, followed by gene ontology annotations. Results: Beta diversity differed significantly between IgAN and healthy controls (p = 0.001). While no single taxon showed consistent differences in abundance, the methanogenesis from acetate pathway was significantly enriched in IgAN, accompanied by an increased proportion of major acetate-producing gut microbial genera. Serum acetate levels were elevated in IgAN (p = 0.03), while fecal acetate levels were comparable to those in healthy controls. In glomerular transcriptomes, functional annotations of 1,227 upregulated and 1,078 downregulated genes in IgAN indicated decreased activities of G protein-coupled receptors, short-chain fatty acid transporters, and beta-1,3-galactosyltransferases. Discussion: IgAN is characterized by gut microbial enrichment in acetate metabolism and increased systemic acetate levels, along with altered intraglomerular expression of metabolic and signaling genes. These findings suggest a gut microbiome–glomerular signaling axis contributing to disease pathogenesis.