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

Beta diversity of the gut microbiome differed significantly between IgAN patients and healthy controls.

• Beta diversity differed significantly between IgAN and healthy controls (p = 0.001)
• Microbial profiling was performed using 16S rRNA-based methods on fecal samples
• The study included 172 IgAN patients and 51 healthy controls
• Additional glomerular disease controls included 15 diabetic nephropathy, 35 minimal change disease, and 63 membranous nephropathy cases

The methanogenesis from acetate pathway was significantly enriched in IgAN gut microbiome.

• No single taxon showed consistent differences in abundance between IgAN and controls
• The methanogenesis from acetate pathway was significantly enriched in IgAN
• An increased proportion of major acetate-producing gut microbial genera was observed in IgAN patients
• Pathway analysis was performed on 16S rRNA-based microbial profiling data

Serum acetate levels were elevated in IgAN patients compared to controls, while fecal acetate levels were comparable.

• Serum acetate levels were elevated in IgAN (p = 0.03)
• Fecal acetate levels were comparable to those in healthy controls
• Acetate levels were measured by liquid chromatography-mass spectrometry
• Both serum and fecal acetate were measured

Glomerular spatial transcriptomic profiling identified 1,227 upregulated and 1,078 downregulated genes in IgAN.

• Glomerular spatial transcriptomic profiling was performed with the GeoMx Digital Spatial Profiler
• DESeq2 analysis was used to identify differentially expressed genes
• 1,227 genes were upregulated and 1,078 genes were downregulated in IgAN glomeruli
• Gene ontology annotations were performed following DESeq2 analysis

Functional annotation of differentially expressed glomerular genes in IgAN indicated decreased activities of G protein-coupled receptors, short-chain fatty acid transporters, and beta-1,3-galactosyltransferases.

• Decreased activities of G protein-coupled receptors were indicated by downregulated gene annotations
• Short-chain fatty acid transporters showed decreased activity in IgAN glomeruli
• Beta-1,3-galactosyltransferases showed decreased activity, which may relate to the known aberrant IgA1 galactosylation in IgAN
• These findings were derived from gene ontology annotations of the 1,078 downregulated genes