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Abstract: FR-PO696

Glomerular Spatial Transcriptomics and Integrated Gut Microbiome Analysis Reveals Pathogenetic Importance of Short-Chain Fatty Acid in IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Park, Sehoon, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)
  • Cho, Jeongmin, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)
  • Koh, Jung Hun, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)
  • Kim, Dong Ki, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)
  • Lee, Hajeong, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of)
Background

IgA nephropathy (IgAN) is the most common primary glomerulonephritis, and the pathogenesis has been reported to be related to the gut microbiome. Additional studies focusing on the linkage between intra-glomerular transcriptomic alterations and associated microbial signals are warranted.

Methods

We performed glomerular spatial transcriptomic profiling of various glomerulopathies without a profound eGFR decrease and healthy controls using the GeoMx Digital Spatial Profiler. This included 8 IgAN, 10 donor kidney biopsy, 6 diabetic nephropathy, 7 focal segmental glomerulosclerosis, 13 minimal change disease, and 16 membranous nephropathy cases. The glomerular transcriptome was compared between the IgAN and each control group using the DeSeq2 method, and gene ontology annotation was performed. For microbial profiling, fecal samples were collected from 247 IgAN, 52 diabetic nephropathy, 27 lupus nephritis, 42 minimal change disease, 72 membranous nephropathy, and 51 healthy control cases and underwent 16S-sequencing. PICRUSt2 analysis was used to predict metagenome functions, which were compared by ALDEx2 between the groups.

Results

We identified 1209 consistently highly expressed genes in the IgAN glomerulus, mainly annotated in major histocompatibility protein binding, immune cell adhesion, and extracellular matrix formation gene ontologies. On the other hand, 1050 genes were consistently lowly expressed in the IgAN glomerulus. Notably, the annotated gene ontologies included beta 1,3 galactosyltransferase and short-chain fatty acid transporters or G protein-coupled receptor signaling pathways. Although there was an absence of a single taxa consistently showing a significant difference in the IgAN microbial community, the pathway analysis indicated that the methanogenesis from acetate pathway was significantly abundant in the IgAN gut microbiome.

Conclusion

We identified that short-chain fatty acid and related signal receptors, G-protein-coupled receptors, were significantly lowly expressed in the IgAN glom, linked to the alteration of acetate, a representative short-chain fatty acid, metabolism pathway in the IgAN microbiome. Further experimental validation studies are ongoing to investigate the pathogenetic significance of the current findings.