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Abstract: SA-PO649

Intestinal Dysbiosis of Mucin-Degrading Bacteria Causes IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation


  • Gleeson, James, INSERM, Paris, Île-de-France, France
  • Chemouny, Jonathan M., INSERM, Paris, Île-de-France, France
  • Benech, Nicolas, INSERM, Paris, Île-de-France, France
  • Metallinou, Eleftheria Theodora, INSERM, Paris, Île-de-France, France
  • Sannier, Aurelie, INSERM, Paris, Île-de-France, France
  • Daugas, Eric, INSERM, Paris, Île-de-France, France
  • Vrtovsnik, Francois, INSERM, Paris, Île-de-France, France
  • Sokol, Harry, INSERM, Paris, Île-de-France, France
  • Monteiro, Renato C., INSERM, Paris, Île-de-France, France

IgA nephropathy (IgAN) is characterized by glomerular deposition of deglycosylated IgA1 (dg-IgA1) bound by autoreactive antibodies. Genome wide association studies and clinical observations implicate the mucosal immune system in disease pathogenesis. We sought to investigate host-microbiota interactions in IgAN.


Faecal samples from IgAN patients (IgAN, n=33), healthy controls (HC, n=65) and disease controls with other causes of CKD (CKD, n=20) were analysed by 16S rRNA DNA sequencing. CaCo-2 cells were used in vitro while C57BL/6J and humanized a1KI-CD89tg mice were used for in vivo experiments. Immunofluorescence microscopy quantified IgA and C3 deposition, RT-PCR quantified gene expression, ELISA quantified proteins. IgA1 glycosylation was measured by HAA lectin, dg-IgA1 specific antibody (KM55, IBL) and mass spectrometry.


Compared to HC and CKD, the intestinal microbiota of IgAN had altered b-diversity (p=0.001, p=0.02) and increased abundance of Akkermansia muciniphila (p=0.001, p=0.03). A. muciniphila (AKK) consistently deglycosylated human IgA1 (p=0.0007); dg-IgA1 passed retrogradely from the luminal to systemic side of mucosal tissue both in vitro and in vivo. Glomerular deposits of IgA1 were found in AKK, but not E. coli, colonised wt mice after oral gavage with exogenous IgA1 (p<0.001). Colonization of a1KI-CD89tg mice with AKK induced an aggravated IgAN phenotype whereas colonisation with E. coli did not (p=0.001). Faecal levels of a-Defensin 6 correlated negatively with faecal AKK (p=0.02). In vitro growth assays and electron microscopy showed inhibition of AKK by a-Defensin 6. IgG colocalized with IgA in glomerular deposits of AKK, but not E. coli, colonized a1KI-CD89tg mice. Affinity of serum IgG from IgAN patients was much greater for human IgA1 incubated with AKK than for controls.


IgA1 is deglycosylated in the intestinal lumen by mucin-degrading bacteria, such as AKK, before passing by retro-transcytosis to the systemic circulation, where it is bound by autoreactive antibodies, and depositing in the mesangium. We provide mechanistic evidence for the causal role of an intestinal dysbiosis in the pathogenesis of autoimmune glomerulonephritis.