Jonathan M Chemouny1,2,3,4,5, Patrick J Gleeson1,2,3, Lilia Abbad1,2,3, Gabriella Lauriero1,2,3,6, Erwan Boedec1,2,3, Karine Le Roux5, Céline Monot5, Maxime Bredel5, Julie Bex-Coudrat1,2,3, Aurélie Sannier3,7, Eric Daugas1,2,3,4, Francois Vrtovsnik1,2,3,4, Loreto Gesualdo6, Marion Leclerc5, Laureline Berthelot1,2,3, Sanae Ben Mkaddem1,2,3, Patricia Lepage5, Renato C Monteiro1,2,3,4,8. 1. INSERM 1149, Center for Research on Inflammation (CRI), Paris, France. 2. CNRS ERL8252, Paris, France. 3. Inflamex Laboratory of Excellence, School of Medicine, Paris Diderot University, Sorbonne Paris Cité, Paris, France. 4. Nephrology Department, Bichat-Claude Bernard Hospital, AP-HP, DHU Fire, Paris, France. 5. Institut Micalis, INRA, AgroParisTech, University Paris-Saclay, Jouy-en-Josas, France. 6. Department of Emergency and Organ Transplantation, Division of Nephrology, Dialysis, and Transplantation, University of Bari, Bari, Italy. 7. Pathology Department, Bichat-Claude Bernard Hospital, AP-HP, DHU Fire, Paris, France. 8. Hemato-Immunology Department, UF Immunity Dysfunctions, Bichat-Claude Bernard Hospital, AP-HP, DHU Fire, Paris, France.
Abstract
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the α1KI-CD89Tg mice. METHODS: Four- and 12-week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouse CD11b antibodies. RESULTS: Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1-mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1-mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease. CONCLUSIONS: These data support an essential role of the gut microbiota in the generation of mucosa-derived nephrotoxic IgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease.
BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the α1KI-CD89Tg mice. METHODS: Four- and 12-week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouseCD11b antibodies. RESULTS: Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1-mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1-mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease. CONCLUSIONS: These data support an essential role of the gut microbiota in the generation of mucosa-derived nephrotoxicIgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease.
Authors: Taylor Person; R Glenn King; Dana V Rizk; Jan Novak; Todd J Green; Colin Reily Journal: J Interferon Cytokine Res Date: 2022-07-06 Impact factor: 3.657