Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice

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.

Modifications of abundances of some bacteria are associated with the severity of IgA nephropathy in Chinese population

“…However, changes in the abundance of other types of gut microbiota were not completely the same as ours, which might result from genetic diversities and differences in environment and eating habits. In addition, Chemouny et al has reported that antibiotics, depleting gut microbiota e ciently, could ameliorate clinicopathological changes in humanized mice with IgAN [21]. As for the reason why we thought that the modi cation of gut microbiota was associated with the progression of IgAN, previous studies have reported that the higher levels of proteinuria and hematuria could serve as biomarkers of poor prognosis, which could guide the treatment [22,23].…”

“…Based on our data, we presumed that gut microbiota might impact on renal impairment through in ammatory signaling pathways. Recently, depletion of gut microbiota using antibiotics was reported to ameliorate clinicopathological changes in a mouse model of IgAN [21].…”

A New Vision of IgA Nephropathy: The Missing Link

“…The ensemble of bacteria, bacteriophages, fungi, protozoa, and viruses that live in the digestive tract of humans, called microbiota, is in contact with the gut epithelium and plays a role in the development of the mucosal-associated lymphoid tissue (MALT) and, reciprocally, the composition of the commensal microbiota depends on MALT function [63,64]. In humans, the MALT is the primary source of IgA [65], and numerous studies indicate that IgA Nephropathy (IgAN) is closely associated with alterations in the gut microbiota [34,66,67]. To date, it is unclear whether dysbiosis precedes the disease or if the IgAN can lead to gut dysbiosis.…”

“…In this scenario, the first therapeutic approach was conducted by Monteiro et al [67]. The authors have demonstrated that antibiotic treatment (ampicillin, vancomycin, neomycin, and metronidazole) of a double transgenic mice model of IgAN reverses the phenotype of the disease; but this antibiotic cocktail may have other collateral effects on the gut and weight.…”

Dysbiosis Promotes Gastric Diseases and Impede Therapies by Hijacking Gut Immune Homeostasis

“…We have also uncovered the stateof-the-art tools that can be exploited to study the gut Microbiome and look to future therapeutic options, such as the manipulation of the gut microbiota by probiotics and various immunoregulatory mechanisms [5] for the management of dysbiosis. Many pre clinical studies suggest that intake of broad spectrum antibiotic efficiently depletes / changes the composition of faecal microbiota and impairs GALT architecture and functions [7].…”