Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice
Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice
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DOI：
10.1093/ndt/gfy323
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发表时间：
2019-07-01
影响因子：
6.1
通讯作者：
Monteiro, Renato C.
中科院分区：
文献类型：
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作者：
Chemouny, Jonathan M.;Gleeson, Patrick J.;Monteiro, Renato C.
免疫球蛋白A肾病（IgAN）是世界范围内最常见的原发性肾小球肾炎。伊加主要由肠道相关淋巴组织（GALT）产生。实验和临床数据都表明肠道微生物群在这种疾病中的作用。我们的目的是确定针对肠道微生物群的干预是否可以影响IgAN的人源化小鼠模型中疾病的发展，α 1（KI）-CD 89（Tg）小鼠。方法将4周龄和12周龄的小鼠分为两组，接受抗生素或载体对照。在实验开始和结束时，当收集血液、肾脏和肠组织时，定量粪便细菌负荷和蛋白尿。定量血清小鼠免疫球蛋白G（mIgG）和人免疫球蛋白A1（hIgA 1）的复合物。肾和肠组织进行了分析后，苏木素和伊红染色和免疫组织化学抗hIgA和抗小鼠CD 11b antibodies.Results抗生素治疗有效地耗尽粪便菌群，受损GALT架构和影响小鼠伊加的生产。然而，虽然hIgA 1和mIgG血清水平不变，抗生素治疗显着防止hIgA 1系膜沉积，肾小球炎症和蛋白尿的发展。这与循环hIgA 1-mIgG复合物的显著减少有关。值得注意的是，最终粪便细菌负荷与IgAN的关键临床和病理生理学特征如蛋白尿和hIgA 1-mIgG复合物密切相关。此外，治疗与广谱抗生素恢复建立diseases.Conclusions这些数据支持的粘膜衍生的肾毒性IgA 1和IgAN的发展，在这种疾病的治疗方法开辟了新的途径的产生肠道菌群的重要作用。
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 alpha 1(KI)-CD89(Tg) 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.