IgA nephropathy: gut microbiome regulates the production of hypoglycosilated IgA1 via the TLR4 signaling pathway

Author:

Zhu Yifan1,He Haidong1,Sun Weiqian1,Wu Jiajun1,Xiao Yong2,Peng Yinshun3,Hu Ping1,Jin Meiping1,Liu Ping1,Zhang DongLiang1,Xie Ting1,Huang Lusheng1,He Weiming4,Wei Minggang5,Wang Lishun6,Xu Xudong1,Tang Yuyan1

Affiliation:

1. Department of Nephrology, Minhang Hospital, Fudan University , Shanghai , P.R. China

2. Department of Emergency, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine , Shanghai , P.R. China

3. School of Public Health, Fudan University , Shanghai , China

4. Department of Nephrology, Affiliated Hospital of Nanjing University of Chinese Medicine , Jiangsu Suzhou , P.R. China

5. Department of Traditional Chinese Medicine, The First Affiliated Hospital of Soochow University , Jiangsu Suzhou , P.R. China

6. Center for Traditional Chinese Medicine and Gut Microbiota, Institute of Fudan-Minhang Academic Health System, Minhang Hospital, Fudan University , Shanghai , China

Abstract

ABSTRACT Background Immunoglobulin A nephropathy (IgAN) is a major cause of primary glomerulonephritis characterized by mesangial deposits of galactose-deficient IgA1 (Gd-IgA1). Toll-like receptors (TLRs), particularly TLR4, are involved in the pathogenesis of IgAN. The role of gut microbiota on IgAN patients was recently investigated. However, whether gut microbial modifications of Gd-IgA1 through TLR4 play a role in IgAN remains unclear. Methods We recruited subjects into four groups, including 48 patients with untreated IgAN, 22 treated IgAN patients (IgANIT), 22 primary membranous nephropathy and 31 healthy controls (HCs). Fecal samples were collected to analyze changes in gut microbiome. Gd-IgA1 levels, expression of TLR4, B-cell stimulators and intestinal barrier function were evaluated in all subjects. C57BL/6 mice were treated with a broad-spectrum antibiotic cocktail to deplete the gut microbiota and then gavaged with fecal microbiota transplanted from clinical subjects of every group. Gd-IgA1 and TLR4 pathway were detected in peripheral blood mononuclear cells (PBMCs) from IgAN and HCs co-incubated with lipopolysaccharide (LPS) and TLR4 inhibitor. Results Compared with the other three groups, different compositions and decreased diversity demonstrated gut dysbiosis in the untreated IgAN group, especially the enrichment of Escherichia-Shigella. Elevated Gd-IgA1 levels were found in untreated IgAN patients and correlated with gut dysbiosis, TLR4, B-cell stimulators, indexes of intestinal barrier damage and proinflammatory cytokines. In vivo, mice colonized with gut microbiota from IgAN and IgANIT patients mimicked the IgAN phenotype with the activation of TLR4/MyD88/nuclear factor-κB pathway and B-cell stimulators in the intestine, and had with enhanced proinflammatory cytokines. In vitro, LPS activated TLR4/MyD88/NF-κB pathway, B-cell stimulators and proinflammatory cytokines in PBMCs of IgAN patients. This process may induce the overproduction of Gd-IgA1, which was inhibited by TLR4 inhibitors. Conclusions Our results illustrated that the gut–kidney axis is involved in the pathogenesis of IgAN. Gut dysbiosis could stimulate the overproduction of Gd-IgA1 via TLR4 signaling pathway production and B-cell stimulators.

Funder

National Natural Science Foundation of China

Natural Science Foundation in Minhang District of Shanghai

Research project of Shanghai Minhang District Health Committee

Minhang District High-Level Specialty Key Physician Training Program

Minhang District Medical Characteristic Specialty Project

Hospital-level Discipline-Chronic Disease Group-Chronic Kidney Disease Project

Jiangsu Provincial Medical Innovation Center

Publisher

Oxford University Press (OUP)

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3