IgA nephropathy: gut microbiome regulates the production of hypoglycosilated IgA1via the TLR4 signaling pathway

Yifan Zhu; Haidong He; Weiqian Sun; Jiajun Wu; Yong Xiao; Yinshun Peng; Ping Hu; Meiping Jin; Ping Liu; DongLiang Zhang; Jiajun Wu; Ting Xie; Lusheng Huang; Weiming He; Minggang Wei; Lishun Wang; Xudong Xu; Yuyan Tang

doi:10.1093/ndt/gfae052

IgA nephropathy: gut microbiome regulates the production of hypoglycosilated IgA1via the TLR4 signaling pathway

Nephrol Dial Transplant. 2024 Feb 24:gfae052. doi: 10.1093/ndt/gfae052. Online ahead of print.

Authors

Yifan Zhu¹, Haidong He¹, Weiqian Sun¹, Jiajun Wu¹, Yong Xiao², Yinshun Peng³, Ping Hu¹, Meiping Jin¹, Ping Liu¹, DongLiang Zhang¹, Jiajun Wu¹, Ting Xie¹, Lusheng Huang¹, Weiming He⁴, Minggang Wei⁵, Lishun Wang⁶, Xudong Xu¹, Yuyan Tang¹

Affiliations

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.

PMID: 38402460
DOI: 10.1093/ndt/gfae052

Abstract

Background: IgA 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 (MN), 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 fromclinical 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 other three groups, different compositions and decreased diversity demonstrated gut dysbiosis in un-treated IgAN, especially the enrichment of Escherichia -Shigella. Elevated Gd-IgA1 levels were found in un-treated 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, copied the IgAN phenotype with the activation of TLR4/MyD88/NF-κB pathway, B-cell stimulators in the intestine, and complied with enhanced proinflammatory cytokines. In vitro, LPS activated TLR4/MyD88/NF-κB pathway, B-cell stimulators and proinflammatory cytokines in the PBMCs from IgAN patients, which resulted in overproduction of Gd-IgA1 and inhibited by TLR4 inhibitor.

Conclusions: Our results illustrated that gut-kidney axis was involved in the pathogenesis of IgAN. Gut dysbiosis could stimulate the overproduction of Gd-IgA1 by TLR4 signaling pathway production and B-cell stimulators.

Keywords: Gd-IgA1; IgA nephropathy; TLR4 signaling pathway; fecal microbiota transplantation; gut microbiome.