Expansion of Escherichia-Shigella in Gut Is Associated with the Onset and Response to Immunosuppressive Therapy of IgA Nephropathy

Significance Statement Gut dysbiosis contributes to dysfunctional mucosal immunity, which may lead to production of nephrotoxic immune complexes specific to IgA nephropathy (IgAN). However, the key bacterial taxa closely associated with IgAN onset and treatment response have not been determined. We conducted a comprehensive observational study and found that, compared with healthy controls, patients with IgAN have a distinct gut microbial composition characterized by excessive expansion of the taxonomic chain Proteobacteria–Gammaproteobacteria–Enterobacteriales–Enterobacteriaceae–Escherichia-Shigella. Escherichia-Shigella contributed the most to the abundant taxonomic chain and performed best in the bacterial diagnosis model for distinguishing patients with IgAN from healthy controls. Strikingly, immunosuppressive therapy reversed the expansion of genus Escherichia-Shigella and increased bacterial diversity, but only in patients who achieved clinical remission. These results identify a crucial role of Escherichia-Shigella expansion in IgAN. Background Gut dysbiosis is postulated to participate in the pathogenesis of IgA nephropathy (IgAN). However, the key bacterial taxa closely associated with IgAN onset and treatment response have not been identified. Methods We recruited 127 patients with IgAN who were treatment naive and 127 matched healthy controls (HCs) who were randomly divided into discovery and validation cohorts to investigate the characteristics of their gut microbiota and establish a bacterial diagnosis model for IgAN. A separate cohort of 56 patients and HCs was investigated to assess crossregional validation. A further 40 patients with primary membranous nephropathy (MN) were enrolled to probe disease-specific validation. A subgroup of 77 patients was prospectively followed to further dissect the association between alterations in gut microbiota and treatment response after 6 months of immunosuppressive therapy. Fecal microbiota samples were collected from all participants and analyzed using 16S ribosomal RNA sequencing. Results Decreased α -diversity (Shannon, P =0.03), altered microbial composition (Adonis, P =0.0001), and a striking expansion of the taxonomic chain Proteobacteria – Gammaproteobacteria – Enterobacteriales – Enterobacteriaceae – Escherichia-Shigella (all P <0.001) were observed in patients with IgAN who were treatment naive, which reversed only in patients who achieved clinical remission after 6 months of immunosuppressive therapy. Importantly, seven operational taxa units, of which Escherichia-Shigella contributed the most, were determined to be the optimal bacterial classifier of IgAN (AUC=0.8635, 0.8551, 0.8026 in discovery, validation, and cross-regional validation sets, respectively), but did not effectively distinguish patients with IgAN versus those with MN (AUC=0.6183). Bacterial function prediction further verified enrichment of the shigellosis infection pathway in IgAN. Conclusion Gut dysbiosis, characterized by a striking expansion of genus Escherichia-Shigella , is a hallmark of patients with IgAN and may serve as a promising diagnostic biomarker and therapeutic target for IgAN. Further studies are warranted to investigate the potential contribution of Escherichia-Shigella in IgAN pathogenesis.