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

Abstract

BackgroundGut 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.MethodsWe 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.ResultsDecreased 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.ConclusionGut 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.

Systematic Microbiome Dysbiosis Is Associated with IgA Nephropathy

“…Previous studies on the IgAN microbiome usually focused on oral or gut microbiota ( 12 , 14 – 18 ). Our study provided the first systematic survey of microbial diversity across four distinct niches of IgAN patients, revealing niche-specific patterns of microbial dysbiosis.…”

“…In tonsils, patients with IgAN had higher proportions of Rahnella , Ruminococcus_g2 , and Clostridium_g21 , according to one study of 21 patients and 23 controls in a Korean population ( 13 ). Many studies on the gut microbial composition in IgAN patients have suggested an increase in some pathogenic genera, such as Escherichia - Shigella ( 14 – 18 ) and Eggerthella ( 15 ), with a reduction in some beneficial bacteria, such as Bifidobacterium and Blautia spp. ( 16 ).…”

Lactobacillus species ameliorate membranous nephropathy through inhibiting the aryl hydrocarbon receptor pathway via tryptophan‐produced indole metabolites

“…The latest study showed that gut microbiome plays an essential role in onset of MN and can be used as a noninvasive diagnostic tool (Shang et al, 2022). Zhao et al reported that Escherichia‐Shigella , as the biggest contributor among seven operational taxa units, could optimally classify IgAN, but cannot distinguish between IgAN and IMN, which instead is associated with enrichment of shigellosis infection pathway in IgAN (Zhao, Bai, et al, 2022). In addition, Luan et al reported that Alloprevotella , Granulicatella , Prevotella , Streptococcus and Prevotella_7 in salivary samples showed a high relative abundance in IMN patients compared with healthy controls.…”

Freshwater transfer affected intestinal microbiota with correlation to cytokine gene expression in Asian sea bass

“…In the digesta-associated microbiota of the FW group, Escherichia-Shigella was significantly negatively related to il10, tgfβ1 , and il17F. Escherichia-shigella is considered as a pathogen to humans and animals ( Falkow et al, 1963 ; Zhao et al, 2022 ). Its pathogenic function may explain its negative interaction with anti-inflammatory cytokines.…”