Gut Microbiome-derived Lipopolysaccharide Contributes to Pathogenesis of Murine Lupus Nephritis

Abstract

Introduction: Pathogenesis of lupus nephritis is complex and involves both genetic and environmental factors. Emerging evidence suggests that translocation of microbial products such as lipopolysaccharide (LPS) from the gut may enter the circulation and induce inflammatory responses at distant sites. This study investigated the role of LPS in the pathogenesis of murine lupus nephritis. Methods: Eight weeks old NZB/W F1 mice were randomized to receive a) drinking water or (b) ampicillin and neomycin for 20 weeks. Intestinal mucosal permeability was investigated with LPS‐FITC administration, and ZO‐1 and occludin expression. Quantitative changes to the gut microbiota were assessed by 16S rRNA sequencing. Results: Serum LPS level was significantly higher in NZB/W F1 mice with active nephritis compared with age‐matched BALB/c mice (P < 0.05). Histopathologic features of active nephritis in NZB/W F1 mice were accompanied by increased LPS binding protein, CD14 and TLR‐4 expression in proximal renal tubular epithelial cells. Mice with active nephritis also showed increased gut permeability to orally fed LPS‐FITC, with decreased ZO‐1 and occludin expression in the colonic epithelium. 16S rRNA analysis showed a progressive decrease in Gram‐positive bacteria phyla Actinobacteria and Firmicutes and an increase in Gram‐negative bacteria phyla Bacteroides and Proteobacteria as nephritis progressed. Antibiotic treatment significantly decreased serum LPS level, and attenuated abnormalities observed in both the colon and kidney (P < 0.05, for both), and also proteinuria. Conclusion: Our data demonstrate that progressive murine lupus nephritis is associated with increased gut‐derived circulating LPS, which could contribute to renal tubulo‐interstitial inflammation.