Acetate from Microbiota Contributes to Pathogenesis of Murine Lupus Nephritis

Abstract

Background: Pathogenesis of lupus nephritis is complex, and involves both genetic and environmental factors. Emerging evidence suggests that translocation of microbial products from the gastrointestinal (GI) tract into the circulation may have impact on distant organs. Acetate is a short chain fatty acid (SCFA) generated by gut microbiota. We previously showed that lupus nephritis patients had higher serum acetate levels compared to healthy subjects, and serum acetate level correlated with lupus disease activity. We investigated the role of acetate in the pathogenesis of murine lupus nephritis. Methods: Eight week old NZB/W F1 mice were randomized to receive (a) drinking water, (b) sodium acetate, or (c) ampicillin and neomycin for 20 weeks. Intestinal mucosal permeability was investigated with dextran-FITC administration, and ZO-1 and claudin-1 expression. Expression of SCFA receptors GPR-41 and GPR-43 was investigated with cytochemical staining. The effect of acetate on mediators of inflammation was investigated in HK-2 cells. Results: Serum acetate level was significantly higher in NZB/W F1 mice with active disease compared with age-matched BALB/c mice (P<0.05). Renal histology in untreated NZB/W F1 mice showed mesangial expansion, immune cell infiltration, progressive glomerulosclerosis, tubular atrophy and interstitial fibrosis; and increased GPR-41 and GPR-43 expression in proximal renal tubular epithelial cells. Also, active lupus nephritis was accompanied by increased gut permeability and decreased ZO-1, claudin-1, GPR-41 and GPR-43 expression in 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 lupus nephritis progressed. Mice fed acetate showed higher level of proteinuria and reduced survival. In contrast, antibiotic treatment attenuated abnormalities observed in the colon and kidney, and significantly decreased serum acetate level and proteinuria (P<0.05, for both). HK-2 cells exposed to acetate for 24h showed induction of IL-6, IL-8, TNF-α, TGF-β1 and SNAIL mRNA. Conclusions: The data demonstrate that murine lupus nephritis is associated with a change in gut microbiota and increased circulating microbial acetate, which may contribute to renal tubulo-interstitial inflammation and fibrosis.