Gut microbiota dysbiosis and associated immune response in systemic lupus erythematosus: impact of disease and treatment

Abstract

BACKGROUND: Gut microbial dysbiosis and leaky gut play a role in systemic lupus erythematosus (SLE). Geographical location and dietary habits affect the microbiome composition in diverse populations. This study explored the gut microbiome dysbiosis, leaky gut, and systemic immune response to gut bacterial consortium in patients with SLE exhibiting mild/moderate and severe disease activity. METHODS: Fecal and blood samples were collected from patients with SLE and healthy volunteers. Genomic DNA was extracted from the stool samples and subjected to 16S rRNA amplicon sequencing and microbiome profiling. Additionally, enzyme-linked immunosorbent assays were employed to determine the serum lipopolysaccharide level, as an assessment of gut permeability, and the systemic immune response against gut bacteria. RESULTS: Patients with SLE showed significantly lower gut bacterial richness and diversity, indicated by observed OTUs (56.6 vs. 74.44; p = 0.0289), Shannon (3.05 vs. 3.45; p = 0.017) and Simpson indices (0.91 vs. 0.94; p = 0.033). A lower Firmicutes-to-Bacteroidetes ratio (1.07 vs. 1.69; p = 0.01) was observed, with reduced genera such as Ruminococcus 2 (0.003 vs. 0.026; p = 0.0009) and Agathobacter (0.003 vs. 0.012; p < 0.0001) and elevated Escherichia-Shigella (0.04 vs. 0.006; p < 0.0001) and Bacteroides (0.206 vs. 0.094; p = 0.033). Disease severity was associated with a higher relative abundance of Prevotella (0.001 vs. 0.0001; p = 0.04). Medication effects included lower Romboutsia (0.0009 vs. 0.011; p = 0.005) with azathioprine and higher Prevotella (0.003 vs. 0.0002; p = 0.038) with cyclophosphamide. Furthermore, categorization by prednisolone dosage revealed significantly higher relative abundances of Slackia (0.0007 vs. 0.00002; p = 0.0088), Romboutsia (0.009 vs. 0.002; p = 0.0366), and Comamonas (0.002 vs. 0.00007; p = 0.0249) in patients receiving high-dose prednisolone (> 10 mg/day). No differences in serum lipopolysaccharide levels were found, but SLE patients exhibited elevated serum gut bacterial antibody levels, suggesting a systemic immune response. CONCLUSION: This study confirms the gut microbiome dysbiosis in patients with SLE, influenced by disease severity and specific medication usage.