Background/Purpose: Multiple studies have demonstrated that commensal bacteria play an immunoregulatory role and that gut dysbiosis is associated with inflammatory diseases. This study was conducted to test the hypothesis that gut dysbiosis plays a role in SLE. We have used a congenic model of lupus, the B6.Sle1.Sle2.Sle3 (TC) mice, which share >95% of their genome with B6 controls to ask if differences in microbiota between could synergize with lupus susceptibility genes to modulate autoimmune pathology.
Methods: The 16S rDNA sequences of fecal bacteria were compared between the two strains. Global fecal and serum metabolomic profiles were obtained using high-resolution mass spectrometry (Thermo Q-Exactive) coupled with ultra-high performance liquid chromatography. Tryptophan (Trp) metabolites were quantified with the same instruments relative to internal standards. Germ-free (GF) B6 mice were populated with fecal contents from either B6 or TC mice, and evaluated 4 weeks later. TC and B6 mice were treated with an antibiotic cocktail starting at 6 weeks of age and evaluated after 6 months of treatment. B6 and TC mice were either housed separately or co-housed in a mixed strains environment at weaning and evaluated 6 months later. B6 and TC mice were fed with Trp-deficient, Trp-supplemented (1%) and control chow starting at 2 months of age and evaluated 7 months later. Immunophenotypes were evaluated by flow cytometry. Serum and fecal antibodies were measured by ELISA. Kidney and gut pathology was evaluated by histology.
Results: TC and B6 mice have a different distribution of gut bacteria based on 16S rDNA sequencing. The colon and duodenum of aged TC mice showed a significant amount of immune cell infiltrate, which correlated with the severity of renal pathology. TC fecal transfers to GF B6 mice showed that microbiota from aged TC mice was sufficient to induce the production of serum anti-dsDNA IgG. TC microbiota also expanded germinal center (GC)-like organization in Peyer’s patches and follicular helper T (TFH) cells in the mesenteric lymph node. These changes were not observed with microbiota from young pre-disease TC mice. Treatment of TC mice with antibiotic cocktail significantly delayed anti-dsDNA IgG induction and expanded Treg and follicular regulatory T (TFR) cells. Co-housing TC and B6 mice revealed significant interactions between susceptibility genes and microbiota. Remarkably, the frequency of TFH cells was decreased in co-housed TC mice, corresponding to a drastic reduction of autoantibodies and amelioration of renal disease. Co-housed TC and B6 mice showed a similar fecal metabolome profile, which was significantly different from those of independently housed mice. Trp metabolites were among the metabolites found at different levels between TC and B6 stools. Similarly to what has been reported by others in SLE patients, TC mice have increased levels of serum and fecal kynurenine, one of Trp metabolites, as compared to B6. Accordingly, a Trp-supplemented chow accelerated autoimmune pathology in TC mice.
Conclusion: Overall, our results show that a dysregulated gut microbiota amplifies lupus pathogenesis in mice, and suggest that this is mediated at least in part by bacteria modifying Trp metabolism.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/gut-dysbiosis-contributes-to-autoimmune-pathogenesis-in-lupus-prone-mice/