Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with no known cure. The crosstalk between the gut microbiota and the immune system plays an important role in the tolerance induction to self-antigens both in the intestinal mucosa and at the systemic level.
The MRL/lpr mouse model exhibits lupus-like symptoms early in life due to multiple SLE susceptible loci of the MRL background, plus the Faslpr mutation that offers an accelerated model. Recently, we experienced a loss of disease phenotype in our in-house colony compared to the previous published phenotype of MRL/lpr mice. We thus compared mice newly obtained from The Jackson Laboratory (JAX) with our in-house MRL/lpr mice and found that the phenotypic drift, most significantly the attenuation of glomerulonephritis, was present in both colonies. In addition, while JAX mice and mice in our colony are genetically identical, there were minor differences in disease that might be due to differences in splenic microRNAs and the gut microbiota.
Once confirming that our MRL/lpr mouse model was as good as that from JAX, we continued our investigation of the role of Lactobacilli in the pathogenesis of lupus-like disease in MRL/lpr mice. We previously published that the mixture of Lactobacillus reuteri (L. reuteri), L. oris, L. johnsonii, L. gasseri, and L. rhamnosus significantly attenuated disease in MRL/lpr mice by restoring the imbalance between regulatory T cells and T helper-17 cells. To further understand the role of Lactobacillus spp., we treated MRL/lpr mice with the combined culture supernatant of the 5 strains containing secreted metabolites, given that the metabolites may induce an immunosuppressive response. The results showed significant attenuation of the inflammation of the spleen and renal lymph nodes similar to the effect of the bacteria themselves. There was also a trending decrease of double-stranded DNA autoantibodies with the combined supernatant. We thus tested the strains individually but none was able to recapitulate the effect of the bacterial mixture. This suggests cell-to-cell contact among different strains of lactobacilli may be required in ameliorating the disease. With these results, we now have a better understanding of the role of probiotic Lactobacillus spp. against SLE. Future investigations will focus on the potential therapeutic effect of Lactobacillus spp. as a combination.
Additionally, our group generated a Cx3cr1-deficient MRL/lpr mouse which exhibits a distinct phenotype of exacerbated glomerulonephritis with concurrent change of the gut microbiota composition compared to Cx3cr1+/+ MRL/lpr littermates. Interestingly, upon correction of the gut microbiota with Lactobacillus administration, the phenotype of exacerbated glomerulonephritis was reversed, suggesting that CX3CR1 controls glomerulonephritis in MRL/lpr mice through a gut microbiota-dependent mechanism. In addition, a collaborative project revealed that Cx3cr1 deficiency-mediated pathogenic mechanisms also contributed to SLE-associated cardiovascular disease in MRL/lpr mice. The results of these studies will lead to the identification of new therapeutic targets for the treatment of two severe manifestations, glomerulonephritis and cardiovascular disease, that together account for most of the morbidity and mortality in SLE. / Doctor of Philosophy / Systemic lupus erythematosus (SLE) is an autoimmune disease with no known cure. Commensal microbiota, mostly bacteria living in our gut, and the immune system have a strong relationship in maintaining a healthy state of the gut as well as the whole body. Alterations in the gut microbiota, known as dysbiosis, can facilitate SLE in human and animal models. Current treatments for SLE are primarily focused on using immunosuppressants, but the side effects are still a concern. The use of long-term nonselective immunosuppressant conducts a higher incidence of severe infections in SLE patients. It is thus necessary to develop new approaches and treatments against SLE. My dissertation research is focused on understanding how commensal bacteria influence in the pathogenesis of SLE. My studies have shown that environmental factors can manipulate the gut microbiota leading to different disease outcomes. In addition, following upon previously published studies from our laboratory, I have delineated the mechanism how a mixture of probiotic Lactobacilli can exert a beneficial effect against lupus. Finally, I have revealed a new, CX3CR1-mediated mechanism through which the gut microbiota controls kidney disease in the MRL/lpr lupus-prone mouse model.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/111556 |
| Date | 18 August 2022 |
| Creators | Cabana-Puig, Xavier |
| Contributors | Biomedical and Veterinary Sciences, Luo, Xin, Allen, Irving C., Reilly, Christopher Michael, Caswell, Clayton Christopher |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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