Abstract
Autoimmune diseases, such as systemic lupus erythematosus, are characterized by excessive inflammation in response to self-antigens. Loss of appropriate immunoregulatory mechanisms contribute to disease exacerbation. We previously showed the suppressive effect of vancomycin treatment during the “active-disease” stage of lupus. In this study, we sought to understand the effect of the same treatment given before disease onset. To develop a model in which to test the regulatory role of the gut microbiota in modifying autoimmunity, we treated lupus-prone mice with vancomycin in the period before disease development (3–8 weeks of age). We found that administration of vancomycin to female MRL/lpr mice early, only during the pre-disease period but not from 3 to 15 weeks of age, led to disease exacerbation. Early vancomycin administration also reduced splenic regulatory B (Breg) cell numbers, as well as reduced circulating IL-10 and IL-35 in 8-week old mice. Further, we found that during the pre-disease period, administration of activated IL-10 producing Breg cells to mice treated with vancomycin suppressed lupus initiation, and that bacterial DNA from the gut microbiota was an inducer of Breg function. Oral gavage of bacterial DNA to mice treated with vancomycin increased Breg cells in the spleen and mesenteric lymph node at 8 weeks of age and reduced autoimmune disease severity at 15 weeks. This work suggests that a form of oral tolerance induced by bacterial DNA-mediated expansion of Breg cells suppress disease onset in the autoimmune-prone MRL/lpr mouse model. Future studies are warranted to further define the mechanism behind bacterial DNA promoting Breg cells.
Highlights
Recent evidence suggests an association between the composition of gut microbiota and the pathogenesis of systemic lupus erythematosus (SLE), a systemic autoimmune disease affecting over 5 million people worldwide [1,2,3]
We chose vancomycin because it is not absorbed in the gastrointestinal tract [32], so any effect on the immune system should be mediated by local effects on the gut microbiota
These results indicate that gut microbiota has a time-dependent influence on the development of lupus, and that vancomycin-mediated modulation of gut microbiota before disease initiation could exacerbate lupus in female MRL/lpr mice
Summary
Recent evidence suggests an association between the composition of gut microbiota and the pathogenesis of systemic lupus erythematosus (SLE), a systemic autoimmune disease affecting over 5 million people worldwide [1,2,3]. Oral administration of a mixture of five Lactobacillus strains largely attenuated lupus-like symptoms in these mice [13], suggesting an essential role of the balance of microbiota genera in SLE pathogenesis. Germ-free MRL/lpr female mice exhibited very similar lupus disease course and clinical parameters compared to mice housed under conventional conditions [14]. This indicates that entire removal of gut microbiota throughout the lifespan neither attenuates nor exacerbates lupus. Whether there are other regulatory effects of the gut microbiota besides a role in the effector phase of disease, remains unresolved
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