Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with no known cure. Despite years of study, the etiology of SLE is still unclear. Both genetic and environmental factors have been implicated in the disease mechanisms. Gut microbiota as an environmental factor and the immune system interact to maintain tissue homeostasis, but whether this interaction is involved in the pathogenesis of SLE is unclear. In a classical model of lupus nephritis, MRL/lpr, we found decrease of Lactobacillales but increase of Lachnospiraceae in the gut microbiota. Increasing Lactobacillales in the gut by suppling a mixture of 5 Lactobacillus strains improved renal function of these mice and prolonged their survival. Further studies revealed that MRL/lpr mice possessed a "leaky" gut, which was reversed by increased Lactobacillus colonization. Inside the kidney, oral Lactobacillus treatment also skewed the Treg-Th17 balance towards a Treg phenotype. To remove Lachnospiraceae that was higher in lupus-prone mice than controls, we administered vancomycin orally to MRL/lpr mice after disease onset from 9 to 15 weeks of age. Vancomycin functions by removing Gram-positive bacteria such as Lachnospiraceae but sparing Lactobacillus spp. The treatment during active lupus reshaped the gut microbiota and significantly ameliorated systemic autoimmunity and kidney histopathology at 15 weeks of age. However, when vancomycin treatment was initiated from a very early age, the beneficial effect was not observed. Strikingly, mice given vancomycin only at the young age exhibited an even worse disease outcome. Indeed, regulatory B (Breg) cells were found to be reduced after the vancomycin treatment at young age. Importantly, adoptive transfer of Breg cells at 6-7 weeks of age rescued the beneficial effect, which indicates that Breg cells, inducible by vancomycin-sensitive gut microbiota, plays an important role in suppressing lupus disease initiation and progression. Finally, we demonstrated that bacterial DNA from the gut microbiota might be the inducer of Breg cells, as bacterial DNA administration at young age reproduced the beneficial effect seen in the Breg adoptive transfer experiment. Future studies are required to examine the clinical efficacy of targeting gut microbiota as a novel treatment against SLE. / Ph. D. / Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with no known cure. SLE affects over 5 million people worldwide, especially women of childbearing age. Lupus nephritis is a manifestation of SLE occurring in the kidney which affects more than 50% of SLE patients and is a major cause of morbidity and mortality in SLE. Current treatments for lupus nephritis are primarily nonselective immunosuppressants, which can cause a higher incidence of severe infections. There is an imperative need for the development of new therapeutic strategies against SLE. Our research team was the first to describe the dynamics of gut microbiota in a mouse model of SLE. My dissertation research studying the role of gut microbiota in the pathogenesis of lupus-like disease in mice showed that there were both pathogenic and beneficial bacteria co-existing in the gut microbiota of lupus-prone mice. My studies revealed not only the effects of different bacteria on lupus pathogenesis, but also the immunological mechanisms by which they exert the effects. The results suggest that modulation of the gut microbiota through diet, probiotics, and/or prebiotics to selectively enhance the abundance and activity of beneficial bacteria may be an attractive strategy for disease prevention and treatment of SLE patients. Nevertheless, studies on human samples and clinical trials are required to confirm the translational application of this strategy.