Abstract
BackgroundSystemic lupus erythematosus, characterized by persistent inflammation, is a complex autoimmune disorder with no known cure. Immunosuppressants used in treatment put patients at a higher risk of infections. New knowledge of disease modulators, such as symbiotic bacteria, can enable fine-tuning of parts of the immune system, rather than suppressing it altogether.ResultsDysbiosis of gut microbiota promotes autoimmune disorders that damage extraintestinal organs. Here we report a role of gut microbiota in the pathogenesis of renal dysfunction in lupus. Using a classical model of lupus nephritis, MRL/lpr, we found a marked depletion of Lactobacillales in the gut microbiota. Increasing Lactobacillales in the gut improved renal function of these mice and prolonged their survival. We used a mixture of 5 Lactobacillus strains (Lactobacillus oris, Lactobacillus rhamnosus, Lactobacillus reuteri, Lactobacillus johnsonii, and Lactobacillus gasseri), but L. reuteri and an uncultured Lactobacillus sp. accounted for most of the observed effects. Further studies revealed that MRL/lpr mice possessed a “leaky” gut, which was reversed by increased Lactobacillus colonization. Lactobacillus treatment contributed to an anti-inflammatory environment by decreasing IL-6 and increasing IL-10 production in the gut. In the circulation, Lactobacillus treatment increased IL-10 and decreased IgG2a that is considered to be a major immune deposit in the kidney of MRL/lpr mice. Inside the kidney, Lactobacillus treatment also skewed the Treg-Th17 balance towards a Treg phenotype. These beneficial effects were present in female and castrated male mice, but not in intact males, suggesting that the gut microbiota controls lupus nephritis in a sex hormone-dependent manner.ConclusionsThis work demonstrates essential mechanisms on how changes of the gut microbiota regulate lupus-associated immune responses in mice. Future studies are warranted to determine if these results can be replicated in human subjects.
Highlights
Systemic lupus erythematosus, characterized by persistent inflammation, is a complex autoimmune disorder with no known cure
Lactobacillus spp. attenuate lupus nephritis (LN) When comparing the bacterial composition in the gut microbiota of lupus-prone lpr mice vs. MRL control mice, we found that female lpr mice had a significantly lower abundance of Lactobacillales in the gut microbiota than MRL controls at 5 weeks of age and prior to the onset of lupus-like disease (Additional file 1: Figure S1A)
Since the gut microbiota of young MRL mice contained a higher abundance of Lactobacillales than lpr mice, we sought to determine if the decrease in disease could be due to the elevated Lactobacillales in lpr mice that were transferred from MRL mice upon cecal transplantation
Summary
Systemic lupus erythematosus, characterized by persistent inflammation, is a complex autoimmune disorder with no known cure. Immunosuppressants used in treatment put patients at a higher risk of infections. Little is known on the role of gut microbiota in systemic lupus erythematosus (SLE). SLE is a very complex autoimmune disorder with no known cure. Patients taking long-term immunosuppressants are prone to higher incidence of and more severe infections [3]. There is an imperative need for new treatment strategies against LN. To accomplish this task, a better understanding of disease pathogenesis is required
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