Abstract
Intestinal dysbiosis, characterized by a reduced Firmicutes/Bacteroidetes ratio, has been reported in systemic lupus erythematosus (SLE) patients. In this study, in vitro cultures revealed that microbiota isolated from SLE patient stool samples (SLE-M) promoted lymphocyte activation and Th17 differentiation from naïve CD4+ lymphocytes to a greater extent than healthy control-microbiota. Enrichment of SLE-M with Treg-inducing bacteria showed that a mixture of two Clostridia strains significantly reduced the Th17/Th1 balance, whereas Bifidobacterium bifidum supplementation prevented CD4+ lymphocyte over-activation, thus supporting a possible therapeutic benefit of probiotics containing Treg-inducer strains in order to restore the Treg/Th17/Th1 imbalance present in SLE. In fact, ex vivo analyses of patient samples showed enlarged Th17 and Foxp3+ IL-17+ populations, suggesting a possible Treg-Th17 trans-differentiation. Moreover, analyses of fecal microbiota revealed a negative correlation between IL-17+ populations and Firmicutes in healthy controls, whereas in SLE this phylum correlated directly with serum levels of IFNγ, a Th1 cytokine slightly reduced in patients. Finally, the frequency of Synergistetes, positively correlated with the Firmicutes/Bacteroidetes ratio in healthy controls, tended to be reduced in patients when anti-dsDNA titers were increased and showed a strong negative correlation with IL-6 serum levels and correlated positively with protective natural IgM antibodies against phosphorylcholine.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease triggered by a combination of environmental and genetic factors that result in a breakdown in tolerance towards self-antigens[1]
Given the gut dysbiosis recently reported in systemic lupus erythematosus (SLE) patients[39], we aimed to evaluate the influence of fecal microbiota obtained from SLE patients (SLE-M) and healthy controls (HC-M) in the in vitro differentiation of regulatory T cells (Treg), as well as Th1 and Th17 effector populations from naïve CD4+ T lymphocytes
To estimate the effect of enriching the gut microbiota with strains able to increase the Treg subset, 5, 10 or 30% of SLE-M were replaced with the same amounts of Bifidobacterium bifidum LMG13195 (Bb), a strain known to induce Foxp[3] expression[23,41], or with a mixture of two Clostridia strains (Cl) with a putative Treg-inducer effect (Ruminococcus obeum DSM25238 and Blautia coccoides DSM935)[42,43]
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease triggered by a combination of environmental and genetic factors that result in a breakdown in tolerance towards self-antigens[1]. Several studies suggest that alterations in the gut microbiota composition, known as dysbiosis, may be a critical factor in the development of numerous immune-mediated pathologies, probably in disease-susceptible hosts, through the generation of an imbalance between Th and Treg cells[19,28,29,30,31]. In this sense, intestinal dysbiosis has been associated with the development of several autoimmune diseases, including inflammatory bowel disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis[32,33,34,35,36,37,38]. We analyzed the possible relationship between the SLE-associated gut dysbiosis and the presence of immune parameters characteristic of these patients, such as the Treg/Th populations, cytokine levels, disease activity and the production of both pathogenic anti-dsDNA and protective natural IgM anti-phosphoryl choline antibodies
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