Control of lupus nephritis by changes of gut microbiota

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-017-0300-8) contains supplementary material, which is available to authorized users.

The microbiome in autoimmune diseases

“…It also demonstrated an improvement of renal disease through the decrease in IgG2a (one of the major immune deposits) and of the IFN‐γ level. However, such evidence was not present in male mice, suggesting that the influence of microbiome is sexually related, dependent and indicating a role for sex hormones in the regulatory function of the gut microbiota on lupus . In accordance with other findings, Bankole et al .…”

“…It also demonstrated an improvement of renal disease through the decrease in IgG2a (one of the major immune deposits) and of the IFN- level. However, such evidence was not present in male mice, suggesting that the influence of microbiome is sexually related, dependent and indicating a role for sex hormones in the regulatory function of the gut microbiota on lupus [83]. In accordance with other findings, Bankole et al [84] highlighted an increase of Protebacteria phyla and family of Lachnospiraceae and a decrease of Rikenellaceae, Odoribacteraceae, Christensenellaceae and Peptococcaceae families in samples from 21 patients with SLE.…”

“…© 2018 British Society for Immunology, Clinical and Experimental Immunology, 195:[74][75][76][77][78][79][80][81][82][83][84][85] …”

The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility

“…For example, segmented filamentous bacteria may predispose individuals to Th17-mediated diseases and asthma in murine studies [78, 79] but can protect against type 1 diabetes in NOD mice [80]. Intestinal dysbiosis has also been linked to systemic lupus erythematosis [81, 82], and it is speculated that sex differences in the GIT microbiota play a role in the greater female susceptibility to autoimmune diseases [57, 58, 83]. …”

Abundance and nuclear antigen reactivity of intestinal and fecal Immunoglobulin A in lupus-prone mice at younger ages correlate with the onset of eventual systemic autoimmunity

“…Intriguingly, a recent report showed, in addition to differences in the gut microbiota composition, relatively higher levels of total IgA in stool samples of SLE patients compared to that of healthy controls 9 . On the other hand, serum IgA levels, but not IgG or IgM levels, were diminished in lupus-prone mice that received oral treatment with Lactobacillus, which suppresses lupus nephrites 23 . Importantly, anti-DNA antibodies of IgA class are found in the serum of patients with SLE [24][25][26][27][28][29] , suggesting that they may be of gut primed B cell origin.…”