Diet and gut microbiota against systemic lupus erythematosus

Daniel F. Zegarra Ruiz

Yale University, USA


Diet is known to profoundly alter host metabolism and immunity through its effects on gut microbial communities. A decrease in consumption of key dietary compounds, such as fiber, has led to changes in the microbiota landscape and increased the incidence of metabolic and immune related diseases. It has been shown that the microbiota and their metabolites play a role in modulating systemic and mucosal immune responses. In addition, numerous studies have exposed a role of the microbiota in the exacerbation or suppression of multiple autoimmune disorders through direct or indirect approaches. Diet-microbiota-host interactions are poorly understood in immune-mediated diseases. Systemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease leading to chronic inflammation in various organs and tissues due to adaptive immune responses to self-antigens. SLE is characterized by a type I interferon (IFN) signature mediated principally by plasmacytoid dendritic cells (pDCs), an exacerbated IL17A secretion by pathogenic T helper 17 (Th17) cells and by the production of autoantibodies, such as anti-DNA or anti-RNA antibodies, that promote the formation of immune complexes (IC) that deposit in multiple organs. We hypothesized that resistant starch (RS) ameliorates SLE through diet-induced microbial metabolic host effects. We fed SLE-prone TLR7tg C57BL/6 and (NZWxBXSB)F1 hybrid mice with RS from 4-30 weeks of age and defined the gut microbial communities, short-chain fatty acid (SCFA) production, as well as gut and systemic CD4 T helper cell subsets. RS significantly reduced SLE-related mortality (n=10-12 each, p<0.05) in SLE-prone mice. Unexpectedly, fecal SCFAs were not altered by RS despite cecal enlargement suggesting modulation of non-fermenting gut microbial communities. Fecal samples from 18 mice were collected longitudinally and sequenced using 2x250bp paired-end reads on a MiSeq platform. RS increased microbiota β diversity with increased abundance of Lactococcus and Bacteroidales, while persistently suppressing Prevotella and other pro-inflammatory strains. Next, small intestine and colonic lamina propria (LP), mesenteric lymph node (mLN) and splenic T cells were analyzed. RS significantly reduced LP Th17 (p=0.003), regulatory T cells (Treg) (p=0.004), and Foxp3+ IL-17+ (p=0.007) CD4 T cell subsets. Outside the gut, these T cell subsets were also reduced in mLN and spleen. Taken together, we conclude that RS acts in autoimmune-prone hosts not through microbial SCFA induction of Tregs but more likely through suppression of pathobionts and inflammatory Th17 subsets that are known to contribute to systemic autoimmunity. Future studies are aimed at defining the gut metabolome and dissecting the mechanisms using gnotobiotic models.

***This work is supported by the NIH (K08AI095318, P30DK079310, T32AI07019) and the Lupus Research Institute.

Keywords: Diet, Microbiota, Lupus


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