Gut dysbiosis and tryptophan metabolism in lupus

Summary Gut microbial dysbiosis has become appreciated as a major intrinsic environmental contributor to lupus pathogenesis, with cross-sectional studies in patients with systemic lupus erythematosus (SLE), and in mouse models of the disease showed the presence of globally different gut microbial communities at time of high disease activity, when compared to healthy controls (HCs). About 40% of patients with flares of lupus nephritis had intestinal expansions of Blautia (Ruminococcus) gnavus (Rg) and concomitant production of high-level serum antibodies (Ab) to a novel membrane lipoglycan (LG) produced by certain Rg strains, demonstrating that LG passed through a functionally impaired gut barrier to activate the peripheral immune system. In a murine gut colonization model, induction of serum anti-LP IgG antibodies correlated with spontaneous production of anti- dsDNA IgG and high lupus disease activity. Colonization with Rg isolates from SLE patients altered the intestinal barrier and promoted autoAb production in healthy B6 controls through vertical transmission. We have shown that gut colonization by fecal microbiota from the B6.Sle1.Sle2.Sle3 triple congenic (TC) lupus-prone mice transfers autoimmune activation in B6 mice without bacterial translocation. Instead, TC mice present a skewed tryptophan (Trp) metabolism that is largely of bacterial origin, and that promotes CD4+ T cell activation. In this model, autoimmune activation and the composition of the microbiota were altered by manipulating dietary Trp levels. A skewed serum and fecal Trp metabolism correlate with disease activity in SLE patients. Recent reports showed that bacterial Trp metabolites play a major pathogenic role in mouse models of SLE, MS, and RA, three autoimmune diseases with documented gut dysbiosis. In support of a causal relationship between a dysbiotic Trp metabolism and lupus, we have shown that high dietary Trp promotes Rg blooms in TC mice associated with gut inflammation and autoimmune activation. Rg depletion ameliorated disease while colonization of TC mice with LG-producing RG2 but not LG-producing “naked” RG1, promoted autoAb production and T cell activation. Moreover, RG1 and RG2 process Trp differently, and Trp enhanced the growth of Rg2 but not Rg1. Therefore, Rg is present in TC mice where it is expanded by Trp, and it is sufficient to accelerate disease. These results support the premise that Rg blooms are a major driver of lupus pathogenesis, and that we have the tools to address the mechanisms by which it occurs. We propose in the second cycle of funding of this project to identify the factors that are necessary for Rg to bloom (Aim 1), and to determine the mechanisms by which Rg promotes disease, either directly by interacting with the immune system (Aim 2) or indirectly by modifying the intestinal microbiota (Aim 3). Rg is the only bacteria species associated with lupus pathogenesis in both humans and mice. The proposed experiments will bring an understanding of the novel mechanisms by which this pathobiont expands preferentially in lupus hosts and enhances autoimmune activation, which could lead to a better targeted and effective therapeutic approach to treat this disease.