Promotion of Autoimmune Arthritis via Tryptophan Metabolism and Production of the Bacterial-Derived Tryptophan Metabolite Indole

Abstract

Abstract Dysbiosis of gut bacterial communities in autoimmunity is a noted phenomenon in both murine models and human patients; however, the mechanisms of dysbiosis that promote disease pathogenesis remain unclear. In agreement with such studies, our lab has published that administration of antibiotics to deplete the microbiota late in the course of murine collagen-induced arthritis (CIA) significantly ameliorated disease. To understand the mechanisms by which microbiota depletion would significantly decrease CIA, we analyzed cecal metabolites by LC-MS during CIA and after antibiotic treatment and observed significant changes in various tryptophan metabolite levels. Interestingly, mice placed on a tryptophan-free diet had significantly decreased CIA development and increased in regulatory T cell (Treg) populations in the spleen. Further studies identified increases in indole, a bacterial-derived, tryptophan metabolite that strongly correlated with CIA progression. Direct administration of indole during CIA promoted disease and led to increases in T follicular cell (Tfh) and B cell populations in the peyer’s patches and mesenteric lymph nodes. Ex vivo stimulation of murine splenic B cells with indole resulted in significantly increased IgG production and a ≈10% increase in the frequency of CD23+ B cells. Our results suggest that gut dysbiosis due to CIA results in altered tryptophan metabolism and indole production, which promotes CIA pathogenesis via activation of T and B cell populations and antibody production. Precise understanding of which indole metabolites are involved and how they influence mucosal and systemic immune responses will help elucidate the role of intestinal dysbiosis in autoimmunity.