Microbiota-associated tryptophan catabolism induces autoimmune activation in a lupus murine model

The mechanisms involved in systemic lupus erythematosus (SLE) manifestations and progression remain elusive. Gut dysbiosis affects both humans and mice with SLE. Here, we demonstrate the inherent dysbiotic microbiota of lupus-prone mice, and how autoimmune phenotypes are induced if it is transferred into germfree mice. By elucidating the fecal metabolites, we focused on tryptophan (Trp) that presents an altered metabolism in SLE patients, potentially affecting the murine lupus. We found that high level of kynurenine (Kyn) in both the serum and fecal samples of lupus-prone mice, which was profoundly decreased after antibiotic treatment, potentially highlighting the relevance of gut commensals in Trp catabolism. Notably, low dietary Trp prevented autoimmune pathology, while high dietary Trp exacerbated the disease in mice. Further, modifying the levels of dietary Trp reprogrammed microbial taxa in lupus-prone mice and the congenic normal controls. Conclusively, the interplay among gut dysbiosis, Trp metabolism, and the genetic susceptibility suggest that Trp metabolism altered by microbial dysbiosis in lupus susceptible mice may be one of the mechanisms contributing to autoimmune activation. Thus, our findings may serve as a potential target for developing therapeutic interventions to perhaps mitigate lupus progression.