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The advantage of reducing dietary tryptophan
Alterations in the gut microbiota may contribute to autoimmunity through bacterial-mediated immune dysregulation. Tryptophan, an essential amino acid, is critically involved in kynurenine biosynthesis. High kynurenine concentrations have been observed in patients with systemic lupus erythematosus and in lupus-prone mice. Choi et al. now demonstrate that gut bacterial dysbiosis found in lupus-prone mice dysregulates tryptophan metabolism, which, in turn, exacerbates progression of lupus disease. They also show that autoimmunity can be mitigated by reducing dietary tryptophan. The authors suggest a model in which genetic susceptibility induces autoimmunity, which leads to gut bacterial dysbiosis and an increase in tryptophan metabolism that enhances lupus pathogenesis.
Abstract
The autoimmune disease systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies. It has been postulated that gut microbial dysbiosis may be one of the mechanisms involved in SLE pathogenesis. Here, we demonstrate that the dysbiotic gut microbiota of triple congenic (TC) lupus-prone mice (B6.Sle1.Sle2.Sle3) stimulated the production of autoantibodies and activated immune cells when transferred into germfree congenic C57BL/6 (B6) mice. Fecal transfer to B6 mice induced autoimmune phenotypes only when the TC donor mice exhibited autoimmunity. Autoimmune pathogenesis was mitigated by horizontal transfer of the gut microbiota between co-housed lupus-prone TC mice and control congenic B6 mice. Metabolomic screening identified an altered distribution of tryptophan metabolites in the feces of TC mice including an increase in kynurenine, which was alleviated after antibiotic treatment. Low dietary tryptophan prevented autoimmune pathology in TC mice, whereas high dietary tryptophan exacerbated disease. Reducing dietary tryptophan altered gut microbial taxa in both lupus-prone TC mice and control B6 mice. Consequently, fecal transfer from TC mice fed a high tryptophan diet, but not a low tryptophan diet, induced autoimmune phenotypes in germfree B6 mice. The interplay of gut microbial dysbiosis, tryptophan metabolism and host genetic susceptibility in lupus-prone mice suggest that aberrant tryptophan metabolism may contribute to autoimmune activation in this disease.
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