Gut microbiota dysbiosis and altered tryptophan catabolism contribute to autoimmunity in lupus-susceptible mice

Abstract

<jats:p>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.<jats:italic>Sle1.Sle2.Sle3</jats:italic>) 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. </jats:p>

Intestinal Dysbiosis and Tryptophan Metabolism in Autoimmunity

“…A unique advantage of the TC model is the 95% genetic similarity between TC and non-autoimmune C57BL6 (B6) mice, thus allowing B6 to serve as a true nonautoimmune genetic control. No differences were observed in microbial diversity, but some taxa were enriched in autoantibody positive TC mice, including Paraprevotellaceae, Paraprevotella, Lactobacillales, Lactobacillaceae, and Lactobacillus (21). The increased abundance of Prevotella is consistent with the results obtained in SLE (7,13) and RA patients (6,15,17), as well as the TRL7 transgenic model of lupus (20).…”

“…Intestinal dysbiosis has also been shown in the B6.Sle1.Sle2.Sle3 triple congenic (TC) spontaneous model of lupus (18,21). A unique advantage of the TC model is the 95% genetic similarity between TC and non-autoimmune C57BL6 (B6) mice, thus allowing B6 to serve as a true nonautoimmune genetic control.…”

“…Intestinal dysbiosis has been documented in human and murine autoimmunity (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Specific classes of microbes that may be associated with disease have been identified (6,9,17,22), but causal links between specific bacteria and autoimmune manifestations are still rare.…”

“…In addition, whether or not dysbiosis plays a role in disease initiation or amplification remains to be elucidated. There are three main mechanisms by which the microbiota could play a role in autoimmunity: molecular mimicry (23)(24)(25), an impaired intestinal barrier that may promote bacterial translocation (20,26), and an altered abundance of microbial metabolites with immunoregulatory functions (21). Each of these mechanisms has the potential to promote inflammation and consequent tissue damage, especially when combined with genetic susceptibility to autoimmune diseases.…”

Special issue on the human microbiome: from symbiosis to therapy

“…Special issue on the human microbiome: from symbiosis to therapy Amit Sharma 1 and Sin-Hyeog Im 1,2 The symbiotic microbes harbored at various sites in the human body are increasingly being appreciated as a dynamic extension of the human host. Earlier investigations appreciated the coevolution of the microbiome with the host, particularly that associated with the gut, to achieve metabolic efficiency for the host and nutrient provision for the microbes.…”