Background Tryptophan (Trp) is an essential amino acid that is used for the biosynthesis of key compounds such as serotonin (5HT), kynurenine (Kyn), and AhR ligands. The gut microbiome is a critical participant in Trp metabolism through which it modulates many biological pathways, including immune activation with the generation of AhR ligands. High Kyn and low 5HT levels have been found in patients with SLE. Disturbances in gut bacterial communities, defined as dysbiosis, have been found in lupus patients and lupus mice. Moreover, a recent study demonstrated that the translocation of gut pathobiont in a lupus mouse model as well as in SLE patients related with autoimmune pathogenesis. The hypothesis tested in this study is that the interplay between gut microbiota, Trp metabolism, and genetic susceptibility modulates systemic autoimmunity.
Methods We used the B6.Sle1.Sle2.Sle3 (TC) lupus-prone mouse model that shares over 95% of its genome with control B6 mice. Sequencing of fecal 16S rDNA was performed by standard methods. Serum and feces Trp metabolites were quantified by mass spectroscopy. Gnotobiotic (GF) B6 mice were colonized with feces from either TC or B6 mice, their immune phenotypes analyzed 4 weeks later. The immunophenotypes of TC mice analyzed after 4 month exposure to various levels of dietary Trp.
Results TC and B6 mice have a distinct gut microbiota, and transfers of TC fecal microbiota induce a transient autoimmunity in GF B6 mice. Autoimmune activation was also mitigated by horizontal microbiota transfers between co-housed TC and B6 mice. As SLE patients, TC mice present high Kyn and low 5HT levels in their serum and feces, and this metabolite imbalance was eliminated by a broad-spectrum antibiotic treatment. Furthermore, variations in dietary Trp modulated autoimmune pathogenesis: a low Trp diet prevented the development of autoimmunity while a high Trp diet accelerated disease progression, and the production of their anti-dsDNA IgG was positively correlated with their Kyn level. Finally, feces from TC mice fed with high Trp levels induced a higher autoimmune activation than feces from TC mice fed with low Trp levels in GF B6 mice.
Conclusions These results demonstrate the existence of interactions between lupus susceptibility genes and gut dysbiosis, where the full disease phenotype requires the presence of both. Furthermore, our results suggest that gut dysbiosis alters Trp metabolism in genetically lupus susceptible mice by expanding Trp-catabolizing bacteria and that some of these alterations contribute to autoimmune activation.
Acknowledgements Supported by R21 AI122338 to LM.
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