Gut dysbiosis and tryptophan metabolism in lupus

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Project Summary/Abstract Tryptophan (Trp) is an essential amino acid that is used for the biosynthesis of key compounds such as serotonin (5HT), NAD, kynurenine (Kyn), and AhR ligands. The gut microbiome is a critical participant in Trp metabolism through which it modulates immune activation. High Kyn and low 5HT levels have been found in lupus patients, which has been proposed to be the consequence of increased oxidation or interferon levels associated with this disease. Imbalance of gut microbial populations has been associated with lupus in patients and mouse models. Based on published studies as well as our unpublished results presented here, the premise of this proposal is that gut dysbiosis is an essential player in Trp metabolite imbalance in lupus, and that the interplay between the gut microbiota, Trp metabolism, and genetic susceptibility modulates systemic autoimmunity. Using a congenic model in which lupus-prone mice (B6.Sle1.Sle2.Sle3, or TC for short) share over 95% of their genome with control B6 mice, we showed that transfers of TC fecal microbiota induce a transient autoimmunity in gnotobiotic (GF) B6 mice. As in lupus patients, the serum and feces of TC mice present high Kyn and low 5HT levels, and this metabolite imbalance was eliminated by a broad-spectrum antibiotic treatment. Furthermore, a low Trp diet prevented autoimmunity while a high Trp diet accelerated disease progression. In a NYU cohort of well-characterized lupus patients, disease severity was positively correlated with a reduction of fecal bacterial diversity and negatively correlated with Trp serum levels. A preliminary analysis predicted that SLE patients had a greater abundance of bacteria with an enhanced catabolism of Trp into Kyn. We postulate that clinical lupus disease activity is in part driven by specific gut dysbiosis resulting in greater Trp catabolism and/or increased Trp catabolic products that enhance genetically driven pro-inflammatory pathways. To test this hypothesis, we propose three specific aims: 1. To elucidate the effect of Trp on the immunoregulatory properties of the fecal microbiota of lupus mice. 2. To evaluate the mitigation of gut dysbiosis by dietary Trp in lupus-prone mice. 3. To determine whether altered Trp metabolism in SLE patients is associated with an enrichment for Trp-catabolizing fecal microbiota. With a multidisciplinary approach, we propose to dissect the mechanisms by which genetically-prone (mouse or human) individuals develop autoimmune activation that leads to gut dysbiosis, which feeds back to autoimmune activation. A consequence of this gut dysbiosis is a disruption of Trp metabolism with the generation of metabolites that activate pro-inflammatory pathways such as mTOR and AhR. Lupus genetic susceptibility may also alter the expression of genes in the endogenous Trp pathway. Establishing causal relationships between these variables and the identification of gut taxa responsible for Trp degradation would represent a significant shift in our understanding of a mechanism by which the microbiome could contribute to lupus pathogenesis.