iScience | VOL. 25
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Microbiota-mediated skewing of tryptophan catabolism modulates CD4+ Tcells in lupus-prone mice.

Publication Date May 20, 2022

Abstract

A skewed tryptophan metabolism has been reported in patients with lupus. Here, we investigated the mechanisms by which it occurs in lupus-susceptible mice, and how tryptophan metabolites exacerbate Tcell activation. Metabolomic analyses demonstrated that tryptophan is differentially catabolized in lupus mice compared to controls and that the microbiota played a role in this skewing. There was no evidence for differential expression of tryptophan catabolic enzymes in lupus mice, further supporting a major contribution of the microbiota to skewing. However, isolated lupus Tcells processed tryptophan differently, suggesting a contribution of Tcell intrinsic factors. Functionally, tryptophan and its microbial product tryptamine increased Tcell metabolism and mTOR activation, while kynurenine promoted interferon gamma production, all of which have been associated with lupus. These results showed that a combination of microbial and Tcell intrinsic factors promotes the production of tryptophan metabolites that enhance inflammatory phenotypes in lupus Tcells.

Concepts
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Lupus-susceptible Mice
Lupus Mice
Lupus-prone Mice
Tryptophan Metabolites
mTOR Activation
Skewed Metabolism
Tcells In Mice
Microbial Factors
Production Of Metabolites
Expression Of Enzymes

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