Microbiota-mediated skewing of tryptophan catabolism modulates CD4+ T cells in lupus-prone mice

Brown, Josephine; Abboud, Georges; Ma, Longhuan; Choi, Seung‐Chul; Kanda, Nathalie; Zeumer-Spataro, Leilani; Lee, Jean; Peng, Weidan; Cagmat, Joy G.; Faludi, Tamas; Mohamadzadeh, Mansour; Garrett, Timothy J.; Mandik-Nayak, Laura; Chervonsky, Alexander V.; Perl, András; Morel, Laurence

doi:10.1016/j.isci.2022.104241

Cited by 30 publications

(28 citation statements)

References 53 publications

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“…Moreover, broad shifts in gut microbiota were observed, including a depletion of Lactobacillus during tryptophan restriction and EAE suppression, an observation that adds relevance to our own studies implicating L. reuteri tryptophan-dependent enhancement of CNS autoimmunity. Interestingly, tryptophan depletion also ameliorated disease in other models of autoimmunity including systemic lupus erythematosus and collagen-induced arthritis [ 114 – 116 ]. Importantly, previous studies failed to pinpoint causative gut microbial species associated with enhancement of autoimmunity in the presence of tryptophan.…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus reuteri tryptophan metabolism promotes host susceptibility to CNS autoimmunity

et al. 2022

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Background Dysregulation of gut microbiota-associated tryptophan metabolism has been observed in patients with multiple sclerosis. However, defining direct mechanistic links between this apparent metabolic rewiring and individual constituents of the gut microbiota remains challenging. We and others have previously shown that colonization with the gut commensal and putative probiotic species, Lactobacillus reuteri, unexpectedly enhances host susceptibility to experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. To identify underlying mechanisms, we characterized the genome of commensal L. reuteri isolates, coupled with in vitro and in vivo metabolomic profiling, modulation of dietary substrates, and gut microbiota manipulation. Results The enzymes necessary to metabolize dietary tryptophan into immunomodulatory indole derivatives were enriched in the L. reuteri genomes, including araT, fldH, and amiE. Moreover, metabolite profiling of L. reuteri monocultures and serum of L. reuteri-colonized mice revealed a depletion of kynurenines and production of a wide array of known and novel tryptophan-derived aryl hydrocarbon receptor (AhR) agonists and antagonists, including indole acetate, indole-3-glyoxylic acid, tryptamine, p-cresol, and diverse imidazole derivatives. Functionally, dietary tryptophan was required for L. reuteri-dependent EAE exacerbation, while depletion of dietary tryptophan suppressed disease activity and inflammatory T cell responses in the CNS. Mechanistically, L. reuteri tryptophan-derived metabolites activated the AhR and enhanced T cell production of IL-17. Conclusions Our data suggests that tryptophan metabolism by gut commensals, such as the putative probiotic species L. reuteri, can unexpectedly enhance autoimmunity, inducing broad shifts in the metabolome and immunological repertoire.

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Section: Discussionmentioning

confidence: 99%

Lactobacillus reuteri tryptophan metabolism promotes host susceptibility to CNS autoimmunity

et al. 2022

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“…In an in vitro assay, kynurenine induces mTORC1 activity in double negative T cells but not in CD4 + or CD8 + T cells derived from human (43). Interestingly, kynurenine enhances CD4 + T cells to produce IFN-g in lupus-prone mice, whereas tryptamine stimulates mTORC1 signaling and glycolytic activity in CD4 + T cells (129). It has been proven that gut microbiota predominantly growing in SLE contributes to this aberrant tryptophan metabolism (128,129).…”

Section: Slementioning

confidence: 99%

“…Interestingly, kynurenine enhances CD4 + T cells to produce IFN-g in lupus-prone mice, whereas tryptamine stimulates mTORC1 signaling and glycolytic activity in CD4 + T cells (129). It has been proven that gut microbiota predominantly growing in SLE contributes to this aberrant tryptophan metabolism (128,129). IDO levels are higher in SLE patients (130) and are associated with the active phenotype in the sunny season (131).…”

Section: Slementioning

confidence: 99%

Glycolysis in Innate Immune Cells Contributes to Autoimmunity

Chen

Zhang

et al. 2022

Front. Immunol.

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Autoimmune diseases (AIDs) refer to connective tissue inflammation caused by aberrant autoantibodies resulting from dysfunctional immune surveillance. Most of the current treatments for AIDs use non-selective immunosuppressive agents. Although these therapies successfully control the disease process, patients experience significant side effects, particularly an increased risk of infection. There is a great need to study the pathogenesis of AIDs to facilitate the development of selective inhibitors for inflammatory signaling to overcome the limitations of traditional therapies. Immune cells alter their predominant metabolic profile from mitochondrial respiration to glycolysis in AIDs. This metabolic reprogramming, known to occur in adaptive immune cells, i.e., B and T lymphocytes, is critical to the pathogenesis of connective tissue inflammation. At the cellular level, this metabolic switch involves multiple signaling molecules, including serine–threonine protein kinase, mammalian target of rapamycin, and phosphoinositide 3-kinase. Although glycolysis is less efficient than mitochondrial respiration in terms of ATP production, immune cells can promote disease progression by enhancing glycolysis to satisfy cellular functions. Recent studies have shown that active glycolytic metabolism may also account for the cellular physiology of innate immune cells in AIDs. However, the mechanism by which glycolysis affects innate immunity and participates in the pathogenesis of AIDs remains to be elucidated. Therefore, we reviewed the molecular mechanisms, including key enzymes, signaling pathways, and inflammatory factors, that could explain the relationship between glycolysis and the pro-inflammatory phenotype of innate immune cells such as neutrophils, macrophages, and dendritic cells. Additionally, we summarize the impact of glycolysis on the pathophysiological processes of AIDs, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and ankylosing spondylitis, and discuss potential therapeutic targets. The discovery that immune cell metabolism characterized by glycolysis may regulate inflammation broadens the avenues for treating AIDs by modulating immune cell metabolism.

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“…Brown J et al. demonstrated that intestinal flora promoted the production of tryptophan metabolites, including Kyn, which enhanced T cell activation in lupus mice ( 132 ). Feeding a high tryptophan diet (including an increase in Kyn) to lupus-prone TC mice resulted in dysbiosis of their intestinal flora and stimulated autoantibody production and produced lupus-like disease when their feces were transferred to germ-free kindred B6 mice ( 133 ).…”

Section: Role Of Ahr In the Development Of Slementioning

confidence: 99%

“…The effect of mTOR blockade on cytokine production in SLE patients has been proved ( 177 , 178 ). Tryptophan and its metabolites increase T cell metabolism and mTOR activation, and Kyn promotes IFN-γ production, all of which are associated with the development of lupus in mice ( 132 ). Overall, the pro-inflammatory effects of AhR stimulation by Kyn and the activation of mTOR by Kyn play an important role in the pathogenesis of SLE, there is likely to be a mutually reinforcing relationship between the two.…”

Section: Role Of Ahr In the Development Of Slementioning

confidence: 99%

The key player in the pathogenesis of environmental influence of systemic lupus erythematosus: Aryl hydrocarbon receptor

et al. 2022

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The aryl hydrocarbon receptor was previously known as an environmental receptor that modulates the cellular response to external environmental changes. In essence, the aryl hydrocarbon receptor is a cytoplasmic receptor and transcription factor that is activated by binding to the corresponding ligands, and they transmit relevant information by binding to DNA, thereby activating the transcription of various genes. Therefore, we can understand the development of certain diseases and discover new therapeutic targets by studying the regulation and function of AhR. Several autoimmune diseases, including systemic lupus erythematosus (SLE), have been connected to AhR in previous studies. SLE is a classic autoimmune disease characterized by multi-organ damage and disruption of immune tolerance. We discuss here the homeostatic regulation of AhR and its ligands among various types of immune cells, pathophysiological roles, in addition to the roles of various related cytokines and signaling pathways in the occurrence and development of SLE.

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Microbiota-mediated skewing of tryptophan catabolism modulates CD4+ T cells in lupus-prone mice

Cited by 30 publications

References 53 publications

Lactobacillus reuteri tryptophan metabolism promotes host susceptibility to CNS autoimmunity

Lactobacillus reuteri tryptophan metabolism promotes host susceptibility to CNS autoimmunity

Glycolysis in Innate Immune Cells Contributes to Autoimmunity

The key player in the pathogenesis of environmental influence of systemic lupus erythematosus: Aryl hydrocarbon receptor

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