Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

Sorgdrager, Freek J. H.; Naudé, Petrus J.W.; Kema, Ido P.; Nollen, Ellen A. A.; Deyn, Peter Paul De

doi:10.3389/fimmu.2019.02565

Cited by 248 publications

(237 citation statements)

References 88 publications

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“…In the MAIZE DCS rats, this inflammatory response can be the consequence of a reorganization of the microbiota as is also suggested for the increase in hippurate [31][32][33][34] . As it happens, inflammation in the MAIZE DCS rats is suggested by the joint increase in kynurenine from the tryptophan metabolism 42,43 and in 2,6 quinolinediol with antibiotic properties, which is thought to control an explosive development of the microbial community. It seems to be limited to the intestine 44 .…”

Section: Expression Of Metabolites Suggesting Inflammationmentioning

confidence: 99%

Cecal metabolome fingerprint in a rat model of decompression sickness with neurological disorders

Maistre¹,

Gaillard²,

Martin³

et al. 2020

Sci Rep

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Massive bubble formation after diving can lead to decompression sickness (DCS), which can result in neurological disorders. We demonstrated that hydrogen production from intestinal fermentation could exacerbate DCS in rats fed with a standard diet. The aim of this study is to identify a fecal metabolomic signature that may result from the effects of a provocative hyperbaric exposure. The fecal metabolome was studied in two groups of rats previously fed with maize or soy in order to account for diet effects. 64 animals, weighing 379.0_20.2 g on the day of the dive, were exposed to the hyperbaric protocol. The rats were separated into two groups: 32 fed with maize (Div MAIZE) and 32 fed with soy (Div SOY). Gut fermentation before the dive was estimated by measuring exhaled hydrogen. Following hyperbaric exposure, we assessed for signs of DCS. Blood was analyzed to assay inflammatory cytokines. Conventional and ChemRICH approaches helped the metabolomic interpretation of the cecal content. The effect of the diet is very marked at the metabolomic level, a little less in the blood tests, without this appearing strictly in the clinic status. Nevertheless, 37 of the 184 metabolites analyzed are linked to clinical status. 35 over-expressed compounds let suggest less intestinal absorption, possibly accompanied by an alteration of the gut microbial community, in DCS. The decrease in another metabolite suggests hepatic impairment. This spectral difference of the ceca metabolomes deserves to be studied in order to check if it corresponds to functional microbial particularities.

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Section: Expression Of Metabolites Suggesting Inflammationmentioning

confidence: 99%

Cecal metabolome fingerprint in a rat model of decompression sickness with neurological disorders

Maistre¹,

Gaillard²,

Martin³

et al. 2020

Sci Rep

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show abstract

“…Additionally, kynurenines have been implicated in activating the aryl hydrocarbon receptor (AhR) in T cells which contributes to the generation of regulatory T cells, but also to the capacity of DCs (in this case GM-CSF differentiated bone marrow-derived DCs (GM-DCs)) to generate regulatory T cells [57,58]. Other tryptophan metabolites (e.g., serotonin, kynurenic acid, NAD+, indoles) have been implicated in inflammation as well and could therefore potentially be important during infection [59]. Thus, both the depletion of tryptophan and the generation of its breakdown products can affect mTOR activation and/or contribute to the manipulation of the immune response.…”

Section: Tryptophanmentioning

confidence: 99%

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

Nouwen

Everts

2020

Cells

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Myeloid cells, including macrophages and dendritic cells, represent an important first line of defense against infections. Upon recognition of pathogens, these cells undergo a metabolic reprogramming that supports their activation and ability to respond to the invading pathogens. An important metabolic regulator of these cells is mammalian target of rapamycin (mTOR). During infection, pathogens use host metabolic pathways to scavenge host nutrients, as well as target metabolic pathways for subversion of the host immune response that together facilitate pathogen survival. Given the pivotal role of mTOR in controlling metabolism and DC and macrophage function, pathogens have evolved strategies to target this pathway to manipulate these cells. This review seeks to discuss the most recent insights into how pathogens target DC and macrophage metabolism to subvert potential deleterious immune responses against them, by focusing on the metabolic pathways that are known to regulate and to be regulated by mTOR signaling including amino acid, lipid and carbohydrate metabolism, and autophagy.

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“…Upon IDO activation by stress and inflammatory response, TRP depletion activates the stress response kinase, general control non-depressible 2 (GCN2) by binding to uncharged tRNA. GCN2 activation leads to downregulation of the CD3 zeta (ζ)-chain in CD8 + T cells, blockage of T helper (Th) 17 cell (Th17) cell differentiation and cell cycle entry by T cell receptor-activated T cells, and activation of resting CD4 + Tregs [84]. TRP depletion also inhibits the nutrient-sensing mammalian target of rapamycin 1 pathway to inhibit T effector cell function and growth [85].…”

Section: Tolerogenic Shift Of Adaptive Immune Response By Kynurenine mentioning

confidence: 99%

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

2020

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Worldwide, 50 million people suffer from dementia, a group of symptoms affecting cognitive and social functions, progressing severely enough to interfere with daily life. Alzheimer’s disease (AD) accounts for most of the dementia cases. Pathological and clinical findings have led to proposing several hypotheses of AD pathogenesis, finding a presence of positive feedback loops and additionally observing the disturbance of a branch of tryptophan metabolism, the kynurenine (KYN) pathway. Either causative or resultant of dementia, elevated levels of neurotoxic KYN metabolites are observed, potentially upregulating multiple feedback loops of AD pathogenesis. Memantine is an N-methyl-D-aspartate glutamatergic receptor (NMDAR) antagonist, which belongs to one of only two classes of medications approved for clinical use, but other NMDAR modulators have been explored so far in vain. An endogenous KYN pathway metabolite, kynurenic acid (KYNA), likewise inhibits the excitotoxic NMDAR. Besides its anti-excitotoxicity, KYNA is a multitarget compound that triggers anti-inflammatory and antioxidant activities. Modifying the KYNA level is a potential multitarget strategy to normalize the disturbed KYN pathway and thus to alleviate juxtaposing AD pathogeneses. In this review, the maintenance of KYN metabolism by modifying the level of KYNA is proposed and discussed in search for a novel lead compound against the progression of dementia.

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Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

Cited by 248 publications

References 88 publications

Cecal metabolome fingerprint in a rat model of decompression sickness with neurological disorders

Cecal metabolome fingerprint in a rat model of decompression sickness with neurological disorders

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

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