Tryptophan-Restriction Diets Help to Maintain L-Tryptophan Homeostasis in Tryptophan 2,3-Dioxygenase Knockout Mice

Maeta, Akihiro; Fukuwatari, Tsutomu; Funakoshi, Hiroshi; Nakamura, Toshikazu; Shibata, Katsumi

doi:10.4137/ijtr.s12206

Cited by 9 publications

(8 citation statements)

References 21 publications

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“…So far, studies in Tdo −/− mice have focused mainly on brain and behavioral phenomena, including effects on cerebral serotonin metabolism, hippocampal morphology and anxiety (37,79), but these animals are clearly also valuable for investigating catabolic events following tryptophan ingestion (80) as well as cellular and molecular phenomena involved in inflammation, infection and other states of immunopathology (81). In contrast, as IDO is increasingly recognized as a key regulator of the immune system, and IDO1 has emerged as an attractive pharmacological target for the prevention or treatment of illnesses ranging from viral diseases and cancer (82–84) to neurological and psychiatric disorders (58–60), Ido −/− mice are already being widely used to investigate both the beneficial and the possible detrimental effects of IDO manipulation (40,85–87).…”

Section: Discussionmentioning

confidence: 99%

Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice

Larkin

Sathyasaikumar

Notarangelo

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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In mammals, the majority of the essential amino acid tryptophan is degraded via the kynurenine pathway (KP). Several KP metabolites play distinct physiological roles, often linked to immune system functions, and may also be causally involved in human diseases including neurodegenerative disorders, schizophrenia and cancer. Pharmacological manipulation of the KP has therefore become an active area of drug development. To target the pathway effectively, it is important to understand how specific KP enzymes control levels of the bioactive metabolites in vivo. Here, we conducted a comprehensive biochemical characterization of mice with a targeted deletion of either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), the two initial rate-limiting enzymes of the KP. These enzymes catalyze the same reaction, but differ in biochemical characteristics and expression patterns. We measured KP metabolite levels and enzyme activities and expression in several tissues in basal and immune-stimulated conditions. Although our study revealed several unexpected downstream effects on KP metabolism in both knockout mice, the results were essentially consistent with TDO-mediated control of basal KP metabolism and a role of IDO in phenomena involving stimulation of the immune system.

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Section: Discussionmentioning

confidence: 99%

Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice

Larkin

Sathyasaikumar

Notarangelo

et al. 2016

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…Blocking monoclonal anti-CTLA4 (9H10), anti-PD1 (RMP1-14), and control isotype IgG2a (2A3) were purchased from BioXCell and were injected intraperitoneally at the doses indicated in the figure legends. The standard and Trp-low diets were prepared by Special Diet Services Ltd, as described by Maeta and colleagues (46). Besides Trp, the two diets were similar in composition, except for a small excess of the other amino acids in the Trp-low diet.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

Inhibition of Tryptophan-Dioxygenase Activity Increases the Antitumor Efficacy of Immune Checkpoint Inhibitors

Schramme

Crosignani

Frederix

et al. 2020

Cancer Immunology Research

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◥Tryptophan 2,3-dioxygenase (TDO) is an enzyme that degrades tryptophan into kynurenine and thereby induces immunosuppression. Like indoleamine 2,3-dioxygenase (IDO1), TDO is considered as a relevant drug target to improve the efficacy of cancer immunotherapy. However, its role in various immunotherapy settings has not been fully characterized. Here, we described a new small-molecule inhibitor of TDO that can modulate kynurenine and tryptophan in plasma, liver, and tumor tissue upon oral administration. We showed that this compound improved the ability of anti-CTLA4 to induce rejection of CT26 tumors expressing TDO. To better characterize TDO as a therapeutic target, we used TDO-KO mice and found that anti-CTLA4 or anti-PD1 induced rejection of MC38 tumors in TDO-KO, but not in wild-type mice. As MC38 tumors did not express TDO, we related this result to the high systemic tryptophan levels in TDO-KO mice, which lack the hepatic TDO needed to contain blood tryptophan. The antitumor effectiveness of anti-PD1 was abolished in TDO-KO mice fed on a tryptophan-low diet that normalized their blood tryptophan level. MC38 tumors expressed IDO1, which could have limited the efficacy of anti-PD1 in wild-type mice and could have been overcome in TDO-KO mice due to the high levels of tryptophan. Accordingly, treatment of mice with an IDO1 inhibitor improved the efficacy of anti-PD1 in wild-type, but not in TDO-KO, mice. These results support the clinical development of TDO inhibitors to increase the efficacy of immunotherapy of TDO-expressing tumors and suggest their effectiveness even in the absence of tumoral TDO expression.See article by Hoffmann et al., p. 19

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“…To limit NAD + biosynthesis from Trp, we implemented a low level of Trp (0.14%). This Trp level is still sufficient for normal growth in mice . Since white adipose tissue (WAT) may play a crucial role in metabolic flexibility at the whole body level , we focused on metabolic flexibility and WAT function.…”

Section: Introductionmentioning

confidence: 99%

Effects of a wide range of dietary nicotinamide riboside (NR) concentrations on metabolic flexibility and white adipose tissue (WAT) of mice fed a mildly obesogenic diet

Shi

Hegeman

Dartel

et al. 2017

Molecular Nutrition Food Res

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ScopeMetabolic flexibility is the ability to switch metabolism between carbohydrate oxidation (CHO) and fatty acid oxidation (FAO) and is a biomarker for metabolic health. The effect on metabolic health of nicotinamide riboside (NR) as an exclusive source of vitamin B3 is unknown and is examined here for a wide range of NR.Design and methodsNine‐week‐old male C57BL/6JRcc mice received a semi‐purified mildly obesogenic (40 en% fat) diet containing 0.14% L‐tryptophan and either 5, 15, 30, 180, or 900 mg NR per kg diet for 15 weeks. Body composition and metabolic parameters were analyzed. Metabolic flexibility was measured using indirect calorimetry. Gene expression in epididymal white adipose tissue (eWAT) was measured using qRT‐PCR .ResultsThe maximum delta respiratory exchange ratio when switching from CHO to FAO (maxΔRERCHO1→FAO) and when switching from FAO to CHO (maxΔRERFAO→CHO2) were largest in 30 mg NR per kg diet (30NR). In eWAT, the gene expression of Pparγ, a master regulator of adipogenesis, and of Sod2 and Prdx3, two antioxidant genes, were significantly upregulated in 30NR compared to 5NR.Conclusion30NR is most beneficial for metabolic health, in terms of metabolic flexibility and eWAT gene expression, of mice on an obesogenic diet.

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Tryptophan-Restriction Diets Help to Maintain L-Tryptophan Homeostasis in Tryptophan 2,3-Dioxygenase Knockout Mice

Cited by 9 publications

References 21 publications

Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice

Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice

Inhibition of Tryptophan-Dioxygenase Activity Increases the Antitumor Efficacy of Immune Checkpoint Inhibitors

Effects of a wide range of dietary nicotinamide riboside (NR) concentrations on metabolic flexibility and white adipose tissue (WAT) of mice fed a mildly obesogenic diet

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