The end of the road for the tryptophan depletion concept in pregnancy and infection

Abstract

We hypothesize that: (1) L-tryptophan (Trp) is greatly utilized and not depleted in pregnancy; (2) fetal tolerance is achieved in part through immunosuppressive kynurenine (Kyn) metabolites produced by the flux of plasma free (non-albumin-bound) Trp down the Kyn pathway; (3) the role of indoleamine 2,3-dioxygenase (IDO) in infection is not related to limitation of an essential amino acid, but is rather associated with stress responses and the production of Kyn metabolites that regulate the activities of antigen presenting cells and T-cells, as well as increased NAD+ synthesis in IDO-expressing cells; (4) Trp depletion is not a host defence mechanism, but is a consequence of Trp utilization. We recommend that future studies in normal and abnormal pregnancies and in patients with infections or cancer should include measurements of plasma free Trp, determinants of Trp binding (albumin and non-esterified fatty acids), total Trp, determinants of activities of the Trp-degrading enzymes Trp 2,3-dioxygenase (TDO) (cortisol) and IDO (cytokines) and levels of Kyn metabolites. We also hypothesize that abnormal pregnancies and failure to combat infections or cancer may be associated with excessive Trp metabolism that can lead to pathological immunosuppression by excessive production of Kyn metabolites. Mounting evidence from many laboratories indicates that Trp metabolites are key regulators of immune cell behaviour, whereas Trp depletion is an indicator of extensive utilization of this key amino acid.

Binding Properties of Different Categories of Ido1 Inhibitors: A Microscale Thermophoresis Study

“…Results of docking studies of mitomycin-C (13) are in accordance with the assessed K d . Indeed, compound 13 shows the worst g-score among the studied compounds.…”

“…Although the former case leads to prolongation of IDO1's half-life and long-term immune-tolerance; in the latter case, IDO1 is tagged for proteasome degradation eventually leading to inflammatory response. These autoregulatory signaling functions add on the effects arising from the catalytic activity of the enzyme that are mediated by consumption of L-Trp (1) and/or production of bioactive KP metabolites (3-5) [11][12][13].…”

Activation of the tryptophan/serotonin pathway is associated with severity and predicts outcomes in pneumonia: results of a long-term cohort study

“…Finally, the ratios of IDO and TPH are estimated and not measured. In future evaluations, complete measurements of all involved metabolites should be performed including plasma free TRP, determinants of TRP binding (albumin and nonesterified fatty acids), total TRP, TDO, IDO and levels of KYN metabolites [43].…”

Tryptophan and kynurenines: continuing to court controversy

“…This attitude persisted until two new chapters were opened in the early 1980s. One of these, most directly relevant to the article by Badawy et al [1] was the observation that interferon-γ , produced by mammalian cells when exposed to infection or inflammatory conditions, powerfully activated the first enzyme of the extra-hepatic kynurenine pathway, indoleamine 2,3-dioxygenase (IDO). This activation was associated with a suppression of the proliferation of infecting organisms and, since that suppression could be prevented by raising the tryptophan levels (in cell cultures), the mechanism of suppression was simplistically attributed to the reduction in tryptophan preventing protein synthesis and cell division [2][3][4].…”

“…It is in this context that the review by Badawy et al [1] should be viewed. The authors have brought together the arguments for and against the tryptophan depletion concept, criticizing the former by a series of reasoned arguments and reminders that tryptophan regulation is an extremely complex phenomenon in which all the components must be considered.…”