The end of the road for the tryptophan depletion concept in pregnancy and infection
Open accessAbstract
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.
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Recent studies have questioned the significance of tryptophan depletion as an immunosuppressive mechanism.
“However, recent studies have questioned the significance of this mechanism (32,33).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [33]
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“Yet, the precise nature of the benefits that the kynurenine pathway confers on fitness is a matter of ongoing debate (7, 9, 16, 22, 23).”
BackgroundSelf-citation
- Authors
- Badawy, A. A.-B., Namboodiri, A. M. A., & Moffett, J. R.
- Affiliations
- Cardiff Metropolitan University (GB)
- Uniformed Services University of the Health Sciences (US)
- Corresponding author
- Badawy, Abdulla A.-B.
- Venue
- Clinical Science
- Publisher
- Portland Press Ltd.
- Published
- 2016-06-29
- Volume
- 130
- Issue
- 15
- Pages
- 1327-1333
- ISSN
- 0143-5221 (ISSN-L)
- 1470-8736
- PMC
- PMC4926258
- OpenAlex
- W2467541392
- Cited by
- 92
- References
- 62
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 10 · 2019: 15 · 2018: 9 · 2017: 15 · 2016: 5
- FWCI
- 0.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Clinical Science (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Cardiff Metropolitan Research Repository (Cardiff Metropolitan University) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- tryptophan depletion, tryptophan metabolism, kynurenine pathway, indoleamine 2,3-dioxygenase, tryptophan 2,3-dioxygenase, pregnancy, infection, immunosuppression, plasma free tryptophan, tryptophan binding, albumin, free fatty acids, NAD+ synthesis, antigen-presenting cells, T cells, stress response
- MeSH terms
- Antigen-Presenting Cells, Communicable Diseases, Female, Fetus, Humans, Immune Tolerance, Kynurenine, NAD, Pregnancy, Pregnancy Complications, Protein Binding, T-Lymphocytes, Tryptophan, Tryptophan Oxygenase, Oxidative Stress, Indoleamine-Pyrrole 2,3,-Dioxygenase
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