Tryptophan is an essential amino acid whose metabolites play key roles in diverse physiological processes. Due to low reserves in the body, especially under various catabolic conditions, tryptophan deficiency manifests itself rapidly, and both the serotonin and kynurenine pathways of metabolism are clinically significant in critically ill patients. In this review, we highlight these pathways as sources of serotonin and melatonin, which then regulate neurotransmission, influence circadian rhythm, cognitive functions, and the development of delirium. Kynurenines serve important signaling functions in inter-organ communication and modulate endogenous inflammation. Increased plasma kynurenine levels and kynurenine-tryptophan ratios are early indicators for the development of sepsis. They also influence the regulation of skeletal muscle mass and thereby the development of polyneuromyopathy in critically ill patients. The modulation of tryptophan metabolism could help prevent and treat age-related disease with low grade chronic inflammation as well as post intensive care syndrome in all its varied manifestations: cognitive decline (including delirium or dementia), physical impairment (catabolism, protein breakdown, loss of muscle mass and tone), and mental impairment (depression, anxiety or post-traumatic stress disorder).

Department of Anaesthesiology and Intensive Care Medicine University Hospital Ostrava 708 52 Ostrava Czech Republic

Department of Internal Medicine 3rd Faculty of Medicine Charles University Prague and Teaching Thomayer Hospital 140 59 Prague Czech Republic

Institute of Physiology and Pathophysiology Faculty of Medicine University of Ostrava 703 00 Ostrava Czech Republic

Zobrazit více v PubMed

Barik S. The uniqueness of tryptophan in biology: Properties, metabolism, interactions and localizations in proteins. Int. J. Mol. Sci. 2020;21:8776. doi: 10.3390/ijms21228776. PubMed DOI PMC

LeFloćh N., Otten W., Merlot E. Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids. 2011;41:1195–1205. doi: 10.1007/s00726-010-0752-7. PubMed DOI

Cervenka I., Agudelo L.Z., Ruas J.L. Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health. Science. 2017;357:eaaf9794. doi: 10.1126/science.aaf9794. PubMed DOI

Singer M., Deutschman C.S., Seymour C.W., Shankar-Hari M., Annane D., Bauer M., Bellomo R., Bernard G.R., Chiche J.D., Coopersmith C.M., et al. The third international consensus definitions for sespis and septic shock (Sepsis-3) JAMA. 2016;315:801–810. doi: 10.1001/jama.2016.0287. PubMed DOI PMC

Sorgdrager F.J.H., Naudé P.J.W., Kema I.P., Nollen E.A., Deyn P.P.D. Tryptophan metabolism in inflammaging: From biomarker to therapeutic target. Front. Immunol. 2019;10:2565. doi: 10.3389/fimmu.2019.02565. PubMed DOI PMC

Munn D.H., Mellor A.L. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34:137–143. doi: 10.1016/j.it.2012.10.001. PubMed DOI PMC

Munn D.H., Sharma M.D., Baban B., Hardin H.P., Zhang Y., Ron D., Mellor A.L. GCN2 kinase in T cells mediated proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005;22:633–642. doi: 10.1016/j.immuni.2005.03.013. PubMed DOI

Weichhart T., Hengstschläger M., Linke M. Regulation of innate immune cell function by mTOR. Nat. Rev. Immunol. 2015;15:599–614. doi: 10.1038/nri3901. PubMed DOI PMC

Schröcksnadel K., Wirleitner B., Winkler C., Fuchs D. Monitoring tryptophan metabolism in chronic immune activation. Clin. Chim. Acta. 2006;364:82–90. doi: 10.1016/j.cca.2005.06.013. PubMed DOI

Schmidt S.V., Schultze J.L. New insight into IDO biology in bacterial and viral infections. Front. Immunol. 2014;5:384. doi: 10.3389/fimmu.2014.00384. PubMed DOI PMC

Keshavarz M., Solaymani-Mohammadi F., Namdari H., Arjeini Y., Mousavi M.J., Rezaei F. Metabolic host response and therapeutic approaches to influenza infection. Cell. Mol. Biol. Lett. 2020;25:15. doi: 10.1186/s11658-020-00211-2. PubMed DOI PMC

Planes R., Bahraoui E. HIV-1 Tat protein induces the production of IDO in human monocyte derived-dendritic cells through a direct mechanism: Effect on T cells proliferations. PLoS ONE. 2013;8:e74551. doi: 10.1371/journal.pone.0074551. PubMed DOI PMC

Cecchinato V., Tryniszewska E., Ma Z.M., Vaccari M., Boasso A., Tsai W.P., Petrovas C., Fuchs D., Heraud J.M., Venzon D., et al. Immune activation driven by CTLA-4 blokade augments viral replication at mucosal sites in simian immunodeficiency virus infection. J. Immunol. 2008;180:5439–5447. doi: 10.4049/jimmunol.180.8.5439. PubMed DOI PMC

Fox J.M., Sage L.K., Huang L., Barber J., Klonowski K.D., Mellor A.L., Tompkins S.M., Tripp R.A. Inhibition of indoleamine 2,3-dioxygenase enhances the T–cell response to influenza virus infection. J. Gen. Virol. 2013;94:1451–1461. doi: 10.1099/vir.0.053124-0. PubMed DOI PMC

Larrea E., Riezu-Boj J.I., Gil-Guerrero L., Casares N., Aldabe R., Sarobe P., Civeira M.P., Heeney J.L., Rollier C., Verstrepen B., et al. Upregulation of indoleamine 2,3-dioxygenase in hepatitis C virus infection. J. Virol. 2007;81:3662–3666. doi: 10.1128/JVI.02248-06. PubMed DOI PMC

Van der Sluijs K.F., Nijhuis M., Levels J.H.M., Florquin S., Mellor A.L., Jansen H.M., van der Poll T., Lutter R. Influenza–induced expression of indoleamine2,3-dioxygenase enhances interleukin-10 production and bacterial outgrowth during secondary pneumococcal pneumonia. J. Infect. Dis. 2006;193:214–222. doi: 10.1086/498911. PubMed DOI

Lansbury L., Lim B., Baskaran V., Lim W.S. Co-infections in people with COVID-19: A systematic review and meta-analysis. J. Infect. 2020;81:266–275. doi: 10.1016/j.jinf.2020.05.046. PubMed DOI PMC

Lai C.C., Yu W.L. COVID-19 associated with pulmonary aspergillosis: A literature review. J. Microbiol. Immunol. Infect. 2021;54:46–53. doi: 10.1016/j.jmii.2020.09.004. PubMed DOI PMC

Zanoni I., Granucci F. Role of CD14 in host protection against infections and in metabolism regulation. Front. Cell. Infect. Microbiol. 2013;3:32. doi: 10.3389/fcimb.2013.00032. PubMed DOI PMC

Tattevin P., Monnier D., Tribut O., Dulong J., Bescher N., Mourcin F., Uhel F., Tulzo Y.L., Tarte K. Enhanced indoleamine 2,3-dioxygenase activity in patients with severe sepsis and septic shock. J. Infect. Dis. 2010;201:956–966. doi: 10.1086/650996. PubMed DOI

Lögters T.T., Laryea M.D., Altrichter J., Sokolowski J., Cinatl J., Reipen J., Linhart W., Windolf J., Scholz M., Wild M. Increased plasma kynurenine values and kynurenine-tryptophan ratios after major trauma are early indicators for the development of sepsis. Shock. 2009;32:29–34. doi: 10.1097/SHK.0b013e31819714fa. PubMed DOI

Zeden J.P., Fuchs G., Holtfreter B., Schefold J.C., Reinke P., Domanska G., Haas J.P., Gruendling M., Westerholt A., Schuett C. Excessive tryptophan catabolism along the kynurenine pathway precedes ongoing sepsis in critically ill patients. Anaesth. Intensive Care. 2010;38:307–316. doi: 10.1177/0310057X1003800213. PubMed DOI

Jung I.D., Lee M.G., Chang J.H., Lee J.S., Jeong Y.I., Lee C.M., Park W.S., Han J., Seo S.K., Lee S.Y., et al. Blockade of indoleamine 2,3-dioxygenase protects mice against lipopolysaccharide-induced endotoxin shock. J. Immunol. 2009;5:3146–3154. doi: 10.4049/jimmunol.0803104. PubMed DOI

Hu B., Huang S., Yin L. The cytokine storm and Covid-19. J. Med. Virol. 2021;93:250–256. doi: 10.1002/jmv.26232. PubMed DOI PMC

Schefold J.C., von Haehling S., Corsepius M., Pohle C., Kruschke P., Zuckermann H., Volk H.D., Reinke P. A novel selective extracorporeal intervention in sepsis: Immunoadsorption of endotoxin, interleukin 6, and complement-activating product 5a. Shock. 2007;28:418–425. doi: 10.1097/shk.0b013e31804f5921. PubMed DOI

Zaher S.S., Germain C., Fu H., Larkin D.F.P., George A.J.T. 3-hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival. Investig. Opthalmol. Vis. Sci. 2011;52:2640–2648. doi: 10.1167/iovs.10-5793. PubMed DOI PMC

Romani L., Zelante T., De Luca A., Fallarino F., Puccetti P. IL-17 and therapeutic kynurenines in pathogenic inflammation to fungi. J. Immunol. 2008;180:5157–5162. doi: 10.4049/jimmunol.180.8.5157. PubMed DOI

Salazar F., Awuah D., Negm O.H., Shakib F., Ghaemmaghami A.M. The role of indoleamine 2,3-dioxygenase-aryl hydrocarbon receptor pathway in the TLR4-induces tolerogenic phenotype in human DCs. Sci. Rep. 2017;7:43337. doi: 10.1038/srep43337. PubMed DOI PMC

Jiang H.Y., Wek S.A., McGrath B.C., Scheuner D., Kaufman R.J., Cavener D.R., Wek R.C. Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 is required for activation of NF-kappaB in response to diverse cellular stresses. Mol. Cell. Biol. 2003;23:5651–5663. doi: 10.1128/MCB.23.16.5651-5663.2003. PubMed DOI PMC

Liu H., Huang L., Bradley J., Liu K., Bardhan K., Ron D., Mellor A.L., Munn D.H., McGaha T.L. GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology. Mol. Cell. Biol. 2014;34:428–438. doi: 10.1128/MCB.00946-13. PubMed DOI PMC

Ninomiya S., Nakamura N., Nakamura H., Mizutani T., Kaneda Y., Yamaguchi K., Matsumoto T., Kitagawa J., Kanemura N., Shiraki M., et al. Low levels of serum tryptophan underlie skeletal muscle atrophy. Nutrients. 2020;12:978. doi: 10.3390/nu12040978. PubMed DOI PMC

Preiser J.C., Ichai C., Orban J.C., Groeneveld A.B.J. Metabolic response to the stress of critical illness. Br. J. Anaesth. 2014;113:945–954. doi: 10.1093/bja/aeu187. PubMed DOI

Zorowitz R.D. ICU-acquired weakness: A rehabilitation perspective of diagnosis, treatment, and functional management. Chest. 2016;150:966–971. doi: 10.1016/j.chest.2016.06.006. PubMed DOI

Bar-Peled L., Sabatini D.M. Regulation of mTORC1 by amino acids. Trends Cell Biol. 2014;24:400–406. doi: 10.1016/j.tcb.2014.03.003. PubMed DOI PMC

Ham D.J., Caldow M.K., Lynch G.S., Koopman R. Leucine as a treatment for muscle wasting: A critical review. Clin. Nutr. 2014;33:937–945. doi: 10.1016/j.clnu.2014.09.016. PubMed DOI

Supinski G.S., Callahan L.A. Hydroxymethylbutyrate and eicosapentaenoic acid: Preclinical studies to improve muscle function in critical care medicine. In: Rajendram R., Preedy V.R., Patel V.B., editors. Diet and Nutrition in Critical Care. Springer; New York, NY, USA: 2015. pp. 1135–1148.

Martin K.S., Azzolini M., Ruas J.L. The kynurenine connection: How exercise shifts muscle tryptophan metabolism and affects energy homeostasis, the immune system, and the brain. Am. J. Physiol. Cell Physiol. 2020;318:C818–C830. doi: 10.1152/ajpcell.00580.2019. PubMed DOI

Jackman S.R., Witard O.C., Philp A., Wallis G.A., Barr K., Tipton K.D. Branched-chain amino acid ingestion stimulates muscle myofibrillar protein synthesis following resistance exercise in humans. Front. Physiol. 2017;8:390. doi: 10.3389/fphys.2017.00390. PubMed DOI PMC

Dukes A., Davis C., El Refaey M., Upadhyay S., Mork S., Arounleut P., Johnson M.H., Hill W.D., Isales C.M., Hamrick M.W. The aromatic amino acid tryptophan stimulates skeletal muscle IGF1/p70s6k/mTOR signaling in vivo and the expression of myogenic genes in vitro. Nutrition. 2015;31:1018–1024. doi: 10.1016/j.nut.2015.02.011. PubMed DOI PMC

Lee M.N., Ha S.H., Kim J., Koh A., Lee C.S., Kim J.H., Jeon H., Kim D.H., Suh P.G., Ryu S.H. Glycolytic flux signals to mTOR through glyceraldehyde-3-phosphate dehydrogenase-mediated regulation of Rheb. Mol. Cell. Biol. 2009;29:3991–4001. doi: 10.1128/MCB.00165-09. PubMed DOI PMC

Johannesson E., Simrén M., Strid H., Bajor A., Sadik R. Physical activity improves symptoms in irritable bowel syndrome: A randomized controlled trial. Am. J. Gastroenterol. 2011;106:915–922. doi: 10.1038/ajg.2010.480. PubMed DOI

Cavallazzi R., Saad M., Marik P.E. Delirium in the ICU: An overview. Ann. Intensive Care. 2012;2:49. doi: 10.1186/2110-5820-2-49. PubMed DOI PMC

Girard T.D., Pandharipande P.P., Ely E.W. Delirium in the intensive care unit. Crit. Care. 2008;12:S3. doi: 10.1186/cc6149. PubMed DOI PMC

Stone T.W., Darlington L.G. The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br. J. Pharmacol. 2013;169:1211–1227. doi: 10.1111/bph.12230. PubMed DOI PMC

Hafstad Solvang S.E., Nordrehaug J.E., Tell G.S., Nygard O., McCann A., Ueland P.M., Midttun O., Meyer K., Vedeler C.A., Aarsland D., et al. The kynurenine pathway and cognitive performance in community-dwelling older adults. The Hordaland Health Study. Brain Behav. Immun. 2019;75:155–162. doi: 10.1016/j.bbi.2018.10.003. PubMed DOI

Anderson G., Carbone A., Mazzoccoli G. Tryptophan metabolites and aryl hydrocarbon receptor in severe acute respiratory syndrome, coronavirus-2 (SARS-CoV-2) Pathophysiology. Int. J. Mol. Sci. 2021;22:1597. doi: 10.3390/ijms22041597. PubMed DOI PMC

Káňová M., Kohout P. Serotonin-its synthesis and roles in the healthy and the critically ill. Int. J. Mol. Sci. 2021;22:4837. doi: 10.3390/ijms22094837. PubMed DOI PMC

Haspel J.A., Anafi R., Brown M.K., Cermakian N., Depner C., Desplats P., Gelman A.E., Haack M., Jelic S., Kim B.S., et al. Perfect timing: Circadian rhythms, sleep, and immunity- an NIH workshop summary. JCI Insight. 2020;5:e131487. doi: 10.1172/jci.insight.131487. PubMed DOI PMC

Calvo J.R., Gonzáles-Yanes C., Maldonado M.D. The role of melatonin in the cells of the innate immunity: A review. J. Pineal Res. 2013;55:103–120. doi: 10.1111/jpi.12075. PubMed DOI

Juybari K.B., Pourhanifeh M.H., Hosseinzadeh A., Hemati K., Mehrzadi S. Melatonin potentials against viral infections including COVID-19: Current evidence and new findings. Virus Res. 2020;287:198108. doi: 10.1016/j.virusres.2020.198108. PubMed DOI PMC

Lewis M.C., Barnett S.R. Postoperative delirium: The tryptophan dyregulation model. Med. Hypotheses. 2004;63:402–406. doi: 10.1016/j.mehy.2004.01.033. PubMed DOI

Dunne S.S., Coffey J.C., Konje S., Gasior S., Clancy C.C., Gulati G., Meagher D., Dunne C.P. Biomarkers in delirium: A systematic review. J. Psychosom. Res. 2021;147:110530. doi: 10.1016/j.jpsychores.2021.110530. PubMed DOI

Roager H.M., Licht T.R. Microbial tryptophan catabolites in health and disease. Nat. Commun. 2018;9:3294. doi: 10.1038/s41467-018-05470-4. PubMed DOI PMC

Comai S., Bertazzo A., Brughera M., Crotti S. Tryptophan in health and disease. Adv. Clin. Chem. 2020;95:165–218. PubMed

Inoue S., Hatakeyma J., Kondo Y., Hifumi T., Sakuramoto H., Kawasaki T., Taito S., Nakamura K., Unoki T., Kawai Y., et al. Post-intensive care syndrome: Its pathophysiology, prevention, and future directions. Acute Med. Surg. 2019;6:233–246. doi: 10.1002/ams2.415. PubMed DOI PMC

Káňová M., Máca J. Post-Intensive Care Syndrome. Am. J. Biomed. Sci. Res. 2020;10:572–573. doi: 10.34297/AJBSR.2020.10.001577. DOI