Post-COVID Conditions:
Why You Might Need More Tryptophan

By Adin Smith, MS | Posted November 2, 2021

Image of SARS-CoV-2 viral spike proteins

One of the risk factors for poor COVID-19 recovery may be due to low tryptophan levels in your body.[1]Eroğlu İ, et al. Altered tryptophan absorption and metabolism could underlie long-term symptoms in survivors of coronavirus disease 2019 (COVID-19). Nutrition. 2021;90:111308. 

A recent study showed that over half of COVID survivors reported health problems lasting more than six months.[2]Groff D, et al. Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection: A Systematic Review. JAMA Netw Open. 2021;4(10):e2128568. Long COVID or Post-COVID Conditions are terms used to describe the broad range of symptoms and health problems that may arise more than four weeks after contracting SARS-CoV-2, the virus that causes COVID-19.[3]Post-COVID Conditions. (Accessed on Oct. 23rd, 2021). https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html

Signs and symptoms include: [4]Wanga V, et al. Long-Term Symptoms Among Adults Tested for SARS-CoV-2 — United States, January 2020–April 2021. MMWR Morb Mortal Wkly Rep 2021;70:1235–1241. [5]Motiejunaite J, et al. Hyperventilation: A Possible Explanation for Long-Lasting Exercise Intolerance in Mild COVID-19 Survivors? Front Physiol. 2021;11:614590. Published 2021 Jan 18.

  • Fatigue 
  • Shortness of breath 
  • Chest pain or irregular heart rhythms
  • Brain fog (impaired thinking and memory ability)
  • Changes in mood (i.e., depression or anxiety)
  • Headache or sleep problems
  • Diarrhea, abdominal pain, or other digestive issues
  • Loss of smell or taste
  • Muscle or joint pain
  • Exercise intolerance 
  • Chronic cough 
  • Alterations in menstrual period cycles

What is Tryptophan?

Tryptophan is an essential amino acid that must be obtained from your diet as the body cannot produce it.[6]L-Tryptophan Monograph. Altern Med Rev. 2006 Mar;11(1):52-6. PMID: 16597195. Most people consume enough tryptophan by consuming plant and animal proteins such as turkey, chicken, tofu, spinach, eggs, and pumpkin seeds.[7]Hulsken S, et al. Food-derived serotonergic modulators: effects on mood and cognition. Nutr Res Rev. 2013 Dec;26(2):223-34. However, viral infections often result in rapid tryptophan depletion—which may increase the need for tryptophan intake.[8]Mehraj V, et al. Tryptophan Catabolism in Chronic Viral Infections: Handling Uninvited Guests. Int J Tryptophan Res. 2015;8:41-48.

How Does COVID-19 Cause Tryptophan Decline?

Recent reports show that individuals hospitalized with COVID-19 have much lower tryptophan blood levels than uninfected populations.[9]Lionetto L, et al. Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2. Biochim Biophys Acta Mol Basis Dis. 2021;1867(3):166042. [10]Thomas T, et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight. 2020;5(14):e140327. Published 2020 Jul 23. Tryptophan gets broken down and converted to other vital compounds during infection to help fine-tune the immune system. This infection-related depletion of tryptophan is also necessary for starving pathogens, as tryptophan serves as an energy source for bacterial or viral replication.[11]Boergeling Y, et al. Targeting a metabolic pathway to fight the flu. FEBS J. 2017 Jan;284(2):218-221., [12]Moffett JR, et al. Tryptophan and the immune response. Immunol Cell Biol. 2003 Aug;81(4):247-65. SARS-CoV-2 may also trigger chronic inflammation long after the virus has cleared, leading to further reductions in tryptophan.

Even though tryptophan breakdown is part of the body’s normal response to infection, stress, and inflammation, restoring tryptophan may be necessary after COVID-19.

Intestinal Viral Spread May Cause Further Reductions in Tryptophan

Theoretically, SARS-CoV-2 infection could spread from the lungs to the gut.[13]Ahlawat S, Asha, Sharma KK. Immunological co-ordination between gut and lungs in SARS-CoV-2 infection. Virus Res. 2020;286:198103. Proponents of this theory claim that the lungs may become hyper-permeable (“leaky”), allowing the virus to escape the lungs, enter the bloodstream, and eventually infect the lower digestive tract. Evidence supporting this claim comes from reports of live virus found in the stool of patients with COVID-19.[14]Xiao F, Sun J, Xu Y, et al. Infectious SARS-CoV-2 in Feces of Patient with Severe COVID-19. Emerging Infectious Diseases. 2020;26(8):1920-1922. [15]Zhang Y, Chen C, Zhu S, et al. Isolation of 2019-nCoV from a stool specimen of a laboratory confirmed case of the coronavirus disease 2019 (COVID-19) CCDC Weekly. 2020;2:123–124. Additionally, research shows that up to 70% of COVID-19 patients experience gastrointestinal symptoms (i.e., nausea, diarrhea, and abdominal pain), implying that SARS-CoV-2 infection may extend into the gut.[16]Guo M, Tao W, Flavell RA, Zhu S. Potential intestinal infection and faecal-oral transmission of SARS-CoV-2. Nat Rev Gastroenterol Hepatol. 2021;18(4):269-283. [17]Chen A, et al. Are Gastrointestinal Symptoms Specific for Coronavirus 2019 Infection? A Prospective Case-Control Study From the United States. Gastroenterology. 2020;159(3):1161-1163.

SARS-CoV-2 infects the body’s cells by binding its viral spike proteins to a unique cell receptor called angiotensin-converting enzyme 2 (ACE2).[18]Gheblawi M, et al. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System. Circ Res. 2020 May 8;126(10):1456-1474. ACE2 is highly expressed in the small intestine. It plays a functional role in supporting the structures responsible for transporting and absorbing amino acids.[19]Viana SD, et al. ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities – Role of gut microbiota dysbiosis. Ageing Res Rev. 2020;62:101123. [20]Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. J Pathol. 2004;203(2):631-637. When SARS-CoV-2 infects the gut, its spike proteins may reduce the availability of ACE2 to assist with tryptophan absorption.[21]Qin WH, et al. Gut ACE2 Expression, Tryptophan Deficiency, and Inflammatory Responses. Cell Mol Gastroenterol Hepatol. 2021;S2352-345X(21)00129-6. [22]Zhang H, Li HB, Lyu JR, et al. Specific ACE2 expression in small intestinal enterocytes may cause gastrointestinal symptoms and injury after 2019-nCoV infection. Int J Infect Dis. 2020;96:19-24. 

What Are the Potential Ramifications of Low Tryptophan Levels?

1) Low Brain Serotonin

Tryptophan provides the nutritional building blocks necessary for making serotonin (an important chemical messenger). Serotonin plays a vital role in regulating mood, memory, and cognition.[23]Jenkins TA, Nguyen JC, Polglaze KE, Bertrand PP. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients. 2016;8(1):56. If a lack of tryptophan absorption occurs during COVID-19, it may lower serotonin levels within the brain and central nervous system. Low serotonin levels due to lack of tryptophan may lead to memory and cognition issues (the so-called “Brain Fog”) and alterations in mood (i.e., anxiety and depression)—all commonly reported symptoms among individuals with Post-COVID Conditions.

A new study shows serotonin reuptake inhibitor (SSRI) use was associated with a modest 8% risk reduction in COVID-19-related mortality compared to those not using an SSRI.[24]Oskotsky T, et al. Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants. JAMA Netw Open. 2021;4(11):e2133090. This preliminary study has some inherent limitations, and whether SSRIs are an effective tool for COVID-19 treatment needs further investigation.

2) Low Melatonin Production

Like serotonin, melatonin also comes from tryptophan. Melatonin is a vital hormone and signaling molecule produced in the brain that helps regulate sleep cycles. Melatonin also acts as a powerful antioxidant and immune system regulator.[25]Bahrampour Juybari K, et al. Melatonin potentials against viral infections including COVID-19: Current evidence and new findings. Virus Res. 2020;287:198108. [26]Srinivasan V, Maestroni GJ, Cardinali DP, Esquifino AI, Perumal SR, Miller SC. Melatonin, immune function and aging. Immun Ageing. 2005;2:17. Preliminary studies suggest that melatonin may also support lung health—a unique property with potential relevance to COVID-19 outcomes.[27]Zhang L, et al. Melatonin prevents lung injury by regulating apelin 13 to improve mitochondrial dysfunction. Exp Mol Med. 2019 Jul 4;51(7):1-12.

3) NAD+ Production

Tryptophan is a building block that the body needs to make nicotinamide adenine dinucleotide (NAD+)—a vital molecule responsible for supporting numerous functions in the body such as DNA repair and energy metabolism, and immune system function.[28]Grahnert A, et al. Review: NAD +: a modulator of immune functions. Innate Immun. 2011 Apr;17(2):212-33.

Experimental studies show that certain forms of vitamin B3, known as “NAD boosters,” have the potential to support the body during COVID-19 infection.[29]Esam Z, Akhavan M, Lotfi M, Bekhradnia A. Molecular docking and dynamics studies of Nicotinamide Riboside as a potential multi-target nutraceutical against SARS-CoV-2 entry, replication, and … Continue reading The premise of this claim comes from experimental studies showing that NAD administration may benefit the immune system by supporting certain enzymes involved in activating the innate immune response—the body’s first line of defense against pathogens.[30]Heer CD, Sanderson DJ, Voth LS, et al. Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity. J Biol Chem. 2020;295(52):17986-17996. More research is needed to prove whether taking NAD precursors (including tryptophan) may affect health outcomes related to COVID-19.

Conclusion

Studies show that COVID-19 often causes tryptophan depletion. COVID-19 survivors may benefit from increasing their dietary tryptophan intake to help restore tryptophan levels. However, more research is urgently needed to assess the potential effects of tryptophan replenishment on Long COVID or Post-COVID Conditions.

References

References
1Eroğlu İ, et al. Altered tryptophan absorption and metabolism could underlie long-term symptoms in survivors of coronavirus disease 2019 (COVID-19). Nutrition. 2021;90:111308.
2Groff D, et al. Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection: A Systematic Review. JAMA Netw Open. 2021;4(10):e2128568.
3Post-COVID Conditions. (Accessed on Oct. 23rd, 2021). https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
4Wanga V, et al. Long-Term Symptoms Among Adults Tested for SARS-CoV-2 — United States, January 2020–April 2021. MMWR Morb Mortal Wkly Rep 2021;70:1235–1241.
5Motiejunaite J, et al. Hyperventilation: A Possible Explanation for Long-Lasting Exercise Intolerance in Mild COVID-19 Survivors? Front Physiol. 2021;11:614590. Published 2021 Jan 18.
6L-Tryptophan Monograph. Altern Med Rev. 2006 Mar;11(1):52-6. PMID: 16597195.
7Hulsken S, et al. Food-derived serotonergic modulators: effects on mood and cognition. Nutr Res Rev. 2013 Dec;26(2):223-34.
8Mehraj V, et al. Tryptophan Catabolism in Chronic Viral Infections: Handling Uninvited Guests. Int J Tryptophan Res. 2015;8:41-48.
9Lionetto L, et al. Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2. Biochim Biophys Acta Mol Basis Dis. 2021;1867(3):166042.
10Thomas T, et al. COVID-19 infection alters kynurenine and fatty acid metabolism, correlating with IL-6 levels and renal status. JCI Insight. 2020;5(14):e140327. Published 2020 Jul 23.
11Boergeling Y, et al. Targeting a metabolic pathway to fight the flu. FEBS J. 2017 Jan;284(2):218-221.
12Moffett JR, et al. Tryptophan and the immune response. Immunol Cell Biol. 2003 Aug;81(4):247-65.
13Ahlawat S, Asha, Sharma KK. Immunological co-ordination between gut and lungs in SARS-CoV-2 infection. Virus Res. 2020;286:198103.
14Xiao F, Sun J, Xu Y, et al. Infectious SARS-CoV-2 in Feces of Patient with Severe COVID-19. Emerging Infectious Diseases. 2020;26(8):1920-1922.
15Zhang Y, Chen C, Zhu S, et al. Isolation of 2019-nCoV from a stool specimen of a laboratory confirmed case of the coronavirus disease 2019 (COVID-19) CCDC Weekly. 2020;2:123–124.
16Guo M, Tao W, Flavell RA, Zhu S. Potential intestinal infection and faecal-oral transmission of SARS-CoV-2. Nat Rev Gastroenterol Hepatol. 2021;18(4):269-283.
17Chen A, et al. Are Gastrointestinal Symptoms Specific for Coronavirus 2019 Infection? A Prospective Case-Control Study From the United States. Gastroenterology. 2020;159(3):1161-1163.
18Gheblawi M, et al. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System. Circ Res. 2020 May 8;126(10):1456-1474.
19Viana SD, et al. ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities – Role of gut microbiota dysbiosis. Ageing Res Rev. 2020;62:101123.
20Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. J Pathol. 2004;203(2):631-637.
21Qin WH, et al. Gut ACE2 Expression, Tryptophan Deficiency, and Inflammatory Responses. Cell Mol Gastroenterol Hepatol. 2021;S2352-345X(21)00129-6.
22Zhang H, Li HB, Lyu JR, et al. Specific ACE2 expression in small intestinal enterocytes may cause gastrointestinal symptoms and injury after 2019-nCoV infection. Int J Infect Dis. 2020;96:19-24.
23Jenkins TA, Nguyen JC, Polglaze KE, Bertrand PP. Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis. Nutrients. 2016;8(1):56.
24Oskotsky T, et al. Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants. JAMA Netw Open. 2021;4(11):e2133090.
25Bahrampour Juybari K, et al. Melatonin potentials against viral infections including COVID-19: Current evidence and new findings. Virus Res. 2020;287:198108.
26Srinivasan V, Maestroni GJ, Cardinali DP, Esquifino AI, Perumal SR, Miller SC. Melatonin, immune function and aging. Immun Ageing. 2005;2:17.
27Zhang L, et al. Melatonin prevents lung injury by regulating apelin 13 to improve mitochondrial dysfunction. Exp Mol Med. 2019 Jul 4;51(7):1-12.
28Grahnert A, et al. Review: NAD +: a modulator of immune functions. Innate Immun. 2011 Apr;17(2):212-33.
29Esam Z, Akhavan M, Lotfi M, Bekhradnia A. Molecular docking and dynamics studies of Nicotinamide Riboside as a potential multi-target nutraceutical against SARS-CoV-2 entry, replication, and transcription: A new insight. J Mol Struct. 2022;1247:131394.
30Heer CD, Sanderson DJ, Voth LS, et al. Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity. J Biol Chem. 2020;295(52):17986-17996.

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