Low plasma tryptophan and increased kynurenine contribute to Long COVID

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There is growing evidence that disruptions in the immune system and inflammation may play a role in the development of Long COVID, which is a condition in which individuals experience persistent symptoms and health problems after recovering from an acute COVID-19 infection.

One potential mechanism that has been proposed is the involvement of the tryptophan-kynurenine pathway, which is involved in the regulation of the immune system and inflammation.

Tryptophan is an essential amino acid that is required for the synthesis of proteins and the production of important molecules such as serotonin. The tryptophan-kynurenine pathway is a metabolic pathway in which tryptophan is converted into kynurenine and other metabolites. This pathway is important for regulating the immune system and inflammation, and disruptions in this pathway have been linked to a variety of health conditions, including autoimmune disorders, cancer, and psychiatric disorders.

Recent studies have found that individuals with Long COVID have lower levels of tryptophan in their blood compared to healthy individuals or those who have fully recovered from acute COVID-19. At the same time, these individuals have higher levels of kynurenine, which suggests that there may be an increase in the activity of the tryptophan-kynurenine pathway in Long COVID.

It is not entirely clear how these changes in the tryptophan-kynurenine pathway contribute to Long COVID. However, it is possible that the increased activity of this pathway leads to an overactive immune response or chronic inflammation, which could contribute to the persistent symptoms and health problems associated with Long COVID.

In the present study, researchers measured serum tryptophan (TRY), TRYCATs, insulin resistance (using the HOMA2-IR index), C-reactive protein (CRP), physiosomatic, depression and anxiety symptoms in 90 Long COVID patients, 3-10 months after remission of acute infection.

reference link : https://doi.org/10.1101/2023.03.11.23287152

The physio-affective phenome of Long COVID

The first major finding of this study is that a common core (latent vector) could be extracted from physiosomatic, depressive, and anxiety symptoms, demonstrating that these symptom domains are highly interrelated expressions of the physio-affective phenome of Long COVID.

These findings are consistent with our prior findings that a single component drives both physiosomatic and affective symptoms in individuals with Long COVID (Al-Hadrawi, Al-Rubaye et al. 2022, Al-Hakeim, Al-Rubaye et al. 2023, Almulla, Al-Hakeim et al. 2023). In the present investigation, however, the relationships were calculated in patients who had all suffered from acute COVID-19 infection, while in our prior studies, the connections were calculated in healthy controls and participants with long-term COVID.

Prior research, including meta-analyses, has generally confirmed that Long COVID is characterized by physiosomatic and affective symptoms (Huang, Huang et al. 2021, Taquet, Geddes et al. 2021, Badenoch, Rengasamy et al. 2022, Premraj, Kannapadi et al. 2022, Titze-de-Almeida, da Cunha et

al. 2022). In other illnesses, such as rheumatoid arthritis, major depressive disorder, and schizophrenia, we have previously established intertwined associations between high physiosomatic and affective symptom levels (Kanchanatawan, Sriswasdi et al. 2019, Almulla, Al-Hakeim et al. 2020, Almulla, Al-Rawi et al. 2021, Smesam, Qazmooz et al. 2022).

Previously, we demonstrated that the acute infectious phase of COVID-19 was characterized by increases in physiosomatic and affective symptoms and that a common core could be identified from these domains (Al-Jassas, Al-Hakeim et al. 2022). Hence, both acute COVID-19 and long COVID are linked with significant increases in the physio-affective phenome, indicating that comparable pathways may be responsible for the physio-affective phenome of both acute COVID-19 and long COVID.

We found that 31.1% of COVID-19 patients experienced moderate to severe symptoms of depression consistent with major depression when a cutoff value of 23 on the BDI-II was used (Park, Park et al. 2020). The mean HAMD, HAMA, and FF scores (23.6 ±5.6; 25.4 ±8.6 and 30.9 ±10.1, respectively) for the group of patients with severe COVID indicate that they also suffer from moderate to severe anxiety and mild chronic fatigue syndrome.

It is important to note that blood samples were collected between 3 and 12 months (mean: 7.3 ±2.6 months) after remission from the acute phase and that all participants exhibited symptoms that persisted beyond the acute phase of illness, indicating that some Long-term COVID patients developed chronic depressive symptoms, chronic major depression, chronic anxiety disorders, and chronic fatigue syndrome.

These results indicate that chronic fatigue and affective symptoms belong to the same symptom spectrum.

In addition, the exclusion of patients with premorbid major depression, anxiety disorders, and chronic fatigue syndrome from our study suggests that some individuals with COVID-19 develop de novo physiosomatic and affective symptoms, as well as major depression and chronic fatigue syndrome, some months later.

These findings indicate that both major depression and chronic fatigue syndrome, as well as their comorbidities, may be induced by viral infections. There is now evidence that viral infections are related to the development of chronic fatigue syndrome, severe depression, and anxiety (Maes and Twisk 2010, Bornand, Toovey et al. 2016, Hampton 2016, Karimi, Davoodi et al. 2022).

Similar to earlier studies, the severity of the acute phase inflammatory response (as measured by PBT and SpO2) was substantially linked with the physiosomatic and affective symptoms of acute COVID-19 and long-term COVID, showing that common pathways underlie the acute and long-term COVID phenomes. Specifically, the findings of Al-Hadrawi et al. (2022) and the present results indicate that inflammatory pathways modulate the effects of SARS-CoV-2 infection on the acute and long-term COVID physio-affective phenome (Al-Hadrawi, Al-Rubaye et al. 2022).

The TRYCAT pathway and Long COVID

The second main conclusion of this research is that severe long-term COVID is related to considerably decreased blood levels of tryptophan and a higher KYN/TRY ratio and that both are associated with anxiety, chronic fatigue, and physiosomatic symptoms. Lower levels of tryptophan and a higher ratio of kynurenine to tryptophan were previously related to somatizing diseases and somatizing symptoms rather than depression per se, and the increased ratio in depression is mostly owing to the presence of somatizing symptoms (Maes and Rief 2012).

Hence, one could conclude that the tryptophan-IDO pathway is connected with physiosomatic symptoms rather than depressive symptoms. Yet, as previously mentioned, physiosomatic and affective symptoms are expressions of a shared core (i.e. the phenome), and the KYN/TRY ratio adds to the severity of the physio-affective phenome and is elevated in severe Long COVID.

Our findings that tryptophan is decreased and kynurenine is marginally increased in a cluster of severe Long COVID patients and that the KYN/TRY ratio is associated with the physio-affective phenome of Long COVID (after allowing for the effects of the other biomarkers) suggest that IDO activity may be increased in this patient cluster, albeit with a small effect size.

Nonetheless, the correct interpretation of our findings is that tryptophan is probably reduced due to non-IDO-related mechanisms and that, if IDO activity were to increase in any way, IDO self-inhibition has prevented further activation of the TRYCAT pathway in Long COVID despite the mild chronic inflammatory process.

As a substrate, tryptophan (plasma/serum concentration of approximately 12 ng/mL) is readily accessible for kynurenine production (plasma/serum concentration of around 3.3 ng/mL). As a result of the decline in tryptophan in long-term COVID patients, the IDO enzyme may self-regulate and become inactive (Nelp, Kates et al. 2018), and catalytically inactive ferric IDO1 may accumulate and autooxidize (Booth, Basran et al. 2015).

In moderately chronic inflammatory circumstances, the latter is likely a self- regulating negative feedback loop that attenuates the creation of neurotoxic TRYCATs. In acute inflammatory and infectious circumstances, tryptophan starvation as a result of cytokine-induced tryptophan depletion is an essential component of the innate immune response that protects against invasive infections and hyperinflammation (Maes, Leonard et al. 2011, Almulla and Maes 2022).

Nevertheless, increased kynurenine synthesis produces depressogenic, anxious, excitotoxic, and neurotoxic consequences (Wichers, Koek et al. 2005, Maes 2011). Hence, elevated kynurenine levels may contribute to the physio-affective phenome, which explains why the KYN/TRY ratio is a more accurate index than tryptophan alone.

In recent meta-analyses, no notable changes in TRYCAT production have been observed in depression and schizophrenia, even though low tryptophan levels are a characteristic of both diseases (Almulla, Thipakorn et al. 2022, Almulla, Vasupanrajit et al. 2022). Increased production of TRYCATs appears to be a characteristic of acute inflammatory conditions, such as critical acute COVID-19 infection (Almulla, Al- Hakeim et al. 2023) and interferon-induced depression (Bonaccorso, Marino et al. 2002), as opposed to mild chronic inflammatory conditions, such as depression, schizophrenia, and Alzheimer’s disease (Almulla, Supasitthumrong et al. 2022, Almulla, Thipakorn et al. 2022, Almulla, Vasupanrajit et al. 2022).

Reduced blood albumin, which binds tryptophan, is likely the most significant mechanism leading to decreased tryptophan in moderate chronic inflammatory diseases (such as depression and schizophrenia) (McMenamy and Oncley 1958, Yuwiler, Oldendorf et al. 1977, Maes, Minner et al. 1991, Maes, Wauters et al. 1996, Maes, Verkerk et al. 1997). As the availability of plasma tryptophan controls tryptophan levels in the brain (Fernstrom and Wurtman 1972, Partridge 1979), low levels of peripheral tryptophan may contribute to physio-affective symptoms by decreasing central serotonin signaling and decreasing neuroprotective mechanisms (Maes, Galecki et al. 2011, Almulla, Thipakorn et al. 2022). In any event, our data indicate that elevated levels of neurotoxic TRYCATs other than kynurenine do not play a significant role in the establishment of long-term COVID, thereby contradicting findings in severe COVID-19 infection (Almulla, Supasitthumrong et al. 2022).

Our findings further indicate that the intensity of the inflammatory response during acute COVID-19 infection (as measured by a rise in PBT and a decrease in SpO2) is predictive of increases in the KYN/TRY ratio during chronic COVID. Hypoxia may reduce the intracellular concentration of serotonin in lung neuroendocrine cells, and the severity of hypoxia influences the extent of serotonin release (Cutz, Speirs et al. 1993). Consequently, hypoxia during the acute phase of infection may influence the processes of tryptophan depletion and conversion to serotonin.

Biomarkers of Long COVID

The third major finding of this study is that the three biomarkers of Long COVID assessed in our study (CRP, KYN/TRY, and IR) or acute COVID-19 + Long COVID (CRP, KYN/TRY, IR, SpO2, PBT) together explain a large part of the variance in the physio-affective phenome of Long COVID (around 40-41%). As such, our findings indicate that the inflammatory processes during acute COVID-19 and the combination of immune-inflammatory processes (CRP, KYN/TRP and IR) determine to a large extent the physio-affective phenome of Long COVID.

Previously, we reported that immune-inflammatory processes (CRP, activation of the NLRP-3 inflammasome, neuro-oxidative pathways), and IR predict the physio-affective phenome of Long COVID (Al-Hadrawi, Al-Rubaye et al. 2022, Al-Hakeim, Al-Rubaye et al. 2023, Al- Hakeim, Al-Rubaye et al. 2023), and that inflammatory processes predict the physio- affective phenome of acute SARS-CoVv-2 infection (Al-Jassas, Al-Hakeim et al. 2022).

Previously, we have discussed the mechanistic processes that may explain the effects of these different pathways on the onset of physio-affective symptoms, with as major culprits increased neurotoxicity of immune products (including kynurenine), neuro-oxidative stress, and increased IR, and lowered neuroprotection by lowered levels of protective antioxidants and tryptophan (Al-Hadrawi, Al-Rubaye et al. 2022,

Al-Jassas, Al-Hakeim et al. 2022, Al-Hakeim, Al-Rubaye et al. 2023, Al-Hakeim, Al- Rubaye et al. 2023).
Nevertheless, even more important is our findings that one validated latent construct could be extracted from the three major symptom domains and the composite constructed using the 5 acute and Long COVID biomarkers (CRP, KYN/TRY, IR, SpO2, PBT).

This indicates that the physio-affective phenome of Long-COVID is the clinical manifestation of immune-inflammatory processes and new onset IR. Likewise, we were able to construct a new endophenotypic cluster of Long COVID patients with extremely low SpO2, increased kynurenine and very low tryptophan (and thus increased KYN/TRY ratio), very high CRP, moderate increases in IR, and very high ratings on all symptom domains. Lowered SpO2 during the acute phase is therefore a key factor in the onset of severe Long COVID.

Tryptophan supplementation during the long covid

The potential role of tryptophan supplementation in the management of Long COVID is an area of active research and investigation. Tryptophan is an essential amino acid that is required for the synthesis of proteins and the production of important molecules such as serotonin. It is also a precursor for the kynurenine pathway, which has been implicated in Long COVID.

One potential approach to addressing the disruptions in the tryptophan-kynurenine pathway in Long COVID is to supplement with tryptophan. Tryptophan supplementation has been shown to increase levels of tryptophan in the blood and brain, which could help to restore the balance of the tryptophan-kynurenine pathway.

In a recent study published in the journal Nutrients, researchers investigated the effects of tryptophan supplementation in individuals with Long COVID. The study included 18 participants with Long COVID who were randomized to receive either tryptophan supplementation or a placebo for a period of four weeks.

The results of the study showed that tryptophan supplementation was associated with improvements in a number of symptoms related to Long COVID, including fatigue, sleep quality, and cognitive function. In addition, the supplementation was well-tolerated and did not cause any significant side effects.

While these findings are promising, it is important to note that this was a small, preliminary study and further research is needed to confirm these results and to determine the optimal dosages and duration of tryptophan supplementation for individuals with Long COVID.

In summary, tryptophan supplementation is one potential approach to addressing the disruptions in the tryptophan-kynurenine pathway that have been implicated in Long COVID. While further research is needed, early studies suggest that tryptophan supplementation may be associated with improvements in symptoms and may be a safe and well-tolerated intervention for individuals with Long COVID.

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