Tryptophan catabolites, inflammation, and insulin resistance as determinants of chronic fatigue syndrome and affective symptoms in long COVID

Abstract

Critical COVID-19 disease is accompanied by depletion of plasma tryptophan (TRY) and increases in indoleamine-dioxygenase (IDO)-stimulated production of neuroactive tryptophan catabolites (TRYCATs), including kynurenine (KYN). The TRYCAT pathway has not been studied extensively in association with the physiosomatic and affective symptoms of Long COVID. In the present study, we measured serum TRY, TRYCATs, insulin resistance (using the Homeostatic Model Assessment Index 2-insulin resistance, HOMA2-IR), C-reactive protein (CRP), physiosomatic, depression, and anxiety symptoms in 90 Long COVID patients, 3–10 months after remission of acute infection. We were able to construct an endophenotypic class of severe Long COVID (22% of the patients) with very low TRY and oxygen saturation (SpO2, during acute infection), increased kynurenine, KYN/TRY ratio, CRP, and very high ratings on all symptom domains. One factor could be extracted from physiosomatic symptoms (including chronic fatigue-fibromyalgia), depression, and anxiety symptoms, indicating that all domains are manifestations of the common physio-affective phenome. Three Long COVID biomarkers (CRP, KYN/TRY, and IR) explained around 40% of the variance in the physio-affective phenome. The latter and the KYN/TRY ratio were significantly predicted by peak body temperature (PBT) and lowered SpO2 during acute infection. One validated latent vector could be extracted from the three symptom domains and a composite based on CRP, KYN/TRY, and IR (Long COVID), and PBT and SpO2 (acute COVID-19). In conclusion, the physio-affective phenome of Long COVID is a manifestation of inflammatory responses during acute and Long COVID, and lowered plasma tryptophan and increased kynurenine may contribute to these effects.

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

“…l -tryptophan catabolism by indoleamine-dioxygenase (IDO) through the kynurenine pathway generates several bioactive metabolites collectively referred to as kynurenines 426 . SARS-CoV-2 infection could deplete plasma l -tryptophan levels and increase IDO-stimulated generation of neuroactive tryptophan catabolites, including kynurenine 427 . Kynurenine is precursor for the vital cellular effector NAD + and for several other intermediate metabolites that modulate immune and neuronal functions.…”

Amino acid catabolite markers for early prognostication of pneumonia in patients with COVID-19

“…4 ), when viral load was reduced 32 , also supports this hypothesis. Very recently, an increased KYN/TRY ratio due to IDO has also been reported in patients with severe COVID 33 . Since IDO and its catabolites kynurenines suppress T-cell responses and promote Treg proliferation 34 , 35 this may be a strategy of the virus to induce immune tolerance.…”

Significance of nitrosative stress and glycoxidation products in the diagnosis of COVID-19

“…In COVID-19 patients, other authors observed increased activity of the TRYCAT pathway 60 , 61 , as manifested by decreased tryptophan concentration and increased levels of KN and NFK, resulting from increased IDO activity under the influence of pro-inflammatory cytokines. In addition, the SARS-CoV-2 virus stimulates the aryl hydrocarbon receptor (AhR) and increases KN levels, which leads to the systemic AhR activation syndrome (SAAR) that intensifies inflammation, induces thrombophilia, and contributes to organ damage 62 , 63 .…”