Hypothesis: Altered tryptophan absorption and metabolism could underlie long-term symptoms in survivors of .. (COVID-19), 2021, Eroglu et al

Full title: Altered tryptophan absorption and metabolism could underlie long-term symptoms in survivors of coronavirus disease 2019 (COVID-19)

Highlights

• Coronavirus disease 2019 (COVID-19) causes long-term symptoms including fatigue, depression, sleep disturbances, and muscle weakness.

• COVID-19 causes altered metabolism of tryptophan in favor of the kynurenine pathway and disturbed tryptophan absorption due to altered expression of intestinal angiotensin-converting enzyme 2.

• Both an increased kynurenine pathway and decreased absorption of tryptophan could be main contributors to long-term symptoms of COVID-19.

Abstract
The global pandemic of COVID-19 has been lasting for more than one year and there is little known about the long-term health effects of the disease. Long-COVID is a new term that is used to describe the enduring symptoms of COVID-19 survivors. Huang et al. reported that fatigue, muscle weakness, sleep disturbances, anxiety, and depression were the most common complaints in COVID-19 survivors after 6 months of the infection. A recent meta-analysis showed that 80% of COVID-19 survivors have developed at least one long-term symptom and the most common five were fatigue, headache, attention deficit disorder, hair loss, and dyspnea. In this paper, we discuss the hypothesis that altered tryptophan absorption and metabolism could be the main contributor to the long-term symptoms in COVID-19 survivors.

Open access, https://www.sciencedirect.com/science/article/pii/S0899900721001702

 

Rather than the IDO metabolic trap hypothesis posited by Ron Davis and Robert Phair -- wherein there is an excess of tryptophan that cannot be converted to kynurenine because the IDO2 enzyme fails to be produced --, this paper implicitly assumes that the IDO pathway works normally and that instead an excess of kynurenine causes long-term symptoms.

KP [kynurenine pathway] and long-COVID symptoms

As discussed before, the most commonly seen long-term symptoms in people who have had COVID-19 are depression, fatigue, sleep disturbances, attention disorders, anxiety, muscle weakness, and dyspnea. When taken together, KP activation may also contribute these symptoms.

The “kynurenine shunt” refers to the increased degradation of tryptophan toward kynurenine and away from serotonin production [14]. Increased IDO activity has been related to depression in studies, owing to both serotonin depletion and neurotoxic effects of KP metabolites [15]. Fatigue, the most common long-term symptom in people who have had COVID-19, is divided into central and peripheral fatigue, with central fatigue causing complex weakness and making recovery difficult [16]. Several studies have revealed that increased metabolites of the KP in the brain trigger central fatigue and memory issues by inducing neurotoxicity [17-20]. The long-term symptoms seen in COVID-19 infection could be related to the kynurenine shunt.

Although there has been evidence of increased KP activation in acute COVID-19, there is no evidence in long-term COVID-19 survivors. Studies in this area can aid in our understanding of the pathophysiology underlying COVID-19’s long-term symptoms.​

 

If there is any merit in this paper - and I can't judge today - then it suggests that problems are arising with the metabolites of tryptophan. And for anyone interested in doing an n=1 experiment some of the things mentioned in the diagram below are available over the counter, at least in some countries, in some form or other (5-HTP i.e. 5-hydroxy-tryptophan, melatonin, niacin, and tryptophan itself).

Source : https://upload.wikimedia.org/wikipedia/commons/2/24/Tryptophan_metabolism.svg

 

I do believe that my ME involves abnormalities in my kynurenine pathway. Too much QUIN would probably explain some (most) of my symptoms. I think niacin made me feel worse because without dietary intake of it, my enzymes would convert more of the excess QUIN into niacin.

 

Yes, both sorts of hypotheses have been made for a variety of conditions over the last few decades. There still seems to be a lack of strong evidence, despite the popularity of these hypotheses.

 

People have been writing and rewriting a variation of this paper in the depression literature since the late 1980s. This approach has yielded zero results in terms of therapeutics.

 

Not adding much here but Robert Phair's theory relates to intracellular [IDO2] conversion of tryptophan to kynurenine - not necessarily reflected in blood levels of kynurenine.

 

If it was due to genetic factors, it could affect many cell types and still likely cause an imbalance in blood plasma...

 

Don't really know because some cells rely on IDO1/2 and others do not --- not sure whether the effect would be to lower blood levels.

EDIT - this* may support the view that blood levels would be affected by faulty IDO2 in liver --- but it may not that simple i.e. perhaps not all cells, which use the IDO1/2 pathway, would be trapped [high intracellular tryptophan]? E.g. liver cells might not be trapped?


*"In addition to its indispensable role in protein synthesis, the essential amino acid l-tryptophan (Trp) is the precursor of many physiologically important metabolites produced during the course of its degradation along 4 pathways, 3 of which are of quantitatively minor significance, with the fourth, the kynurenine (K) pathway (KP), accounting for ~95% of overall Trp degradation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398323/