These metabolic pathways can really be something. Pathways by their nature can be kind of all-encompassing. We could think of the bigger ones like major rivers that send out tributaries that affect multiple systems. Tryptophan and the kynurenine pathways are one of those. In fact, tryptophan is such a potentially important substance for ME/CFS that hypotheses have popped up proposing that either of two diametrically opposed tryptophan issues could be causing or contributing to the disease.
Tryptophan and kynurenine have been under consideration in chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) for over a decade. Now that it’s popped up in long COVID, it’s a good time to take a deep dive into a rather complex subject.
Thankfully, two Australian efforts, “Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle?” and “The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome“, provided a nice start.
Tryptophan is an essential amino acid that we must derive from our diet. The precursor to serotonin, melatonin, and vitamin B3, tryptophan can affect the body in many different ways.
Tryptophan metabolism, or breakdown, can go in two directions – down the kynurenine pathway, or down a pathway that produces serotonin and melatonin. The vast majority of it goes down the kynurenine pathway – the ultimate outcome of which is the production of a crucial energy source, NAD+.
On the way to producing NAD+, though, some bad things can happen. If you want to know the details, check out the paragraph in parentheses below. The crucial thing to note is that of the six metabolites produced in the two kynurenine pathways, four of them (kynurenic acid, (3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3HAA), and quinolinic acid (QUIN)) are toxic.
(Two kynurenine pathways are present:
- Toxic – TRYP is catabolized to KYN which is then converted to 3-hydroxykynurenine (3-HK). 3-HK is then metabolized to 3-hydroxyanthranilic acid (3HAA) and quinolinic acid (QUIN).
- Protective – Kynurenine is converted into kynurenic acid (KYNA), a neuroprotective metabolite that shuts down the toxic metabolite quinolinic acid.)
The Beginning – the Gut
It gets a little tiresome to say, but the problems, as so many do, may begin in the gut. Studies in ME/CFS have consistently shown a less diverse, more pro-inflammatory gut that contains less of the protective butyrate species. Plus, leaky gut – particularly after exercise – has been found.
Through its production of helpful substances, the gut has been called the brain’s peacekeeper, but if it can’t keep the peace, problems can happen and some of them involve tryptophan. The digestion of dietary proteins in the small intestine leads to the release of tryptophan, which can be absorbed through the intestines, enter the bloodstream and make its way up into the brain. Tryptophan is also broken down into several compounds (serotonin, kynurenine, indolyl compounds, and tryptamine) that play important roles in gut-brain axis communication.
In fact, most of the kynurenine found in the brain comes from outside of it. Kynurenine is then metabolized in the brain, where it either produces important substances like NAD+ and serotonin, or toxic substances like quinolinic acid. The brain, then, needs a steady dose of tryptophan and kynurenine from the gut to operate properly.
The reduced levels of butyrate-producing bacteria and short-chain fatty acids (SCFAs) found in ME/CFS patients’ guts could result in greater tryptophan breakdown in the gut, resulting in reduced levels of tryptophan. The same is true with regard to the increased levels of Bacteroides bacteria.
Problems in the gut, then, could ultimately result in less serotonin and melatonin being available in the brain.
A Toxic Brain?
It’s important to note that while tryptophan and kynurenine can pass through the blood-brain barrier to the brain, the toxic metabolites (3-HK, 3HAA, Quin) can’t. These substances are only produced in the brain itself – largely by microglial cells but also by astrocytes, and possibly by macrophages that have made their way into the brain.
Two metabolites at the very end of the chain are helpful: NAD+ is an essential energy source and KYNA is a neuroprotective NMDA receptor antagonist; that is – it turns down the activity of the excitatory NMDA receptor which, if overactivated, can turn on the pain producing pathways.
Of all of the detrimental metabolites, quinolinic acid stands out. It’s a nasty compound that triggers the production of reactive oxygen and nitrogen species (RNS) that rip open the lipid linings of cells and damage proteins and even the nucleic acids inside cells. It’s also a neurotoxic NMDA receptor agonist; i.e. it turns on the NMDA receptors found on the neurons, causing a massive influx of calcium ions that can overly excite and harm them. It can also harm the integrity of the blood-brain barrier.
This dual nature of the kynurenine metabolism, with its protective or toxic pathways, led one multiple sclerosis researcher to call the kynurenine pathway, “perhaps the most important regulator of the production of both neuroprotective and neurotoxic compounds” (in the brain).
The Key Factor – Inflammation
But why might this critical pathway flip from producing helpful substances like serotonin and melatonin to toxic metabolites in diseases like ME/CFS, fibromyalgia, and long COVID? What makes people with these diseases potentially vulnerable to kynurenine pathway problems?
In a word – inflammation. As noted earlier, the two major sites of TRYP breakdown in the brain are microglial cells (neuroinflammation) and astrocytes. In fact, the microglia are the main source of quinolinic acid in the brain. Macrophage infiltration into the brain – which Avindra Nath has found in long COVID, and Jarred Younger is assessing in ME/CFS – is another potential source of quinolinic acid. Note also that the gut in ME/CFS appears to be pro-inflammatory, and inflammation in the gut can translate into inflammation in the brain as well.
An ongoing neuroinflammatory process in the brain, such as Younger, Herbert Reinz-Polter and others have proposed, could activate the toxic kynurenine pathway and result in the production of high levels of quinolinic acid. One review article stated, “kynurenine pathway activity is correlated with the elevated neuroinflammation in many diseases of the central nervous system.”
Besides producing large amounts of oxidative stress, quinolinic acid could then ramp up NMDA receptor activity, potentially causing an excitotoxic state that causes neurons to flame out – all the while reducing levels of the feel-good neurotransmitter serotonin. That’s a recipe for an overheated, twitchy, pain and flu-like symptom-producing brain.
Maes proposed tryptophan metabolism issues are present in both ME/CFS and schizophrenia. Given how effective low doses of the antipsychotic Abilify have been for some people with ME/CFS, tryptophan pathway issues in the brain could explain why this drug can be helpful in these two very disparate diseases. A recent hypothesis paper that highlighted the “remarkable phenomenological and neuroimmune overlaps” between ME/CFS and multiple sclerosis proposed tryptophan metabolism issues are in play in that disease as well.
- Tryptophan metabolism and the kynurenine pathway are so potent that two diametrically opposed hypotheses involving them propose they could be causing ME/CFS/FM and long COVID.
- Tryptophan is an essential amino acid that is produced in the gut by the breakdown of proteins. It’s metabolized in two ways: most of it is broken down in the kynurenine pathways and a small amount is broken down to produce serotonin and melatonin. The kynurenine pathway also produces a vital energy source – NAD+ that is involved in many cellular interactions.
- If the gut microbiome is disturbed – and it is in ME/CFS/FM and long COVID – tryptophan may not be broken down properly. Since most of the tryptophan and kynurenine in the brain comes from the gut, and these factors play an essential role in the brain, proper gut functioning is essential for brain health. Plus, the pro-inflammatory composition of the gut in ME/CFS/FM and long COVID could translate to neuroinflammation in the brain.
- The kynurenine pathway shoots off into two branches – one that produces toxic metabolites like quinolinic acid and one that produces neuroprotective factors like kynurenic acid. These metabolites, it should be noted cannot pass through the blood-brain barrier and are only produced in the brain itself
- This brings up the question of what might cause toxic kynurenic metabolites to be produced in the brains of people with ME/CFS/FM and long COVID. The answer is inflammation. Inflammation in the brain triggers kynurenic metabolism to produce toxic elements like quinolinic acid that produce oxidative stress, harm neurons, impair mitochondrial functioning, and activate the microglial cells all the while reducing serotonin and melatonin levels.
- That’s essentially a recipe for an overheated, twitchy, pain and flu-like symptom-producing brain – making it no wonder that the kynurenine pathway is being investigated in many neurological disorders.
- Reduced NAD+ levels can result in reduced energy production. Another NAD+ pathway called the salvage pathway might be able to help restore at least some NAD+ levels. (See the blog for a link to possible treatments).
- While the evidence is limited in ME/CFS/FM and long COVID in general it points to kynurenine dysregulation in these diseases. Still, much more work needs to be done before we can say that’s happening.
- Two other hypotheses (Metabolic Trap, Cortene) posit that the opposite situation has occurred and that high serotonin levels are causing ME/CFS.
The NAD+ Mitochondrial Angle
The “good side” of the kynurenine pathway breaks down tryptophan to produce NAD + – an essential energy source for the cell. In fact, the kynurenine pathway is the sole source of de novo NAD+ production. While other pathways to produce NAD+ exist, the kynurenine pathway is the most efficient.
With many reactions in the Krebs, or TCA, cycle and glycolysis requiring NAD+, it’s an incredibly important factor. Hyperactivation of the kynurenine pathway could limit the availability of NAD+ and potentially exacerbate the symptoms of ME/CFS.
Decreased levels of NAD+ could affect everything from energy production to calcium homeostasis (blog on this coming up), apoptosis (cell suicide), ageing, DNA repair, immunogenicity and gene expression regulation. In short, whacking NAD+ is potentially a very big deal and some believe low NAD+ levels play a big role in ME/CFS.
ME/CFS – the Evidence
More work obviously needs to be done, but several studies suggest something has gone wrong with the kynurenine pathways in ME/CFS.
Significantly higher concentrations of free TRP in ME/CFS patients, found in 2003 and 2005, suggested it was not being metabolized correctly. A 2021 study found that kynurenic acid – the great protector – was less neuroprotective than expected in ME/CFS/FM. The lower KA/QA ratio suggested that increased levels of the toxic quinolinic acid were present. Finally, a recent study showed that patients with ME/CFS have a higher level of 3HK – a toxic metabolite – and lower levels of kynurenine.
In 2014, Blankfield asserted that both ME/CFS and fibromyalgia “appear to meet the criteria of a tryptophan-kynurenine pathway disorder with potential neuroimmunological sequelae.”
Lastly, Fisher’s finding of reduced mitochondrial functioning in ME/CFS could be a function of an overactive toxic kynurenine pathway that’s reducing NAD+ production by whacking the mitochondria with oxidative stressors.
Increased pain sensitivity is a possibility as well. A fibromyalgia study showed that high levels of tryptophan were associated with reduced pain intensity, while high relative levels of kynurenine (KYN/TRP) were associated with increased pain levels.
The role that tryptophan metabolism may play in post-infectious illnesses, however, really got going with long COVID.
In a study that also emphasized lipid and carnitine dysregulation, tryptophan levels returned to normal in recovered COVID-19 patients but remained low in long-COVID patients. Another study found that kynurenine levels were still increased in long-COVID patients but not in recovered patients up to 4 months after the acute infection. The authors suggested that Epstein-Barr virus reactivation, EBV reactivation, and high IL-6 and kynurenine levels may form a kind of diagnostic triad for long COVID. They proposed that increased kynurenine levels reflect a systemic subclinical chronic inflammation that isn’t picked up by standard immune assays.
Another study, however, found kynurenine pathway metabolite levels returning to normal after six months (but fatty acid problems remained). Still another found alterations in these metabolites in some patients but not others.
A gut study found decreased activity in the tryptophan pathways in long-COVID patients with more gut symptoms. The gut-brain axis next showed up in spades when the same pathways were also found to be decreased in those long-COVID patients with more depression, anxiety, etc. Indeed, the authors pointed out that the proportion of patients with significant mental health symptoms before COVID-19 jumped dramatically six months afterward (from 8-54%) in people with long COVID, and suggested that aberrant tryptophan metabolism could contribute. Note that similar reductions in butyrate-producing bacteria and short-chain fatty acids that have been found in ME/CFS have been found in long COVID (and multiple sclerosis).
Besides problems with fatty acid metabolism, a long-COVID exercise study found evidence of issues with taurine and tryptophan.
The authors of a small but successful long-COVID drug trial of Guanificine also reported that they believe that increased kynurenine levels in long COVID were hampering the functioning of the prefrontal cortex – thus causing cognitive, autonomic, and other issues.
A Different Take
Sending the pathway in the opposite direction could have similar effects. In 2019, Robert Phair produced the Metabolic Trap model for ME/CFS, which proposed a dysfunctional IDO2 enzyme results in tryptophan being metabolized mostly to serotonin instead of kynurenine. Besides whacking energy levels via a dramatically reduced production of NAD+, the Trap would produce an explosion of serotonin in the brain. Interestingly, Cortene proposed that a similar serotonin overload occurs in ME/CFS as well.
Boosting NAD+ Levels
One consequence of a hyperactivated toxic kynurenine pathway is reduced Na+ production. Note that if the kynurenine pathway has gone off the rails and is inhibiting NAD+ production, NAD+ might be able to be boosted using a “salvage pathway” that involves its precursors nicotinic acid (NA), nicotinamide (NAM), nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR).
Find out more about that in the niacin blog.
Evidence for dysregulated tryptophan metabolism in ME/CFS/FM and long COVID exists in several places. Problems with the gut flora could lead to reduced production of core metabolites, such as tryptophan and kynurenine, that the brain needs. Plus, the pro-inflammatory gut found in these diseases could help produce the inflammatory condition in the brain that turns kynurenine metabolism in a toxic direction.
The evidence of neuroinflammation in ME/CFS/FM and long COVID is rather sparse at the moment but is growing, with few studies pointing otherwise. If a neuroinflammatory condition exists, it could turn kynurenine metabolism in a toxic direction, causing it to produce substances like quinolinic acid, which produce oxidative stress, more inflammation, increased pain sensitivity and the symptoms associated with sickness behavior (fatigue, flu-like symptoms, depression). At the same time, it was doing that, the toxic pathway could reduce the production of feel-good substances like serotonin and melatonin, and inhibit mitochondrial activity.
This pathway is under investigation in many neurological illnesses, but with few studies done, researchers are still nowhere near showing that it’s producing the problems in ME/CFS/FM and long COVID. The potential to produce mischief, though, is clearly present.
An uptick in interest in this pathway in long COVID could, if it continues, resolve if tryptophan and kynurenine metabolism is playing a key role in these diseases.
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