Amsterdam scientists find an enzyme (IDO2) that could be the culprit of #LongCovid: Prolonged IDO2 activity & associated cellular stress in PASC.

[junkcrap50]

They found the IDO2 enzyme in "insane amounts" in Long Covid patients in all kinds of cells causing "a kind of collective suicide" as well as impaired mitochondrial function and Krebs Cycle dysfunction. They say it's clear that IDO2 continues to rage after the virus is defeated and IDO1 production ceases.

They found that a a specific kynurenine metabolite (and others) which continues to stimulate more IDO2 enzyme production. These metabolites can "spread systemically and thus, in the absence of adequate AHRR activity, can induce IDO2 at sites throughout the body."

Incredibly, they have discovered an experimental cancer drug (not yet approved but in researched & in development)that sharply lowers IDO2 amounts and stops the destruction of cells, which is "likely to restore cell functioning." It works as a aryl hydrocarbon receptor (AHR) antagonist disrupting a positive feedback loop in the kynurenine-AHR-IDO2 axis. So,

• Did Ron Davis & Robert Phair's hypothesis get validated?
• Could IDO2 or a discovered metabolite that be a reliable biomarker?
• Could the drug be used to escape the trap?

See quotes from article and the full paper abstract below.

Here is a google translated PDF of the article: https://docs.google.com/document/d/1RExZS00rQhPcmqgs-EcN67_UCDwN3u3guxueaL8PM3E/edit
Here is the article in Dutch: https://www.volkskrant.nl/wetenscha...-wetenschappers-zitten-op-een-spoor~ba477769/
Here is the research paper: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00294-3/fulltext

Some quotes from the article:

A life without post-covid something closer? Amsterdam scientists are on track
by author Ellen de Visser is medical editor on the science editorial board ofde Volkskranta.

Tens of thousands of Dutch people have been walking around with complaints since they got corona years ago. The cause is still unknown. Scientists in Amsterdam have now found an enzyme that could be the culprit. “I thought, wow, this could be really important.”

If what the Amsterdam immunologist René Lutter has seen under his microscope takes place in the body, then the serious complaints of patients with post-covid syndrome can be tackled with an experimental cancer drug. Lutter remembers the moment when he saw the startling images in his lab: the substances that drove patients' blood cells to a kind of collective suicide, were barely traceable after administration of the drug. The palette of purple and red colors had faded. And that after just eight days.
....
In one of the work rooms in the hospital, he draws the series of substances that arise after a corona infection, the production of which – that is the most important finding – can be brought to a halt: with a drug that is being developed against cancer. Their research report was published at the end of July in magazine eBiomedicine, part of The Lancet.
....
In the blood, in the brain, in the lungs, in the heart: if the Amsterdam researchers study the organs of deceased covid patients under the microscope, they will find in the course of 2021 everywhere the enzyme IDO-2. And not just a little, no 'an insane amount', says Lutter.

Until then, immunologists have mainly focused their research on post-covid syndrome on IDO-1, an enzyme produced by the body to fight a virus. Once the virus is defeated, production of that IDO-1 ceases. The Amsterdammers discover that cells produce another enzyme, IDO-2, in response to the coronavirus. They don't know why that is, but it is clear that IDO-2 continues to rage.

They see the consequences in the deceased patients: the enzyme has initiated the production of a series of substances that have damaged cells so much that they have died or no longer function properly. In December 2021, the researchers will publish their findings in a international journal for pathologists.
....
When they examine the immune cells of nine patients more closely, they discover, for example, that the energy factories in those cells function less well. It fits in with what Appelman sees happening in his patients: 'Any form of exertion, whether physical or cognitive, can cause a relapse.'
...
IDO-2 stimulates the production of another substance that continues to activate the antenna, resulting in the production of new enzymes. This creates a flywheel, a process that maintains itself. “We think that explains why the complaints persist,” says Lutter.

This is not just a discovery, explains doctor-researcher Appelman. This means that for the first time there is a clear starting point for a treatment: if that brake can be repaired in the cells of post-covid patients, this may reduce their complaints.

There is such a repair agent, Lutter discovered after a search in the medical literature: it is a substance that is currently being tested by a number of pharmaceutical companies in cancer patients. He buys a bit of it and discovers its powerful effect when he adds the stuff to the blood of six patients in the lab. In all, the amount of the enzyme in the cells decreases sharply. With the immediate result that much less damage to the cells occurs.
....

Here is the abstract of the research paper:

Prolonged indoleamine 2,3-dioxygenase-2 activity and associated cellular stress in post-acute sequelae of SARS-CoV-2 infection​

• Lihui Guo n , Brent Appelman n , Kirsten Mooij-Kalverda , Riekelt H. Houtkooper , Michel van Weeghel , Frédéric M. Vaz , et al.

Open Access Published: July 26, 2023 DOI:https://doi.org/10.1016/j.ebiom.2023.104729

Summary​

Background​

Post-acute sequela of SARS-CoV-2 infection (PASC) encompass fatigue, post-exertional malaise and cognitive problems. The abundant expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase-2 (IDO2) in fatal/severe COVID-19, led us to determine, in an exploratory observational study, whether IDO2 is expressed and active in PASC, and may correlate with pathophysiology.

Methods​

Plasma or serum, and peripheral blood mononuclear cells (PBMC) were obtained from well-characterized PASC patients and SARS-CoV-2-infected individuals without PASC. We assessed tryptophan and its degradation products by UPLC-MS/MS. IDO2 activity, its potential consequences, and the involvement of the aryl hydrocarbon receptor (AHR) in IDO2 expression were determined in PBMC from another PASC cohort by immunohistochemistry (IHC) for IDO2, IDO1, AHR, kynurenine metabolites, autophagy, and apoptosis. These PBMC were also analyzed by metabolomics and for mitochondrial functioning by respirometry. IHC was also performed on autopsy brain material from two PASC patients.

Findings​

IDO2 is expressed and active in PBMC from PASC patients, as well as in brain tissue, long after SARS-CoV-2 infection. This is paralleled by autophagy, and in blood cells by reduced mitochondrial functioning, reduced intracellular levels of amino acids and Krebs cycle-related compounds. IDO2 expression and activity is triggered by SARS-CoV-2-infection, but the severity of SARS-CoV-2-induced pathology appears related to the generated specific kynurenine metabolites. Ex vivo, IDO2 expression and autophagy can be halted by an AHR antagonist.

Interpretation​

SARS-CoV-2 infection triggers long-lasting IDO2 expression, which can be halted by an AHR antagonist. The specific kynurenine catabolites may relate to SARS-CoV-2-induced symptoms and pathology.

 

[junkcrap50]

Here is their related paper, linked in the article, showing the positive feedback loop of IDO2 from the initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis.

https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.5842

Indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2 activity and severe course of COVID-19​

Lihui Guo, Bernadette Schurink, Eva Roos, Esther J Nossent, Jan Willem Duitman, Alexander PJ Vlaar, Paul van der Valk, Frédéric M Vaz, Syun-Ru Yeh, Zachary Geeraerts … See all authors
First published: 03 December 2021 https://doi.org/10.1002/path.5842 Citations: 10

Abstract​

COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

EDITED to add:
@Cort , is this worthy news to follow up on and write about for HealthRising? (At your leisure of course.)

 

[junkcrap50]

@Siebe beat me to it and posted the news in a different thread in this post.
And also shout out to @Siebe as he made a twitter thread about it:

https://twitter.com/i/web/status/1689562743055986688

Another twitter user reports that the group will be repeating their research in ME/CFS patients:

https://twitter.com/i/web/status/1689612205623320576

 

[linusbert]

so what is an AHR antagonist , where can i order?

i sent them my dna data back thn, they meant my genetics is highly suspectible. so worth a try if there is anything i could take.

 

[Consul]

In one of the latest papers from Maureen Hanson they wrote that they found a profound dysregulation of the kynurenine pathway.

 

[linusbert]

i asked AI if there are natural substances which inhibit the AHR,
it mentions the following:

Spoiler

Yes, there are natural compounds that can act as AHR antagonists. Some compounds found in nature have been identified and studied for their ability to inhibit the activation of the aryl hydrocarbon receptor (AHR). These compounds can be found in various foods, plants, and environmental sources. Here are some examples of natural AHR antagonists:

1. Indole-3-carbinol (I3C): This compound is present in cruciferous vegetables like broccoli, cabbage, and cauliflower. I3C is metabolized during digestion to diindolylmethane (DIM), which can exhibit AHR antagonist properties.

2. Resveratrol: This compound is found in red grapes, red wine, peanuts, and some other plants. Resveratrol has been shown to inhibit AHR activation.

3. Quercetin: Quercetin is a flavonoid present in many fruits and vegetables. It has been suggested to act as an AHR antagonist.

4. Curcumin: This compound found in turmeric has potential AHR antagonist properties.

5. Ellagic Acid: Ellagic acid is present in berry fruits like raspberries, strawberries, and pomegranates and may exhibit AHR antagonist activity.

It's important to note that AHR research is ongoing, and our understanding of the effects of natural compounds on the AHR may have evolved since my last update in September 2021. The exact mechanisms of action and potential health benefits of natural AHR antagonists are subjects of ongoing scientific investigation.

...

Yes, there are additional natural substances that have been studied for their potential AHR antagonist activity. Here are a few more examples:

1. **Epigallocatechin Gallate (EGCG)**: EGCG is a polyphenol found in green tea. It has been investigated for its ability to inhibit AHR activation and its potential health benefits.

2. **Genistein**: Genistein is an isoflavone present in soybeans and soy products. It has been shown to interact with the AHR and modulate its activity.

3. **Sulforaphane**: Sulforaphane is a compound found in cruciferous vegetables like broccoli, Brussels sprouts, and kale. It has been studied for its potential to influence AHR signaling.

4. **Luteolin**: Luteolin is a flavonoid found in various plants, including celery, parsley, and chamomile. It has been explored for its AHR-modulating effects.

5. **Gingerol**: Gingerol is a bioactive compound in ginger with potential AHR antagonist properties.

6. **Berberine**: Berberine is a plant alkaloid found in several plants, including barberry and goldenseal. It has been investigated for its potential to interfere with AHR signaling.

7. **Fisetin**: Fisetin is a flavonoid found in fruits like strawberries, apples, and onions. It has been suggested to have AHR antagonist activity.

These substances are being studied for their potential to modulate AHR activity and affect downstream biological processes. However, the field of AHR research is complex, and the effects of these natural compounds on AHR signaling may vary depending on factors such as concentration, cellular context, and specific ligands. As research continues, more natural substances with AHR antagonist properties may be identified, and our understanding of their mechanisms and potential benefits may deepen.

so it looks like broccoli, brussel spouts, kale ... and their extracts can do this more or less.
so there might be a explanation finally why salad could be healthy

 

[Sizzle]

Here is the article in Dutch: https://www.volkskrant.nl/wetenscha...-wetenschappers-zitten-op-een-spoor~ba477769/

Dutch non paywall version (thanks to @Siebe )

https://12ft.io/proxy?q=https://www...-wetenschappers-zitten-op-een-spoor~ba477769/

 

[Osaca]

I don't really see this corroborating the work of the OMF, at least not directly, but perhaps someone has better information? Apart from IDO-2 being downregulated according to Phair/Davis and high tryptophan, whilst IDO-2 is upregulated here in Long-Covid (of course downregulation might be illness duration dependent), the work by the OMF was basically modeling (with some weak genetic links), which unfortunately didn't seem to hold up in later experiments, for example their kynurenine trial (which also isn't statistically significant in this Long-Covid finding).

Regarding the dutch work there seems to be a bit of splitting and dicing of the data and matching problems accompanied by the usual overlap between Long-Covid and hospitalised with Covid but recovered patients, which however purely stems from data and sample availability problems and is normal for such experimental work, which was not funded by anyone but the researchers themselves.

This group of researchers are committed when it comes to ME/CFS and Long-Covid and very transparent with their research and if the funding agencies by the Dutch government don't, as normally, show themselves from their worst side, we can hope to see more experiments soon. As pointed out above sample collection for ME/CFS is about to start.

It will be interesting to see how this work could line up with the soon to be published work of Wüst et al where they seem to find necrosis as a central problem in muscles after exercise.

 

[MonkeyMan]

Ok, I know this premature, but if this cancer drug is shown to be helpful, might it soon be available to LC and ME/CFS patients on a compassionate basis (like HIV drugs were)? Or do we have to wait years and years for its approval????

 

[Osaca]

Ok, I know this premature, but if this cancer drug is shown to be helpful, might it soon be available to LC and ME/CFS patients on a compassionate basis (like HIV drugs were)? Or do we have to wait years and years for its approval????

If there were a drug that was proven to be effective for LC, it would become available quickly, I'm certain of that. There is significant pressure, economic and social and the patient advocacy groups for LC have a far greater reach than those for ME/CFS ever had. Just yesterday the German chancellor was talking about how a quicker drug approval for Long-Covid might be necessary.

The big problem is the if. Showing that a drug is effective requires large studies followed by, at least, Phase 2 studies all of which requires significant funding. This contrasts the reality of this experimental research which had to be financed by the researchers themselves. Add to that that these cancer drugs haven't even passed Phase 1 for cancer, so the majority of them won't ever be helpful or approved for cancer.

 

[linusbert]

Just yesterday the German chancellor was talking about how a quicker drug approval for Long-Covid might be necessary.

yikes, this gives me the creeps somehow.

they do not even know whats the underlying cause, and we are talking faster drug approval already? we need money for base research, and this is cut down or not increased despite politics talking big.

 

[Rufous McKinney]

The big problem is the if. Showing that a drug is effective requires large studies followed by, at least, Phase 2 studies all of which requires significant funding.

the US supposedly allocated over a billion to study long covid but Where is the Beef?

 

[linusbert]

the US supposedly allocated over a billion to study long covid but Where is the Beef?

your Beef is driving with chains through Ukraine...

 

[ZeroGravitas]

IDO-2 being downregulated according to Phair/Davis and high tryptophan, whilst IDO-2 is upregulated here in Long-Covid

IDO2 expression is not actually downregulated in Phair's tryp-trap hypothesis. So I don't think it's necessarily incompatible with the new study, in this regard... 🤔

IDO2's enzymatic activity is inherently lower (or absent) in most humans, due to various common deleterious mutations. These were presumably able to accumulate because it's almost always a redundant backup enzyme for IDO1.

OK. Here's a quick summary of the essential details of the trap theory.
Malfunction of IDO2 does not cause the IDO metabolic trap. Malfunction of IDO2 predisposes to the IDO metabolic trap.
The trap is inherent in the detailed kinetics of normally functioning IDO1. IDO1 is a substrate-inhibited enzyme. If cellular Trp gets too high, it inhibits IDO1. That's the definition of substrate inhibition.
IDO2 can be seen as a backup for IDO1 at high Trp.
If one or both copies of the IDO2 gene are broken, there is only half as much backup or no backup. When that happens it becomes possible for Trp to increase beyond the point where IDO1 can handle it. IDO1 becomes substrate inhibited, there is no easy mechanism to reverse this substrate inhibition, and that cell becomes trapped in a high Trp, low kynurenine state, which defines the IDO metabolic trap. We are not talking about concentrations in blood; we're talking about concentrations in the trapped cell.

overlap between Long-Covid and hospitalised with Covid but recovered patients

I think the authors were quite careful to avoid the possibility of conflating post-ICU syndromes with PASC. If that's part of what you mean? And their main PASC group was non-hospitalised.

[Edit: for better readability, from discussion section of new paper (my highlight):]

For this study we included non-hospitalized patients, with a proven SARS-CoV-2 infection, who were healthy before infection and developed long-lasting PASC symptoms (post-exertional malaise, cognitive symptoms, fatigue). Non-hospitalization is important as hospitalization can induce various forms of fatigue, such as cachexia and sarcopenia. With that we met the WHO criterium: “PASC is defined as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation”. By sticking to these strict inclusion criteria, and having patients in our cohort that vary with respect to intensity and specific PASC symptoms, we indeed believe that we have analyzed a representative and generalizable cohort of PASC patients.

 

[bob800]

This is getting pretty deep into speculation, but this article connects some (hypothetical) dots: https://www.mdpi.com/2571-841X/6/3/36

Since DA is an AhR agonist, DA inhibition by antipsychotic drugs may have an antagonistic effect on the downstream AhR.

(aripiprazole is mentioned)
The article also mentions Vit D and serotonin as AhR agonists

Also, for those following the speculation about JAK/STAT inhibitors:
https://pubmed.ncbi.nlm.nih.gov/32941808/

Elevated and activated AhR leads to phosphorylation of janus kinase 2 (Jak2), as well as its downstream effector, activator of transcription 3 (STAT3), while inhibition of Jak2/STAT3 signaling by pharmacologic approach attenuates the effects of AhR-mediated

Things are getting pretty interesting

 

[Osaca]

IDO2 expression is not actually downregulated in Phair's tryp-trap hypothesis. So I don't think it's necessarily incompatible with the new study, in this regard... 🤔

I don't at all think the ideas have to contradict each other, I just don't have any reason to believe they corroborate each other based on current data (from what I know high vs low tryp at least aren't confirmations of the same idea). That is also what the authors of the Amsterdam paper, who cite Davis and Phair's work seem to think. But I'm sure Wüst can explain more of this, when he's back from his vacation.

I think the authors were quite careful to avoid the possibility of conflating post-ICU syndromes with PASC. If that's part of what you mean? And their main PASC group was non-hospitalised.

Indeed, the authors are more than aware of overlaps with PICS and Long-Covid (and as such as well as for other reasons take non-hospitalised patients PASC patients which I think should always be the focus in PASC research, the overlap I was trying to refer to was in terms of results not on patient selection), as one would hope, and the PASC Amsterdam UMC COVID-19/ MUSCLE-PASC cohort seems to be reasonabily well selected as they first go through a medical screening and then apply good selection criteria (a lot of the patients that are also part of the MUSCLE-PASC study seem to be medical workers from the first Covid waves).

Different dataset or better to say subsets of this data (for example in the staining experiment) are then compared at different time points. However, I don't want to further scrutinise the sample sets, since as I mentioned above this is an explorative study and the authors received no funding to do this work and I don't see any reason to scrutinise any of their work, nor would I be in any position to do so.

Thanks for the clarification on IDO2, is there any reason to believe that the absence or dysfunction of the backup enzyme, IDO2 as per David/Phair, would lead to higher levels?

 

[Osaca]

the US supposedly allocated over a billion to study long covid but Where is the Beef?

Do people think that is a lot? 6% went to Pathobiology studies and 15% to clincal trials. This 1.1 billion also runs over 4-5 years. When confronted with a "new" disease this really isn't a lot of money...

NIH RECOVER receives a lot of justified criticism for how they've handled these funds with half of them going to an observational study and their lack of knowledge on post-viral illnesses. However, imo the real scandal is to not back up these studies with any long-term funding. The whole point of an observational study is for it to later be followed up by further studies of biomedical research and treatments.

I wonder how far other mulitsystemic diseases would have come with a meager 250mio of funding per year, which in this case is almost equivalent to the government funding of Long-Covid research globally, as the majority of other countries, unions and federations aren't investing a penny into the biomedical research of Long-Covid.

 

[hapl808]

I wonder how far other mulitsystemic diseases would have come with a meager 250mio of funding per year

Nowhere.

 

[ZeroGravitas]

OK, back to the main points! (I know you've updated your thinking on these, Junk.) My letter indexes:

• (A) Did Ron Davis & Robert Phair's hypothesis get validated?
• (B) Could IDO2 or a discovered metabolite that be a reliable biomarker?
• (C) Could the drug be used to escape the trap?

(A) No. This does support OMF's continued interest in tryp & kynurenine. But many observations, and the proposed mechanism, directly contradict Phair's original tryp-trap hypothesis.

Although there may be room for interpretation on some points and potential for co-existence of each phenomena in different contexts. Especially given these were all LC patients, and Prusty says they take a different route to ME. Also, ME itself changes immune profile after 3 years, which they've not hit, yet.

(B) IDO2 itself is confined inside (certain) cells. But they found it elevated inside PBMCs of blood samples, so maybe that's accessible for testing? Not sure how universally affected these innate immune cells are; could issue occur sometimes only in other tissues?

They talk of elevated kynurenine metabolites in serum, too. And reference two 2021 papers that showed this (not looked at yet). I would have thought we'd have seen that in all the metabolomics studies, if it were a viable biomarker (in ME/CFS)..? And kynurenine, itself, shouldn't be high, because it's production is rate limiting (much slower than) the various ways it's broken down. (Circumstantially, my urine kynurinate & quinolinate tested low-normal, xanthurenate mid-mornal, 10 years ago.)

(C) I think hydrocarbon receptor repressor (AHRR) drugs would be the opposite of helpful for any cells in a Phair-type tryp-trap. As they would inhibit one route of removing excess tryptophan accumulation.

But, the authors claim AHRRs worked perfectly to suppress the vicious feedback loop that they propose (and show evidence for). Despite reading all of both papers, I'm not clear if their high IDO2 cells stayed fixed *after* the AHRR drug was removed..? I think that's outside of the remit of their test setups?

Also, in vivo, there would presumably be the risk of any fixed IDO2-expressing cells being re-triggered by other cells/tissues that remained stuck. As they propose systemic spread (from your article quote).

I'm not sure what would stop such an effect automatically spreading to every possible cell in the body? (Making a patient maximally severe.) Presumably thresholding levels and negative feedback mechanisms? There's mention (in the 2021 paper) of naturally occurring AHRRs (repressors) having a lower mRNA expression in lungs of fatal Covid cases and obese persons with higher risk for severe acute infection.

 

[ZeroGravitas]

I'll have a go (please correct me!) at a more detailed breakdown of how these two papers contradict Phair's tryp-trap, expanding on point (A), above:

(1) The PASC patient's PBMCs (monocytes/lymphocytes), which are able to express IDO2, contained high kynurenine and *low* tryptophan. Although this doesn't necessarily say much about various tissues in the body.

(2) Elevated kynurenine metabolites in serum circulation: xanthurenic acid and 3OH-anthranilic acid, in some. In their 2021 paper, they found even higher levels in acute Covid patients before they died. So maybe this is more a feature of acute infection or recent onset?

(3) They co-located high levels of kynurenine metabolites with cells where IDO2 was also present in high quantities. Visualised by staining it with a florescent antibody, in slides of patient tissue samples. IDO1 present to a far lesser extent (implying IDO2 must be functional and making the metabolites).

(4) Autophagy was visualised (another stain) more where there was more IDO2 in tissues. This is the breakdown of cellular structures for their amino acids, which is a result of tryptophan *depletion* inside cells. Apoptosis (cell death) too, as a result of cytotoxic metabolites.

(5) The authors mention Phair's 2019 paper in passing, at the end of their discussion. Showing they've considered its "enzymatically inactive" IDO2 proposal. But don't point out the obvious contradiction of their observations clearly showing functional IDO2. Maybe the article's "insane amounts" hints that there needs to be a lot of IDO2 because its function is very compromised by genetic mutations..?

(6) Also, referencing two 2021 studies finding *elevated* kynurenine metabolites in ME/CFS (not sure where in the body): 52, 53.

In the previous (2021) paper:

(7) No decrease of serotonin in CSF, implies no elevation, either (right?). I think Phair previously proposed high serotonin, in the brain (stem) as a possibile driver of patient neurological symptoms.

(8) Their proposed vicous cycle leans on (I think) more established mechanisms:
• Cytokines (or bacterial LPS) stimulate IDO1.
• IDO1 converts tryp to kynurenine.
• That triggers AhR (receptors) on the same cells.
• AhR stimulates IDO2 production (which is not activated by cytokines, etc) but not IDO1 (which can then dissipate).
• IDO2 makes more kynurenine, which closes the loop. (Not sure what stops this happening whenever it's activated?)
• Typ get depleted (trigger autophagy) and cytotoxic metabolites accumulate (cell stress/death).

Contrasting this with Phair's mechanism, which Ron Davis was still talking about needing to nail down, for sure, in his Cambridge conference lecture, a couple months back [YouTube]. Despite Phair seemingly drawing a line under it already.

Of course, imbalance in either direction would cause big problems.

(I may edit in, or correct, a few points. If I find some more in the mess I've made highlighting parts, when I read through the main paper a few days ago.)