Brain Kynurenine and BH4 Pathways: Relevance to the Pathophysiology and Treatment of Inflammation-Driven Depressive Symptoms

[Learner1]

Why do you think is 5-HTP not advisable?

Because a doctor prescribed if to help my sleep and triggered the IDO2 trap, which took 18 months of hyperbaric oxygen to get rid of.

I'm quite sure it is SAMe that get's depleted and not its precursors. How can SAMe be more counterproductive than its precursors? Feel free to share your theory in the separate post that I opened about the methylation cycle

I don't have any theories. I listen to what my doctors say dnf then read research studies and info on the web. There are a number of reasons that SAMe is not advisable. My doctors have always avoided SAMe got myself and others, and used precursors.

I'd be interested in how you understand that they can reverse PEM? What's their mechanism of action?

They have worked well for me, with glutathione. I seemed to always be short of isoleucine and leucine.

This describes what they do:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156598/

Unless they publish(ed) the affected SNPs, it will be difficult to tell even with a test. I asked for a particular SNP (i.e. rs4503083) in their last video update without an answer. Maybe they're still working on it and don't want to spread misinformation unless it's verified.

No big secret here. There is a slide which lists 5 troublesome SNPs in the YouTube videos from Phair's presentation at the Stanford Symposium. Probably in his paper too.

 

[nerd]

Because a doctor prescribed if to help my sleep and triggered the IDO2 trap, which took 18 months of hyperbaric oxygen to get rid of.

Are you sure it triggered the IDO2 trap and not something else? How did they test this? Why would hyperbaric oxygen help?

I don't have any theories. I listen to what my doctors say dnf then read research studies and info on the web. There are a number of reasons that SAMe is not advisable. My doctors have always avoided SAMe got myself and others, and used precursors.

I'm glad when you have trust in your physicians. From my personal experience, my MDs often had superficial knowledge only and didn't know how a certain metabolism is affected in CFS/ME in particular. From my personal experience, MDs are way too overconfident regarding their own experience and understanding of current science. They would often fall for the trap that a singular study had to be correct because it suited their narrative but they were good at ignoring all the other studies that might show conflicting evidence.

There is one interesting reference in your referenced survey.

D'Antona G, Ragni M, Cardile A, Tedesco L, Dossena M, Bruttini F, Caliaro F, Corsetti G, Bottinelli R, Carruba MO, Valerio A, Nisoli E. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab. 2010 Oct 6;12(4):362-372. doi: 10.1016/j.cmet.2010.08.016. PMID: 20889128.

Abstract

Recent evidence points to a strong relationship between increased mitochondrial biogenesis and increased survival in eukaryotes. Branched-chain amino acids (BCAAs) have been shown to extend chronological life span in yeast. However, the role of these amino acids in mitochondrial biogenesis and longevity in mammals is unknown. Here, we show that a BCAA-enriched mixture (BCAAem) increased the average life span of mice. BCAAem supplementation increased mitochondrial biogenesis and sirtuin 1 expression in primary cardiac and skeletal myocytes and in cardiac and skeletal muscle, but not in adipose tissue and liver of middle-aged mice, and this was accompanied by enhanced physical endurance. Moreover, the reactive oxygen species (ROS) defense system genes were upregulated, and ROS production was reduced by BCAAem supplementation. All of the BCAAem-mediated effects were strongly attenuated in endothelial nitric oxide synthase null mutant mice. These data reveal an important antiaging role of BCAAs mediated by mitochondrial biogenesis in mammals.

Further investigation is needed to assess the role of SIRT1 induction in BCAAem effects on mice survival.

It seems they don't have a model yet for why SIRT1 is upregulated by BCAAs.

 

[nerd]

There is a slide which lists 5 troublesome SNPs in the YouTube videos from Phair's presentation at the Stanford Symposium.

Thanks for the reference to the video. The IDO2 mutations they found indeed aren't very distinct. They aren't categorically significant and they seem to be compound heterozygote (will have to check this later for all SNPs). This makes the identification of dysfunctional IDO2 difficult unless there is an obvious loss-of-function mutation.

According to their data, a large percentage of people might have this kind of IDO2 dysfunction. Ca. 90% get EBV in their lifetime. But CFS/ME isn't that common. It doesn't even affect 5% of the general population. So there must be something else contributing.

Another oddity: Y359STOP and I127V are inversely correlated with SIPS CFS AF. So you're supposed to be more likely to get CFS/ME if you don't have these two variants, which means less damage and more function of IDO2.

By the way, I have both common variants, R248W (rs10109853), and Y359STOP (rs4503083). The chance of getting this genotype is ca. 10%. It's even ca. 20% in my population because these variants are more common within my population. Assuming that R248W has to be homozygous and that Y359STOP is just an inherited confounder, it's still ca. 5% at least. But this is all speculation.

Overall, I don't find the genetic perspective of the IDO trap very convincing. The statistical differences aren't large enough despite their significance. Maybe they'll find additional variants but I doubt it since they already fed their test group's IDO genomes to the software. Unless there is some complex sequential genotype or maybe a yet unmatched haplotype, there is nothing more to find.

 

[Learner1]

Thanks for the reference to the video. The IDO2 mutations they found indeed aren't very distinct. They aren't categorically significant and they seem to be compound heterozygote (will have to check this later for all SNPs). This makes the identification of dysfunctional IDO2 difficult unless there is an obvious loss-of-function mutation.

According to their data, a large percentage of people might have this kind of IDO2 dysfunction. Ca. 90% get EBV in their lifetime. But CFS/ME isn't that common. It doesn't even affect 5% of the general population. So there must be something else contributing.

Another oddity: Y359STOP and I127V are inversely correlated with SIPS CFS AF. So you're supposed to be more likely to get CFS/ME if you don't have these two variants, which means less damage and more function of IDO2.

By the way, I have both common variants, R248W (rs10109853), and Y359STOP (rs4503083). The chance of getting this genotype is ca. 10%. It's even ca. 20% in my population because these variants are more common within my population. Assuming that R248W has to be homozygous and that Y359STOP is just an inherited confounder, it's still ca. 5% at least. But this is all speculation.

Overall, I don't find the genetic perspective of the IDO trap very convincing. The statistical differences aren't large enough despite their significance. Maybe they'll find additional variants but I doubt it since they already fed their test group's IDO genomes to the software. Unless there is some complex sequential genotype or maybe a yet unmatched haplotype, there is nothing more to find.

I suspect there are a lot of other genes (and environmental factors) that interact to spawn a case of ME/CFS.

 

[Learner1]

Are you sure it triggered the IDO2 trap and not something else? How did they test this? Why would hyperbaric oxygen help?

It us the antidote to the metabolic trap according to Ron Davis.

I'm glad when you have trust in your physicians. From my personal experience, my MDs often had superficial knowledge only and didn't know how a certain metabolism is affected in CFS/ME in particular. From my personal experience, MDs are way too overconfident regarding their own experience and understanding of current science. They would often fall for the trap that a singular study had to be correct because it suited their narrative but they were good at ignoring all the other studies that might show conflicting evidence.

There is one interesting reference in your referenced survey.

D'Antona G, Ragni M, Cardile A, Tedesco L, Dossena M, Bruttini F, Caliaro F, Corsetti G, Bottinelli R, Carruba MO, Valerio A, Nisoli E. Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice. Cell Metab. 2010 Oct 6;12(4):362-372. doi: 10.1016/j.cmet.2010.08.016. PMID: 20889128.

Abstract




It seems they don't have a model yet for why SIRT1 is upregulated by BCAAs.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220583/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517633/

https://www.mdpi.com/1422-0067/19/4/954/htm

 

[nerd]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3517633/

The best explanation I found is in this paper (10.1155/2014/239750). They suggest a mutual interaction between AMPK and SIRT1 and that Leucine triggers both in a time-dependent manner. But they also point out that an overexpression could lead to inverse reactions. This would be consistent with the studies on Nicotinamide Riboside and Resveratrol/Pterostilbene, which also stimulates SIRT1 in moderate dosages.

 

[JES]

Thanks for the reference to the video. The IDO2 mutations they found indeed aren't very distinct. They aren't categorically significant and they seem to be compound heterozygote (will have to check this later for all SNPs). This makes the identification of dysfunctional IDO2 difficult unless there is an obvious loss-of-function mutation.

According to their data, a large percentage of people might have this kind of IDO2 dysfunction. Ca. 90% get EBV in their lifetime. But CFS/ME isn't that common. It doesn't even affect 5% of the general population. So there must be something else contributing.

Another oddity: Y359STOP and I127V are inversely correlated with SIPS CFS AF. So you're supposed to be more likely to get CFS/ME if you don't have these two variants, which means less damage and more function of IDO2.

By the way, I have both common variants, R248W (rs10109853), and Y359STOP (rs4503083). The chance of getting this genotype is ca. 10%. It's even ca. 20% in my population because these variants are more common within my population. Assuming that R248W has to be homozygous and that Y359STOP is just an inherited confounder, it's still ca. 5% at least. But this is all speculation.

Overall, I don't find the genetic perspective of the IDO trap very convincing. The statistical differences aren't large enough despite their significance. Maybe they'll find additional variants but I doubt it since they already fed their test group's IDO genomes to the software. Unless there is some complex sequential genotype or maybe a yet unmatched haplotype, there is nothing more to find.

Paraphrasing what Ron Davis says in this video, it could be that an IDO2 mutation is a necessary factor in order for someone to develop ME/CFS, but that having IDO2 doesn't necessarily cause ME/CFS. In the severe patient group that Davis tested, they found IDO2 in all but one of the around 70 patients tested. This information is now two years old, so take that with a grain of salt. I wonder if they have tested more patients by now. If they had found patients without the mutation, you'd think Ron would have moved on from this hypothesis, but who knows.

You are correct in that a large percentage of the general population has at least one damaging mutation in IDO2, according to some of Davis' estimates it was even up to 90% if you count all the mutations they found together.

In a way this reminds a bit of the EBV situation in MS. It seems that practically everyone who develops MS has also had an EBV infection in the past, but then again so does 90-95% of the general population, which is the crux. Still it makes you wonder if vaccination aginst some of these viruses in early age would prevent conditions like ME/CFS or MS.

 

[nerd]

In a way this reminds a bit of the EBV situation in MS. It seems that practically everyone who develops MS has also had an EBV infection in the past, but then again so does 90-95% of the general population, which is the crux. Still it makes you wonder if vaccination aginst some of these viruses in early age would prevent conditions like ME/CFS or MS.

But for EBV-induced diseases, there is more evidence than just an association with the virus. There are also correlations with EBV antibodies and IM duration and severity. I'd certainly think that vaccinations would eliminate the most typical trigger for many diseases. If they had access to all the patients, they could verify which SNPs really affect IDO2 function in their cells. But they only used a CFS/ME patient genome database and compared this to an average healthy genome group.

 

[Springbok1988]

Does the trap hypothesis state homozygosity for the mutation or heterozygosity is the issue? I assume homozygosity but I couldn’t find it in the published paper.

 

[aquariusgirl]

I think they said you can be compound heterozygous for the SNPs they identified. Can anyone confirm?

 

[Springbok1988]

Oh, there it is. You’re right. Thanks!