Oh my God, a new post! Had been worrying you'd dropped off the face of the Internet and I'd never get more non-stupid microbiome content. It's a niche to be sure, but I find your writing doubly relevant as someone who stocks groceries for a living. It's good to have a properly-calibrated level of cynicism about the products I'm pushing without going all RFK.
Note when the study says “Absence of Q impairs sporulation and biofilm formation in B. subtilis” that absence was induced by a mutation, not by deprivation of environmental Q.
Aha, I was wondering if someone would dig this up! As a prize for doing so, a bonus story:
I am also behind that website; it was part of an effort to prevent Q from ending up in what I call the "Statin Trap".
See, US legal code says that, if a compound (even a natural one) is developed or marketed as a drug, it can't later be marketed as a dietary supplement without a special dispensation from the FDA [which has, to date, been granted a total of 0 times] unless it was a dietary supplement first. So you can have a pharmaceutical version of fish oil, for instance, and fish oil can stay a food, because it was a food first. But you can't legally have a supplement version of viagra, because that was a drug first.
I call this the Statin Trap because this is how statins got boxed out of the supplement category and pigeonholed as drugs. See, lovastatin is a natural compound found in Red Yeast Rice, which has been used in Chinese medicine for ages, and was sold as a food/supplement in the US since before whatever drug company went and isolated the compound responsible for its cholesterol-lowering effects, put it through clinical trials, and got it approved as a drug.
So that company wasn't happy when the people selling Red Yeast Rice started advertising their product by saying things like "Hey, you know that new cholesterol drug? This is the exact same active ingredient at the same dose!"
And I get why the drug company would be mad; clinical trials are expensive. So the drug guys sued the red yeast rice guys and won. The case hinged on a split hair, where the ruling was that "marketing a food as a source of a certain chemical is substantially the same as marketing the chemical itself". So the Yeasty Boys can still sell a Red Yeast Rice product, but if they put "100mg lovastatin/monacolin K per serving" on their bottle, they're basically selling counterfeit pharmaceuticals, according to this precedent.
So: a couple years back, there was a company called Stellate, run by one of my lesser nemeses, that was trying to develop queuine as a drug--so we needed to sell it as a food/supplement first, because if the stuff truly is a vitamin that's essential for health and happiness, it should be on the shelf at the CVS with the other vitamins, not locked behind the pharmacy counter with its attendant price gouging, copays, doctors' visits, prescriptions, etc.
But we didn't have a saleable amount of queuine, and we were sort of unclear about whether it could lawfully be sold without more safety data than we had at that point. Fortunately, marketing something like rice or wheat germ as a quantified source of queuine is, according to that red yeast rice/lovastatin precedent, the same as selling queuine itself.
So Professor Q's Queuine Foods was born. The amounts are no higher in those products than in your average rice or wheat germ, but they're quantified and listed--and one thing that's completely unambiguous: those foods are being marketed as a source of queuine!
Stellate has since fallen apart, more or less, so hopefully that argument never has to be put to the test in court, but I think we planted our flag honestly--or as close to honestly as you can come in the modern American legal system. We measured the amounts with the help of Harvard's mass spec lab, we made the website and designed the packaging ("Professor Q" is based on an old photo of my dad lol), we genuinely sold the rice and the wheat germ; I personally packaged and shipped out half a dozen ten-pound boxes of it. I have friends who are still working through theirs.
Strange, I know, and idek if it achieved anything, but at the very least I got familiar with the case law, and learned how to make a Nutrition Facts box up to code.
Another fantastic and informative post. You do a great job of communicating these complicated, specific concepts in a way that even this layman can mostly understand. I'm going to be sending this to several friends!
I'm confused though about this explanation of the Q-depletion mouse study. If the Q-deficient mice were dying because of a toxic buildup of phenylalanine, because their AAAH enzymes weren't running well, because of low BH4 -- then why would adding tyrosine to their diet make this not happen?
Great question! It looks like it's not the excess of phenylalanine that does them in, but the lack of tyrosine (remember, untreated PKU in humans is debilitating but AFAIK not lethal).
The experiment mostly shows that Q deficiency induces enough of a BH4 deficit to stop up phenylalanine hydroxylase.
Even though I don't know enough science to understand a lot of this, I'm happy to know that you are working on this problem. I think you're on the right track.
Hi Stephen! I'm very interested in funding + participating in self-research on queuine and queuosine. I don't have your email address but if you're still looking for help, please reach me at matthew910 at protonmail dot com
P.S. I'm planning to go back to finish my bachelor's degree and have been considering focusing on microbiology as a result of your posts. This stuff seems so exciting!
Would nucleotide supplementation lead to more vitamin Q, maybe due to more substrate for gut bacteria to work on? There's RNA, inosine, and uridine supplements for sale
This aligns very well with my experience - decades of "treatment-resistant depression", OCD, anxiety and insomnia, which turned out to be mostly dairy intolerance and histamine issues. Inflammation -> reduced BH4 -> the world is a gray valley of unenjoyability.
Tryptophan supplementation made it worse, which aligns with the kynurenine pathway.
With dietary changes, it resolved by maybe 70%, but I am nowhere near out of the woods. Excited for your work. Will send you an email.
Do you have any thoughts about the queuine in relation to G-quadruplexes? There was an article by Derek Lowe recently discussing the role of G4s for diseases like Alzheimer's (https://www.science.org/content/blog-post/neurodegeneration-might-come-down-rna). If queuine generally replaces guanine in tRNA, could they also replace guanine in G4, either for functional purposes, or in a way which renders harmful ones unstable and unable to form?
"Has to do with RNA" is a bucket that includes a fuckton of cellular processes, and while queuine does have some known noncanonical functions (seems to be involved in helping epidermal growth factor bind to its receptor, for one) independent of its role in tRNA, I haven't seen anything about it being inserted into other varieties of RNA in eukaryotes. Thanks for sharing the finding either way, though--I'm sure this one will rattle around at the back of my skull for a few years before clicking into place, but I'll let you know when it does.
Yeah, I worried a bit about that, but figured better to just send it than let this post sit in drafts for another month while I try to find time to revise. If you don't have the patience, have a reading robot read it and summarize it for you, I guess. They will of course lead you astray, because there's no substitute for actually thinking about something, but hey.
Also: do the math on how much you can expect to get from milk/yogurt vs. how much it takes to prevent a deficiency.
Scaling up from the germ-free mouse experiments, where 0.1micromolar queuine in the diet was enough to rescue the tyrosine/death phenotype, you get a rough upper bound of 0.34 mg/day for a 70kg man.
Bovine milk is reported to contain 16-17 nanograms per mL. So: To get 0.34mg, you'd need to drink (340ug/17ng/mL)= 20,000mL = 20L.
So, an inconvenient amount.
Ripe coconut water is a little better--anywhere between 0.6L and 4L a day will get you there, but (aside from the hyperkalemia) unfortunately all commercial coconut water AFAIK is from unripe coconuts, which contains no queuine. If you want ripe coconut water, you'll have to get crackin'.
Silence is bias so i’ll just say the post is not too long. I hope you won’t take the advice of Mr. Hall—the last thing i want in my life is fewer words from you.
lol okay, but if the beneficial parts are hidden behind the quality of the content what use is the information? As a reader I don’t want to dig through a boring analysis, I want to know what is being offered, how it helps, and what I can do to obtain it.
The claim that vitamin Q can help with schizophrenia is astronomically huge. And then wading through the fluff to find out that it costs $10,000 to make a supply of it…cmon. Turns out you can probably achieve the same results by taking probiotics and drinking lots of coconut water and milk.
I made an account just so I could tell you not to listen to Nicholas Hall.
There's a certain subset of "biohackers" or people who just want to spend money on random supplements to hopefully make themselves feel better without ever understanding what the hell they're taking or why. And anything microbiome-related will attract those sort on account of it being fringe, unproven, and often quasi-scientific at best (and downright fraudulent at worst).
Articles as well-researched and well-written (I couldn't even spot a typo) as yours are rare in this space, and the background on biological processes critical to understanding these chemicals is important not just for informing people, but also legitimizing the microbiome space as a science and not a pseudoscience in the public's eyes.
So, your articles are a breath of fresh air in an otherwise mostly toxic space. I'm glad you've come back after a year to continue writing, and I hope you write more in the future. Thank you!
Isn’t it the dosage that was tried by volunteers when you cooked the first batch of queuine? I think it seemed low, and I vaguely remember you hinting that much bigger dosages might be required
I mean, look at the RDAs of the B vitamins — pretty sure most are sub mg. But that's to prevent deficiency; some veeeery sketchy math gives an estimate for total body Q of ~130mg IIRC.
Unfortunately, no—the mouse experiments should include a bioavailability factor, but that's on a pure liquid diet in germ-free animals, i.e. not accounting for things like scavenging by the gut microbiome.
Thank you. I haven't educated myself well enough to understand this post in as much depth as I would like to, but as someone diagnosed with MDD I feel more hopeful after reading it. I hope that your work plays a part in paving the way to a better understanding of the links between gut microbiomes and mental health.
Oh my God, a new post! Had been worrying you'd dropped off the face of the Internet and I'd never get more non-stupid microbiome content. It's a niche to be sure, but I find your writing doubly relevant as someone who stocks groceries for a living. It's good to have a properly-calibrated level of cynicism about the products I'm pushing without going all RFK.
Apparently B. subtilis of nattō fame (https://stephenskolnick.substack.com/p/natto-king-of-fermented-foods) is an avid Q de novo synthesizer, relying on it for film formation and sporulation:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10570037
Note when the study says “Absence of Q impairs sporulation and biofilm formation in B. subtilis” that absence was induced by a mutation, not by deprivation of environmental Q.
Nattō wins again?
Any food that will lead to more vItamin Q?
Also, any tips on microbiome and insomnia? When I eat certains food, I have insomnia like beets, kefir or tofu (but not Natto).
Found this:
https://pmc.ncbi.nlm.nih.gov/articles/PMC4425180/
Highest source: "Bovine amniotic fluid"
yummy
Yeah that's the punchline, isn't it? 16 kg of tomatoes, 2L of coconut water, or one shot-glass full of cow fetus juice. Pick your poison
Coconut water seems okay, although the dose is presumably still way too low
There is also this rice and germ site, but it seems to be sold out or abandoned? https://www.queuinefoods.com
Aha, I was wondering if someone would dig this up! As a prize for doing so, a bonus story:
I am also behind that website; it was part of an effort to prevent Q from ending up in what I call the "Statin Trap".
See, US legal code says that, if a compound (even a natural one) is developed or marketed as a drug, it can't later be marketed as a dietary supplement without a special dispensation from the FDA [which has, to date, been granted a total of 0 times] unless it was a dietary supplement first. So you can have a pharmaceutical version of fish oil, for instance, and fish oil can stay a food, because it was a food first. But you can't legally have a supplement version of viagra, because that was a drug first.
I call this the Statin Trap because this is how statins got boxed out of the supplement category and pigeonholed as drugs. See, lovastatin is a natural compound found in Red Yeast Rice, which has been used in Chinese medicine for ages, and was sold as a food/supplement in the US since before whatever drug company went and isolated the compound responsible for its cholesterol-lowering effects, put it through clinical trials, and got it approved as a drug.
So that company wasn't happy when the people selling Red Yeast Rice started advertising their product by saying things like "Hey, you know that new cholesterol drug? This is the exact same active ingredient at the same dose!"
And I get why the drug company would be mad; clinical trials are expensive. So the drug guys sued the red yeast rice guys and won. The case hinged on a split hair, where the ruling was that "marketing a food as a source of a certain chemical is substantially the same as marketing the chemical itself". So the Yeasty Boys can still sell a Red Yeast Rice product, but if they put "100mg lovastatin/monacolin K per serving" on their bottle, they're basically selling counterfeit pharmaceuticals, according to this precedent.
So: a couple years back, there was a company called Stellate, run by one of my lesser nemeses, that was trying to develop queuine as a drug--so we needed to sell it as a food/supplement first, because if the stuff truly is a vitamin that's essential for health and happiness, it should be on the shelf at the CVS with the other vitamins, not locked behind the pharmacy counter with its attendant price gouging, copays, doctors' visits, prescriptions, etc.
But we didn't have a saleable amount of queuine, and we were sort of unclear about whether it could lawfully be sold without more safety data than we had at that point. Fortunately, marketing something like rice or wheat germ as a quantified source of queuine is, according to that red yeast rice/lovastatin precedent, the same as selling queuine itself.
So Professor Q's Queuine Foods was born. The amounts are no higher in those products than in your average rice or wheat germ, but they're quantified and listed--and one thing that's completely unambiguous: those foods are being marketed as a source of queuine!
Stellate has since fallen apart, more or less, so hopefully that argument never has to be put to the test in court, but I think we planted our flag honestly--or as close to honestly as you can come in the modern American legal system. We measured the amounts with the help of Harvard's mass spec lab, we made the website and designed the packaging ("Professor Q" is based on an old photo of my dad lol), we genuinely sold the rice and the wheat germ; I personally packaged and shipped out half a dozen ten-pound boxes of it. I have friends who are still working through theirs.
Strange, I know, and idek if it achieved anything, but at the very least I got familiar with the case law, and learned how to make a Nutrition Facts box up to code.
Another fantastic and informative post. You do a great job of communicating these complicated, specific concepts in a way that even this layman can mostly understand. I'm going to be sending this to several friends!
Super interesting!
I'm confused though about this explanation of the Q-depletion mouse study. If the Q-deficient mice were dying because of a toxic buildup of phenylalanine, because their AAAH enzymes weren't running well, because of low BH4 -- then why would adding tyrosine to their diet make this not happen?
Great question! It looks like it's not the excess of phenylalanine that does them in, but the lack of tyrosine (remember, untreated PKU in humans is debilitating but AFAIK not lethal).
The experiment mostly shows that Q deficiency induces enough of a BH4 deficit to stop up phenylalanine hydroxylase.
Ah, that makes sense, thanks!
Even though I don't know enough science to understand a lot of this, I'm happy to know that you are working on this problem. I think you're on the right track.
Hi Stephen! I'm very interested in funding + participating in self-research on queuine and queuosine. I don't have your email address but if you're still looking for help, please reach me at matthew910 at protonmail dot com
P.S. I'm planning to go back to finish my bachelor's degree and have been considering focusing on microbiology as a result of your posts. This stuff seems so exciting!
Would nucleotide supplementation lead to more vitamin Q, maybe due to more substrate for gut bacteria to work on? There's RNA, inosine, and uridine supplements for sale
This aligns very well with my experience - decades of "treatment-resistant depression", OCD, anxiety and insomnia, which turned out to be mostly dairy intolerance and histamine issues. Inflammation -> reduced BH4 -> the world is a gray valley of unenjoyability.
Tryptophan supplementation made it worse, which aligns with the kynurenine pathway.
With dietary changes, it resolved by maybe 70%, but I am nowhere near out of the woods. Excited for your work. Will send you an email.
Do you have any thoughts about the queuine in relation to G-quadruplexes? There was an article by Derek Lowe recently discussing the role of G4s for diseases like Alzheimer's (https://www.science.org/content/blog-post/neurodegeneration-might-come-down-rna). If queuine generally replaces guanine in tRNA, could they also replace guanine in G4, either for functional purposes, or in a way which renders harmful ones unstable and unable to form?
There's no reason to think so.
"Has to do with RNA" is a bucket that includes a fuckton of cellular processes, and while queuine does have some known noncanonical functions (seems to be involved in helping epidermal growth factor bind to its receptor, for one) independent of its role in tRNA, I haven't seen anything about it being inserted into other varieties of RNA in eukaryotes. Thanks for sharing the finding either way, though--I'm sure this one will rattle around at the back of my skull for a few years before clicking into place, but I'll let you know when it does.
Neat. Another thing to add to my microbiome-maxxing-stack
But how?
According to chatgbt there’s this one clostridium strain from Japan one could take IIRC
This post is way too long and full of a lot of unnecessary fluff. Pare it down. Also, just drink more milk and eat more yogurt.
Yeah, I worried a bit about that, but figured better to just send it than let this post sit in drafts for another month while I try to find time to revise. If you don't have the patience, have a reading robot read it and summarize it for you, I guess. They will of course lead you astray, because there's no substitute for actually thinking about something, but hey.
There's also the scientific paper version, if you're an advanced reader: https://sci-hub.se/10.1016/j.tins.2018.12.005 starts on Page 6.
Also: do the math on how much you can expect to get from milk/yogurt vs. how much it takes to prevent a deficiency.
Scaling up from the germ-free mouse experiments, where 0.1micromolar queuine in the diet was enough to rescue the tyrosine/death phenotype, you get a rough upper bound of 0.34 mg/day for a 70kg man.
Bovine milk is reported to contain 16-17 nanograms per mL. So: To get 0.34mg, you'd need to drink (340ug/17ng/mL)= 20,000mL = 20L.
So, an inconvenient amount.
Ripe coconut water is a little better--anywhere between 0.6L and 4L a day will get you there, but (aside from the hyperkalemia) unfortunately all commercial coconut water AFAIK is from unripe coconuts, which contains no queuine. If you want ripe coconut water, you'll have to get crackin'.
Silence is bias so i’ll just say the post is not too long. I hope you won’t take the advice of Mr. Hall—the last thing i want in my life is fewer words from you.
lol okay, but if the beneficial parts are hidden behind the quality of the content what use is the information? As a reader I don’t want to dig through a boring analysis, I want to know what is being offered, how it helps, and what I can do to obtain it.
The claim that vitamin Q can help with schizophrenia is astronomically huge. And then wading through the fluff to find out that it costs $10,000 to make a supply of it…cmon. Turns out you can probably achieve the same results by taking probiotics and drinking lots of coconut water and milk.
Funny, given how this conversation started I would think you’d know when you’d said your piece.
Funny how funny when funny is funny with funny funny isn’t it funny
I made an account just so I could tell you not to listen to Nicholas Hall.
There's a certain subset of "biohackers" or people who just want to spend money on random supplements to hopefully make themselves feel better without ever understanding what the hell they're taking or why. And anything microbiome-related will attract those sort on account of it being fringe, unproven, and often quasi-scientific at best (and downright fraudulent at worst).
Articles as well-researched and well-written (I couldn't even spot a typo) as yours are rare in this space, and the background on biological processes critical to understanding these chemicals is important not just for informing people, but also legitimizing the microbiome space as a science and not a pseudoscience in the public's eyes.
So, your articles are a breath of fresh air in an otherwise mostly toxic space. I'm glad you've come back after a year to continue writing, and I hope you write more in the future. Thank you!
Very kind of you Luke, thank you. The encouragement and kind words do mean a lot.
What daily dosage do you estimate for queuine supplementation?
0.34mg/day is the upper bound scaling from the mouse experiments.
Isn’t it the dosage that was tried by volunteers when you cooked the first batch of queuine? I think it seemed low, and I vaguely remember you hinting that much bigger dosages might be required
I mean, look at the RDAs of the B vitamins — pretty sure most are sub mg. But that's to prevent deficiency; some veeeery sketchy math gives an estimate for total body Q of ~130mg IIRC.
Is anything known about bioavailability’s percentage of queuine via oral administration? Has your company considered an animal test maybe?
Unfortunately, no—the mouse experiments should include a bioavailability factor, but that's on a pure liquid diet in germ-free animals, i.e. not accounting for things like scavenging by the gut microbiome.
Thank you. I haven't educated myself well enough to understand this post in as much depth as I would like to, but as someone diagnosed with MDD I feel more hopeful after reading it. I hope that your work plays a part in paving the way to a better understanding of the links between gut microbiomes and mental health.