#08 – The Histamine Leaky Gut Connection with Dr. Aaron Gardner

Histamine. It’s an important neurotransmitter found in the brain, in the gut and even in the food we eat. Commonly associated with allergic reactions, there’s more to histamine than meets the eye. In this episode of the podcast, we get into all things histamine. We discuss the genes that play an important role in clearing histamine from the body, the link between histamine intolerance and leaky gut, how to determine whether your histamine levels have gotten too high, supplements to consider for quieting down the immune system and keeping histamine in check, and whether low histamine diets are sustainable. You can view my histamine intolerance blog here and the American Journal of Clinical Nutrition article referenced in the podcast episode here.

This Episode Covers:

• Histamine the neurotransmitter vs. the biogenic amine [7:00];
• Mast cells and their inflammatory role in the body [9:20];
• NGF, Lion’s Mane and why some people have a hard time with certain locations [20:00];
• Histamine genes [27:00];
• Zonulin, leaky gut and histamine [29:00];
• The anxiety histamine link [36:00];
• Core factors that contribute to problems with histamine [43:00];
• Blood type, hydrochloric acid and histamine [53:00];
• Supplements and nutrients to help with histamine metabolism [59:00];
• Are low histamine diets healthy? [1:06];
• It’s not the DAO gene, it’s the AOC1 gene [1:16];

Transcript:

John: Welcome to “The GeneFood Podcast.” I’m your host, John O’Connor. Hey, guys, before we get into the intro for today’s episode, I want to tell you a little bit about what we’re doing right now at Gene Food. For those of you who don’t know and who haven’t checked this out yet, our custom nutrition plans, you can almost think of them as like a Myers Briggs for nutrition. We’re using raw data from 23andMe and Ancestry and creating, basically dividing…we create an algorithm that can divide people into one of 20 diet types based on their genetics.

So if you haven’t seen that product yet, check it out at www.mygenefood.com. And we also have a sister site at leafscore.com, which is leafscore.com. We’ve mentioned this in previous intros. We’ve created a database of nontoxic products. We are definitely concerned at Gene Food with the rising level of toxicity and everything from dog toys to certain types of grains to mattresses. And so we just decided to basically scratch your own itch and create a database of products rated by a Leaf Score, one to five leaves, five leaves being the most ecofriendly.

And if you’re interested in finding products that, you know, are green and ecofriendly to use for you or your family, check us out also at leafscore.com. With that out of the way, today’s episode is all about histamine. When you think of histamine, you probably think of allergy, runny nose, watery eyes, you take an anti-histamine, everything’s cool. But histamine is actually a little bit more of a complicated subject than that and it goes a little deeper. We have genes that code for enzymes that clear histamine from the body and not all of us have the same ability to do that.

And so in some people, when the histamine levels get too high, symptoms start to occur. And that’s called often histamine intolerance. If you’re looking for a foundational tool to look at prior to jumping into the episode, there’s a great article that we’ll link to in the show notes. It was published by the American Journal of Clinical Nutrition. And it gives an overview of all the different symptoms that can come up with histamine. So histamine can affect not only the nose and the eyes, but it can affect sleep, it can affect the respiratory system, it can affect cardiovascular health, low blood pressure, high blood pressure, there’s all sorts of stuff.

Anxiety is a big one. It can definitely affect in mental health. And it’s something that’s not really on people’s radar. You know, histamine can even make some people allergic to common over-the-counter medications like ibuprofen. Certain histamine genes can do that. So there’s a lot to unpack in this episode and we wanna highlight the issue for people out there who may be wondering how to better dial on their diet. They know they need to change something. They’re not sure what it is. They have like, you know, sort of varying degree of food sensitivity or stuff that’s happening seasonally.

In some cases, that might be histamine. So in today’s episode, we bring back Dr. Aaron Gardner, who is familiar to our regular listeners. He’s the geneticist and head of research at Gene Food and he and I walked down the histamine path and explored all things related to this important subject. Okay, Aaron. So today we are talking about…this is a podcast episode that’s very near and dear to my heart. I’ve written about it on the blog, about the issue of histamine and histamine genes and an issue that’s probably not on the radar for a lot of people but maybe should be on the radar for a decent number of people.

Because like we talked about with MTHFR and some of these other polymorphisms that we highlight on our guide to nutrigenomics and on the podcast, we write about, the snips, the “mutations” are actually pretty common. If you look at it, there’s a decent number of people that carry some of the variants that we’re talking about here, in terms of inability to clear histamine. But seeing as though this is the histamine podcast, we probably should start with the basics. What is histamine, for the listeners that don’t know?

Aaron: So I mean, histamine, you might hear people talk about and say that it’s a bad thing. And in excess, it is a bad thing. You don’t want loads of it but we need a little bit of it. So basically, if you have an infection or there’s like an irritant in your body, these special cells called mast cells, which are just found everywhere throughout your body, they detect that irritant or infection. And what they do is they release bucket loads of histamine into the affected area. And this does a couple of different things. So it stimulates the immune cell that causes vessel dilation.

So your blood vessels dilate and allows more blood to flow into the area and that’s what causes like flushing, sort of the red cheeks that people have. It activates all the mucous membranes so in your airways, your nose, and your eyes, it can cause them to secrete mucus. And if you have any sort of allergy, you will recognize those symptoms, you know, the sort of the red skin, the sore itchy skin, the weepy eyes, the sort of snotty nose, all that sort of thing. And that’s what histamine does. It’s trying to clear whatever that irritant is or infection out of the body. And obviously, that’s great.

If it’s a real infection, it’s gonna help get rid of it. But if it’s an allergen or an intolerant or something like that, it’s not gonna be great for you. And if you have proper, improper, ongoing histamine release for a long period of time, it’s probably quite harmful to the body and to the tissues of the body.

John: Yeah. The way that it’s been described, which I think is helpful out there in the world of functional medicine and in some of these conversations that take place on blogs is they talk about everybody having a histamine bucket. So as Aaron pointed out, histamine is a neurotransmitter. Everybody has levels of histamine circulating in the body. You need it but your body also has a process for breaking down histamine and getting rid of it. And if the body can’t get rid of histamine fast enough, it starts to pool and you can think of it almost like a glass of water overflowing.

And when that glass of water overflows, that’s when you start to have some of the symptoms that are associated with conditions like histamine intolerance or even mast cell activation syndrome and some of these things that are becoming more and more prevalent. At least there’s awareness that’s growing around some of these conditions as the science progresses. But to the point, though, of histamine and what is it, it can be a neurotransmitter but it also accumulates in food, Aaron. One of the things that I am just curious to ask is, what’s the difference between histamine, the neurotransmitter, versus histamine, the “biogenic,” I mean, the thing that builds up in food over time?

Aaron: Well, if you think about it chemically, nothing really. It’s just where it’s located in the body. So I mean, our tissue itself will be full of histamine because it’s just released by the cells. It’s just there. And so when you eat, it’s particularly animal products are quite rich in histamine. They’re just gonna have histamine in their tissue as well and you’re just gonna eat it. And rather than it being in the blood system, which is where our circulatory system, which is where our body might release it or release large quantities of it, it just ends up in our gut basically because we’re eating food which is rich in histamine. So there’s not really any difference.

And then the other thing that’s also important to remember is that histamine is derived from an amino acid called histidine, which again, we take in in quite large quantities in our food. So even if the food is not particularly rich in histamine, it can be rich in histidine, the precursor molecule, as well.

John: Right. And in our episode that we did, I don’t know, three or four back now, with our industry insider, the supplement, dissenting opinions on supplement episode, Chris, the guest that I had on, he said, “We’re taking dissenting opinions on supplements.” And one of the things he said was why he’s not always such a fan of collagen even though collagen is like…just everybody is obsessed with collagen. It’s thrown in a million different products and people are advocating for it. And I suppose in some cases, for good reason, but collagen, the amino acid makeup of it, is very high in histidine.

So if you’re somebody that’s doing a poor job of clearing histamine and your body is producing a lot of histamine based on some kind of chronic immune system inflammation, there’s something that’s causing your immune system to be on high alert, whether that’s pollen, whether that’s some kind of issue with mold that you have, whether that’s some kind of uncleared pathogen, whatever the case, and then you take in, you add to that mix, a whole bunch of histidine in collagen, that’s something that could tip your histamine glass and overflow it.

And another point I wanna make is that Aaron is talking about these mast cells which are the…when they were discovered by the German scientist that discovered them, they’re referred to as “well-fed cells” because they contain not only histamine, Aaron, but they also contain like a whole garage of basically the immune system’s military operation, cytokines, growth factors. When these mast cells recognize something that they don’t like, they release a whole bunch of other stuff other than histamine. Can you speak a little bit to what else gets thrown in the mix in the body when the immune system reacts to stimulants?

Aaron: Yeah. So I mean histamine is one of the big ones and that generates that response that you would think of as like an allergic response. But like you say, they kick out loads of cytokines. And what they’re doing is they’re recruiting other immune cells into the area. So if there’s an infection, they’ll try and recruit the immune cells that will be able to actually deal with that infection as well as the sort of mechanical aspects of flushing the system. They’re trying to degrade the bacteria.

And then the other bit that can be really damaging to the tissues are things like the proteases that mast cells release. So these enzymes that basically, like John described them pretty much, it’s the weapons of mass destruction. They’re trying to just obliterate anything that’s in that room site or that injury site, take out the bacteria, stop any infection. And they do that by degrading any tissue that’s present there. And the problem with that is that it can obviously degrade our own tissue.

So if you have a chronic release or chronic activation of these mast cells and they’re constantly churning out these proteases, that’s one of the effects that often leads to damage and remodeling of our tissues. So things like Crohn’s disease where the gut epithelium is remodeled significantly. A lot of that is driven by proteases released by mast cells because they’re just chronically activated.

John: Right. And so the proteases, I think that’s an interesting one that you mentioned because if you look at digestive enzymes, one of the ingredients in a lot of digestive enzymes that is very…that’s in high amounts are proteases because there’s these different enzymes to break down different types of, you know, you have the lactase to break down the sugars and dairy, you have proteases to break down proteins, there’s different enzymes that will break down starches. Do you think that just like with collagen, you’re taking a lot of collagen and you have trouble clearing histamine, you’re probably going against the grain of what your body wants metabolically? What about proteases? Should people that are thinking that they might be in this histamine issue zone avoid those in supplemental form as well?

Aaron: That’s a good question. I think my honest answer would have to be that I don’t know. I think if you have a clinically recognized disorder where you know you’re getting this destruction of the epithelial tissue, so if someone has diagnosed you with Crohn’s, IBS, things like asthma as well because it’s not just your gut that it can affect, then taking extra proteases would probably not be a good idea. If you’re more towards the it’s an intolerance, you’re not on that clinical spectrum of, you know, it’s a proper clinical condition but you may think that you might have a relatively high level of histamine and that’s causing you a general level of…it’s impacting your life generally.

I don’t know if they would have that much extra effect taking them in a supplemental form. Because it also depends on what proteases as well. So I know a lot of those supplements are probably just inactivated as soon as you eat them because the pH that they function at is completely different to the pH of our intestinal tract. So a lot of those supplements just get deactivated straight away.

John: Right. Like so many things just case by case there, it’s probably kind of like a data dead zone. I don’t think there’s a whole lot out there that we could really point to. You mentioned, I was saving this for a little bit later, but you mentioned a clinically diagnosed condition. I think the gold…one of the gold standard tests that I know like allergists will run and different physicians will run to try to diagnose like mast cell activation, one of them, I’m not saying this is the whole battery of tests, but one that I’m aware of is serum tryptase.

And again, tryptase is something that’s released from mast cells when they degranulate but my understanding is, is that it doesn’t stay active in the blood for very long. So I think that can be a marker that’s difficult to test for because it can get…do you know anything about the lifecycle of tryptase in the blood once it’s released from mast cells?

Aaron: I don’t know the exact time but I, like you said, I know that it’s a very short half-life. It gets deactivated very quickly so you have to do it quick. And I think sort of…I know that these tests that you can do under a proper control setting with the proper allergy clinician like the skin prick test or oral immunotherapy, or oral food challenges. They have to be really properly controlled because they wanna administer you something, test for it quickly to make sure that they pick it up with a variety of different markers.

So I think those tests are really valid. The ones where you release, you know, you do the tests at home and you send something off in the mail, I think they’re not the best tests to do to look for things like the tryptases and also histamine activations. If you’re going to do a test, make sure you do it with a proper allergy clinician.

John: Yeah, I don’t think those are the types of tests that…the test that you’re gonna be able to get from like an EverlyWell. I think I’ve been hearing lately, WellnessFX and some places that you can go to to do a decent amount of bloodwork at home that you would otherwise need some kind of like requisition form for but I’ll try to track that down and see if there’s anything in the show notes we can add for people if they’re curious about getting some of these markers done.

Aaron: But it’s interesting because with the work that I do, I’m sort of a genetic. The diseases that I look into, it’s cystic fibrosis is mainly genetic but it’s a respiratory disease so I also talk to clinicians who deal with allergy a lot because we get a lot of asthma cases at the same time. And obviously, people with asthma are worried about other allergies and things like that, maybe you’re gonna make their condition worse. And you see a lot of uptake of these big panels. So looking for things like IgE and IgG. These big panels, you know, basically, they’ll say that you’re allergic to milk, goats, cheese, etc., whatever, and they’ll give you these big charts.

John: For the listeners at home, when you’re mentioning IgE, the IgE is immunoglobulin E which is the kind of the gold standard antibody that Western allergists look at. Could you just give a brief little background on what IgE is before we talk a little more about that?

Aaron: Sure, yeah. So when I was talking about allergy, what that means is that you have something, say, pollen. We’ll use pollen as the example. You are exposed to pollen at an early age and the immune cells in your body wrongly think that that is something that’s gonna be harmful to the body. And so they generate these things called IgE antibodies and those antibodies are specific to that allergen. So you’ll raise IgE antibodies against pollen. And what these IgE antibodies do is they circulate around the body and then they bind onto specific receptors on mast cells. So these mast cells become absolutely coated in IgE, in this case, to pollen. So that’s your first exposure.

The second or any subsequent exposure, that pollen will bind to that IgE which is bound to your mast cells and this is the thing that activates the mast cells. So whenever you’re exposed to that allergen again for a second or a third, fourth time, your mast cells are immediately activated and release all the stuff that we’ve been talking about, the histamine, the proteases, the cytokines. And that’s why you get that really fast immune response upon like subsequent exposures.

John: So what you’re describing is consistent with what a lot of these, for example, I interviewed Dr. Nathan in episode two, and he’s talking about this situation where the mast cells become irritated. Because for the listener at home, we’re getting into some technical stuff but at the end of the day, what we’re kind of…just to zoom out for a sec before we continue with the conversation. What you’re really talking about as you’re talking about…what is your immune system reacting to? People have individual responses.

Aaron is describing somebody who might have a traditional allergy to milk or a traditional allergy to pollen, their immune system is responding to that, someone else might not. But if your immune system is responding to those antigens, it becomes inflamed and the process of becoming inflamed is it rolls out its heavy guns to try to get rid of something that by definition, it can’t, because you’re breathing it in, in the air. So the IgE coats the mast cells and they work in tandem. Does that mean, Aaron, that in the future, once the mast cells have been kind of woken up and they’re kind of like the guard dog barking, they start barking at more things?

Aaron: Well, in very serious cases of allergy, yes, because then, one of the other things that happens is that the number of mast cells present in your tissue can increase. And then you have a greater chance of, you know, the amount of stuff that they release is increased and then there’s also the risk that more of them can become activated for different things. So that’s why people with really severe allergies often have like a wide spectrum of things that they can be allergic to. So it’s not just…someone who’s allergic to grass pollen might also be more likely to be allergic to peanuts, for example.

John: Sure, yeah. I think it’s interesting. I don’t know that the science score would be all that high but in the context of gluten sensitivity and celiac, there’s…I wrote a blog not too long ago about how people that have celiac and go on a gluten free diet and don’t recover, in other words, they go in and they do I think like another endoscopy and they see that their small intestine still has damaged and hasn’t recovered. And one of the reasons that they’ve theorized for that is because even though you’ve removed the gluten protein, the proteins in similar foods like oats and even instant coffee, which is known to have trace amounts of wheat, the body will recognize those proteins that are similar to the wheat proteins in such a way that they continue with the autoimmune reaction even though the canonical, original gluten protein has been removed. Is that kind of what we’re describing here?

Aaron: Yeah, I mean, it sort of depends on which part of the gluten that the IgE antibodies are being raised again. So if it’s a very nonspecific part of a protein that’s present and lots of other things, then they can react to a wide range of things. But yeah, there is also that other case of if you’ve got lots of mast cells present, then you’re more likely to get severe responses from things that might have previously been quite a mild…you know, mild effect in your intestine. If you have a really severe intolerance like you were talking about in Crohn’s or celiac, there’s more mast cells there. They’re gonna respond more quickly to other stimuli as well.

John: Yeah, and my understanding is that they are pretty long-lived cells too. But I mean, so this is something I put on the blog. I mean, you know, the reason why I’m sitting here in New York and I’m not sitting doing this show in Austin is because when I live there, and I’ve mentioned this previously on the blog and on the podcast, but that this environment just completely annihilated me. I mean, I went into get an IgE panel done with an allergist and some of the, for example, like the grass species, I think the reference range was like you registered as allergic if it was like 0.5 and I was like 10, 12, just like off the charts allergic to this stuff.

And one of the things that I noticed in terms of is very N equals 1. It’s just anecdotal. But one of the things that I noticed that I thought was really fascinating was I would…because I travel a lot. So like, for example, I’d go to the Bay Area and I’d take lion’s mane, which is like a supplement that for me, in the Bay Area in California is phenomenal supplement. I notice definitely enhanced cognitive ability, memories are a little bit stickier, overall, just a very good nootropic. I come back to Austin, take the same amount of lion’s mane, and I start to develop really nasty side effects with lion’s mane.

It’s very rare but some people who take lion’s mane will have like…they’ll get certain level itchiness and things like that. And as I looked into it, I realized that lion’s mane, part of the reason why it’s a nootropic is because it increases nerve growth factor which is a neurotrophic factor which basically like helps protect the survival of neurons in the brain. But what else releases growth factors? Back to this whole idea of mast cells. They’re releasing histamine, they’re releasing cytokines, but they’re also releasing growth factors.

So your nerve growth factor levels increase because of this acute allergic reaction because your immune system is on high alert. And then you take a supplement that causes further release of growth factor and you change a supplement from being a very beneficial one in location A where your immune system is relatively quiet to one that it causes you major problems in location B where your immune system is on high alert because of the antigen activity of the pollen that’s in the air that you’re so allergic to. Fascinating stuff.

Aaron: Yeah, I mean, that fits exactly with a lot of the things we talk about. It’s not just about your genetics. It’s never just about your genetics. It’s about your genetics and your environment and it can make a huge difference. So your example is perfect. Your genetics don’t change when you move between Austin and the Bay Area, the environment does though. And then your response to something else that you’re taking in can change massively as well. So when you’re thinking about snips and polymorphisms and things, that’s why it becomes so complex because you have to try and factor in all of these different things to try and get the right picture.

And that’s why it’s always worth looking at things at an individual level, you know, what’s working for me, because you might have something…you might be in a different environment or have different genetics. That means you’re not gonna respond the same way as someone else. And knowing that information is really, really powerful.

John: Yeah, it definitely is. And I wanna get into…I wanna talk about the two biggest genetic markers now for a minute because it’s just very apropos to this conversation and this is “The GeneFood Podcast.” We wanna get into some genes but my sense of things is these…the AOC1 gene that we’re gonna talk about now which helps create the enzymes that break down histamine. That’s, in some respects, this is my personal view, I mean it’s not…this is not something that’s, you know, this is a theory that I’m advancing, but it’s something that can be looked at for people that are more likely to have issues with their location especially when their location contains different allergies.

Because as you said, look, you know, you can only clear X amount of histamine if you get into an environment where the histamine is really, really, really being gunned by something that you’re having an issue with. That, by definition, can mean that location can be one of the big drivers of these issues.

Aaron: Yeah, definitely.

John: So the two big markers are AOC1 and HNMT. Can you speak to…can you tell the audience about these two genes and what they do?

Aaron: There’s a pathway is that we had histidine which is the amino acid and that gets converted to histamine which is the active molecule that we’re talking about and that we’re interested in. And then there’s two enzymes that can break down histamine into different pathways. So one of them, the first one is DAO. And that’s the one encoded for by the AOC1 gene. And this is basically an enzyme that breaks down histamine into another substrate that doesn’t activate the immune system and then it can get processed off. And HNMT does the same thing.

The important bit about HNMT is that it actually pushes them towards the neurotransmitter pathway. So we talk a lot in the blog about another protein called MAOB. That’s the one that’s called the warrior gene. So HNMT is involved in the pathway that ultimately results in that. So they sort of kind of interlink the pathways but the two enzymes do the same thing. They both breakdown histamine.

John: But HNMT is like intracellular histamine in the brain and AOC1 as it produces diamine oxidase is extra cellular histamine usually in the gut, right?

Aaron: Yeah. So one is intracellular, one is extracellular.

John: So AOC1, let’s focus on the clearance of histamine from the gut and the mucous membranes. What percentage of people carry the mutations that would give them a decreased ability to clear histamine? Like how common are those?

Aaron: Oh, I mean, so the most common polymorph…well, not the most common. The one that we’re most interested in AOC1 is one called C47T. And in that one, the T allele is the risk allele. And it’s about 27% of the population will carry at least one copy of that. But it’s not just that one snip in AOC1 that we’re interested in, there are several other ones and they’re all quite high occurrences, you know, like in the 20% to 30% of occurrence. So there’s a high chance that you’re gonna carry at least one of these polymorphisms, if not multiple ones.

John: The flip side of that coin is that probably, most people are gonna have more robustibility. You’re talking about…if you’re looking at a pie chart, still, you know that most people…it’s still a minority thing but one of the things that’s fascinating about studying nutrigenomics is that the nutrients that we eat are co-factors that support these and the production of these enzymes that are coded for specific genes. And not everybody gets the same portion of the enzyme in life. And then, so Aaron might be born with 30% more diamine oxidase than me and that’s gonna allow him to clear histamine better.

But then you construct a person who is born with a little bit less DAO, maybe they have to get their wisdom teeth out or they get sick for some reason. They have to take antibiotics. Antibiotics further reduce the body’s ability to create DAO. So they went from 70% capacity down to maybe 62%. And then they injured their foot or they’re taking a bunch of ibuprofen, which we’re going to get to in a minute, and then the ibuprofen blocks DAL. And then maybe they drink a whole bunch of alcohol all the time. They’re drinking six, seven, eight drinks a week. That further brings down their ability to clear DAO. So in that person, they have the potential for a greater issue with histamine when those issues come up.

Aaron: So yeah, you’re right, exactly. It’s about the environment, the genetic thing. Again, you can have…I could have a twin who has exactly the same genetic profile as me and theoretically should clear histamine in the same way. But like you say, there’s all these other things that can interact with the antibiotics, these non-steroidal anti-inflammatories. But then on the flip side, there are positive things that you can do to improve the function of DAO as well. So it can work both ways.

John: Oh, yeah. We’re gonna get to the co-factors for DAO and some of the dietary stuff here in a minute. But what I was setting that up for is, you have this potential for lifestyle to break down the body’s ability to clear histamine. And then one of the things that in the integrative world that’s really on people’s radar is if you were to ask somebody who’s really smart about nutrition, “Why don’t you eat wheat even though you don’t have gluten sensitivity, even though you don’t have celiac?” What they would say is they’d say, “Well, eating wheat has been shown to increase levels of…theoretically increase levels of zonulin which is a protein that breaks down basically the wall of the gut and contributes to leaky gut.”

Now, Aaron has written a blog post saying leaky gut is not…it’s not like it’s a proven theory. It’s one theory of autoimmune disease though, is that you’re then getting stuff coming through the gut which is supposed to be a closed system, it’s getting into the blood. And just like the immune system recognizes pollen which it doesn’t want there, it recognizes undigested food which it doesn’t want there and it starts attacking that undigested food. So, Aaron, can you speak for a minute about this whole issue of when uncleared histamine will produce zonulin and also why does that happen?

Aaron: Yeah. I’m not quite as down on the leaky gut thing as you said. I think the problem with leaky gut is it gets thrown around a lot for a lot of different disorders and where it doesn’t tie in but it is actually…it can happen in a lot of diseases and it can lead to a lot of the different symptoms. So yeah, like you said, zonulin is an enzyme that can be released by the cells of our body, the epithelial cells, so things in the gut. And what it does is it releases the sort of the tight junctions between these epithelial cells in our guts and it allows things that normally wouldn’t be able to pass through there to pass through.

So sometimes, that can be molecules that the body needs, other times it can be bacteria and other harmful things that the body doesn’t want. And so it’s one of these things that should be very tightly regulated. And then it ties in with histamine quite closely actually. So if you have a large amount of histamine release in the gut, then the morphology of your gut is gonna begin to change. So rather than the nice structures that we should see that allow for lots of efficient transfer of the things we want and keeping those junctions tight to keep things we don’t want out, it can start to damage that mechanically.

But it can also cause or trigger the release of zonulin. So it can kind of be like a double whammy. You’ve got the tissues being damaged itself by the histamine and the other factors that are secreted and it’s also causing more zonulin to be released which is opening those…the attachments between the cells even further, allowing more stuff to come through. And then that, in turn, can generate an even stronger immune response because there’s things getting into the body where they shouldn’t be. It can become more widespread. So it can become like quite a bad negative feedback cycle quite quickly.

John: Yeah. And really, the thing that’s interesting is, for me, at least, is that we talk all the time about food and, you know, this food is inflammatory and that food is inflammatory, and you shouldn’t eat this food and shouldn’t eat that food. And there’s been all this awareness drawn on lectin and stuff like that and I think for a good reason because some people have real sensitivity to those issues. The thing that I wonder is, you know, we’ve identified this could be 30% of people. It’s 30% of people plus the lifestyle factors that degrade diamine oxidase are very common.

And so it could be greater based on that. And I wonder out loud at what point we might draw awareness to this notion that environment, whether it be living in an environment in terms of a house that’s moldy, that’s driving this immune system up regulation or just this plain old stuff that we talked about at the beginning with the immune system responding to a certain pollen, when, if ever, that will be recognized as a contributing factor to this increase in autoimmunity that we’re seeing across the country.

Aaron: Yeah. I mean that’s a very trendy topic. It’s the sort of get you getting into the hygiene hypothesis thing as well. It’s talking about early exposure to things and is that driving a lot of issues as well. I think no allergist in the world would say that there’s no environmental contribution to allergy because you’ve hit the nail on the head. If you’re an allergic to pollen and you move to an area where there’s a much lower count of pollen, then your symptoms are gonna improve and your general health is gonna improve.

It doesn’t even have to be as, like you said, it doesn’t have to just be pollen, it can be exposures in the home as well. So things, chemicals that, you know, dust mites, things in the home, mold spores in the home, and then also the food that we eat as well. So if you know that you have an adverse reaction or you have an intolerance to a particular food type, if you can remove that, you may only be making yourself slightly better. But over a lifetime, that slight improvement could be really dramatic. And so it does need to be…it definitely needs to be thought about when people are thinking about their general health.

John: It needs to be thought about and I think another thing that needs to be thought about is the role that location is gonna play in those food sensitivities to begin with. Because at the end of the day, there’s probably a concert of mechanisms that play in any issue and I’m not sure that we can always reliably identify the mechanism of any given issue even with everything that we do know. But if you consider for a minute that someone’s food sensitivities might not be the canonical or foundational issue that’s triggering them, what could be triggering them is their environment. So you take them out of the environment then you also get rid of the food sensitivity. N equals 1, low science score, fully aware of that, sharing stories. I’ve seen it for myself.

Aaron: I mean, it’s really interesting but it’s just…I guess the big problem is how feasible it is for a lot of people because you’re relatively lucky in that you can take yourself out of an environment and you can see that change but there’s gonna be lots of people where they’re just not able to do it. And that is sort of how we then figure out how you deal with those people where you know that maybe their environment is causing issues that are impacting their general life and then maybe have food intolerances up because of their environment. It’s how can you improve that person’s environment who can’t move because they…

John: For sure. Yeah. Because, again, we touched on this in the last podcast episode. The last thing I think any of these doctors wanna do, it’s not something I wanna do, there’s a fundamental distinction to be made between what one individual may or may not need to do and setting policy. So I don’t think that there should be some policy set that, oh, you figure it out. There you go. You have an allergy. It’s causing your food sensitivities. You need to get all your stuff into a truck right away and you need to move, man. And you need to move like tomorrow. You know what I mean? Just time to move. That’s it. You can forget about that location.

I think that’s a dangerous policy to set because it’s also gonna set people up for moving who don’t even need to. So the flip side of the coin is somebody who might be listening and saying, “Well, this is all complete bullshit and it’s totally psychosomatic.” And you know what, in some cases, it probably is. But it’s not in all cases. There are even studies that we’ve said it on the blog just speaking to this issue of general inflammation and sort of unrest caused by environment where there’s a very reliable link to anxiety and histamine and allergy. So we have a society that’s, you know, I don’t know. You guys in the UK seem like you’re a little more chilled out but here in the U.S., well, is that even true? What’s the anxiety level right now in your neck of the woods, Aaron?

Aaron: I’m getting high with all the stuff that’s going on.

John: With Brexit, that’s raising…

Aaron: With Brexit and all the stuff that’s happening. So it’s getting higher and higher by the day.

John: Yeah. I’ve said it earlier today. It’s like when I walk out of my front door here and I’m dealing with jackhammers and my dog is freaked out and I can just, you know, I think it’s definitely triggering me on a regular basis. But it’s funny. There are studies out there that…there’s a meta-analysis of studies that I cited in one blog that I did where basically, it was like 9 of 11 studies, meta-analysis on anxiety, and then 10 of 12 on depressive symptoms indicated an association between allergy and mood and allergy and anxiety. And then there was another study that showed that there was a link between hay fever and panic attacks.

And against the backdrop of all this stuff, clearing histamine and all this, it makes perfect sense. We’re having on a guest…I’m filming a podcast episode tomorrow with Chris Masterjohn who’s super, very smart PhD and I heard him interviewed on another podcast and the guest was trying to give…get him to give wisdom on how to quote like hack anxiety. And the first thing he turned to in that conversation was histamine. And he talked about another study, which we’ll include in the show notes, where they were looking to put people on a low histamine diet to improve their skin.

But what they found is that in the people that had panic attacks, those panic attacks resolved, which is interesting. So I think that in the toolbox of how we can help people that have anxiety, one of the ways, I think, in some cases, not all cases, but if you’re looking, if you don’t know and you’re looking around, you’re being like, “Man, I feel stressed man. I feel anxious. Why do I feel that way?” Look at your diet. Is it super high in histamine, you’re drinking a lot of alcohol, are you taking antibiotics? That kind of stuff can definitely contribute to that, especially if you have a genetic predisposition.

Aaron: Yeah. It gets even with the hay fever drugs that you can get. You can see the effect that targeting histamine can have on mood. So like the very first generation anti-histamines, everyone knows that they caused a sedative effect. You kind of just feel a bit more relaxed, a bit more sleepy because you’re blocking the action of histamine. In that case, it’s because they were passing the blood brain barrier and they were acting in the brain. So later ones don’t go through that. But that early interaction showed just how much of an effect histamine can have on mood and activity levels.

So if you take this blocker and you get a sedative effect, it stands to reason that if you have high levels of histamine active in your brain, you’re gonna feel the opposite effect. You’re gonna feel wired, you’re gonna feel possibly anxious and things like that. You can just see how it all makes sense.

John: Does histamine convert into glutamate in the brain?

Aaron: No. That was one of the questions we got asked and I did a little blog about it. So it doesn’t directly but there is a sort of a link between histamine and glutamate signaling. So there can be issues with histamine relating to sleep. If you have too higher levels of histamine, it can inhibit the glutamate pathways that promote sleep.

John: And for the listeners that don’t know, glutamate is an excitatory neurotransmitter basically in the brain. You have glutamate as the gas pedal and GABA is the brake. And I know there’s been some…I saw, it was a study about coffee in rats where drinking coffee or administering coffee to rats increased the levels of histamine and glutamate in the brain significantly 30 minutes out or something like that. A lot of people that have issues with histamine, that’s how they also have issues drinking coffee.

Aaron: Yeah. I think that’s on that post actually. I think we can…it’d be pretty good to link that one on because it goes to the link between the histamine and glutamate mostly and I think it actually has a figure from that study.

John: Right. We’ll link to that in the show notes. Another common sense thing to mention here about histamine is Ayurvedic traditions. Basically, Ayurvedic, Ayurveda is the ancient Indian science of health and wellness. And Ayurveda was basically one of the first bio-individual movements out there, maybe the first. These ancient people knew and understood that everybody has different body type, everybody has different sleep cycles. So they divided people up into what are called doshas. And you have Kapha, Pitta, and Vata.

And each different dosha represents a different personality style and body type and they each get different diets. But Ayurvedic traditions have known for a long time to avoid leftovers because the longer food sits out, the more histamine it accumulates. And you can talk about sensitive people on histamine. At the end of the day, if there’s enough histamine in food, you can give it to 100 out of 100 people and everybody is gonna get sick. I mean, at some level, there’s a dose that everybody is…I mean that’s part of what contributes to food poison.

Aaron: Yeah, totally. It might just vary between two people that, you know, one person can get away with eating all of the fermented cabbage and sausage and for most of it but if they eat too much of it, like you say, they’ll fill that bucket and it’ll start overflowing.

John: Yeah. So should we transition over to the kind of some of the common factors that well, we’ve kind of touched on them and danced around them and sort of alluded to them in this conversation but maybe it’s time we should give the audience the core factors that will contribute to what could become an issue with histamine. One of the ones we haven’t touched on yet is gut health. Did you have something to add there, Aaron, in terms of the microbiome and we’re discussing this future scene and some of these issues that I think you wanna talk about?

Aaron: Yeah. I mean, the microbiome is something that I’m getting more and more interested in because the more you read about it, the more you realize just it’s not just about our individual cells, it’s about the cells that are living in our gut, the bacterial species and how this can have really dramatic effects on our health. So we know that bacteria in the gut can do lots of different things, they can do lots of beneficial things for us. They can help break down certain foods. They can break down molecules, allowing them to be absorbed by our gut more easily. But they can also go very badly wrong and we can get an infection in our gut that can massively change things that we’re sort of absorbing or it can even start to damage the gut itself.

So the one that people often talk about is Helicobacter pylori. You know, if you have an overgrowth of Helicobacter pylori in your gut, then you get very high risk of developing stomach ulcers. And that often occurs when your normal gut microbiome is disturbed. And the major cause of that normally is taking antibiotics for some other health reason. You kill all the beneficial bacteria in your gut and then something negative takes over. And when that happens, it kick starts that cycle, basically. You’re starting damaging the gut, the mast cells in the gut get activated because of this damage and because of the bacteria is present. You get that production of zonulin, which is making things worse further. It just keeps going in that cycle. And you basically this is where you get the severe damage to your gut. And all that can be driven by changes in the microbiome, which bacteria present in your intestines.

John: Right. Because you can be eating food that contains histamine. We’re going to get to low histamine diets and what, you know, our take on low histamine diets here in a second. But you could be eating food that is rich in histamine as you’re eating it, maybe it’s a leftover, maybe it’s, you know, a slow cooked turkey leg or whatever the case. But, as Aaron’s pointing out, you could also have a change in the microbiome where you now have species of bacteria in the gut that are either causing mast cells to be irritated, or they could be producing histamine themselves, right, Aaron, like certain species of bacteria are histamine producing.

Aaron: Yeah. So I actually read a really interesting paper just when I was doing a little bit of prep for this podcast. You always focus on the negative aspects of bacteria in the gut. And like you say some of them can even promote histamine themselves directly. But I actually read a really interesting paper about antibiotics and how they suppress the normal gut microbiome. And that they could actually see this in a dietary. It reduced the amount dietary lipids that people were absorbing. So that was kind of looking at it the other way and it showed really nicely how beneficial gut microbiome can be beneficial for health. Soon as you just regulate that and you can flip it and they start…you either flipped to a bacteria that’s producing histamine or it produces histamine as a byproduct of damaging the intestinal lining, then you split very quickly from having good nutritional intake to a bad nutritional intake. And that can all be driven just by a small change in your microbiome.

John: So they found that the change in the microbiome was less favorable for histamine but more favorable for fat metabolism?

Aaron: Yeah. So it was interesting because whenever you read these papers, it’s normally always comes from a negative angle. So it’s showing all the bad effects of having, you know, like Helicobacter pylori in your gut. It’s always about Helicobacter pylori causes this. It shows that you’re more likely to get stomach ulcers. But they showed that like the normal gut microbiome showed how important it was for lipid uptake because as soon as they got rid of it, as soon as they removed the microbiome.

John: Oh, I see. Okay, yeah.

Aaron: So it’s just showing how important it is actually, just for general health, even, you know, keeping your microbiome intact and healthy is fundamental for good nutrition. As soon as you flip out of that and go towards a different bacteria that, like I said, is directly producing histamine, you’re causing damage directly there but you’re also losing that beneficial effect as well. So it’s kind of a two hit thing.

John: Your take is that H. pylori kind of running a mark is one of the big contributing factors to histamine intolerance because it’s causing…

Aaron: Yeah. There’ll be other ones as well. So that’s just the big one because it’s associated with really severe things like the development of stomach ulcers. But there’ll be things or the bacteria things like what are normally compensable bacteria that normally function well, they’re normally helpful. If you get an overgrowth of that particular type of bacteria because the rest of your gut microbiome is being wiped out, that can have a harmful effect. But H. pylori is the big cheese.

John: H. pylori is the big cheese for something that…because my understanding basically is if you’re sexually active adult in the modern world, then you have H. pylori. But it might not become…you know, it might not be like the White Walkers, you know, breaching the wall. It’s in check. It’s kept behind the wall. You got the Nights Watch. When it tries the Nights Watch beats it back and it stays where…but when it gets into Westeros… Even though “Game of Thrones” does not deserve that love that I just gave it because of how terrible and just awful the last season was, it was just like I can’t even… But anyway, so you keep it in check and then it runs amok is what you’re saying?

Aaron: Yeah, exactly. So one of the things we deal with a lot in my work is staph aureus infection. So that can become really harmful to people’s health. But the weird thing is, is that we’re all, absolutely every single one of us is colonized with loads of staph aureus. We would just be all absolutely covered with it, now it’ll be in our airways. It’s when something goes wrong in our normal microbiome and staph aureus can take over, that can cause such big problems. And that’s the one that everyone is worried about. That’s the MRSA, the antibiotic resistant bacteria. So that’s why we’re so worried about it. But in normal health, we’re just covered in the staph.

John: Right. And it’s same with species like Candida. You have Candida in the body and they play nicely with other bacteria. But then if you have some kind of depletion of these other microbes that keep that in check, then it can spread and become more pathogenic. So acetaldehyde, right? Acetaldehyde, I think I’m pronouncing it correctly is like, yes, it’s like you’re drinking alcohol. And one of the byproducts of drinking alcohol metabolizing ethanol acetaldehyde. And then also, if you have malt species or you have certain Candida that are growing in your system and they’ve gotten out of control for whatever reason, acetaldehyde stimulates the activation of mast cells. So it’s like to start to turn this to solutions rather than problems, it seems as though the…

And to be completely candid, I don’t know that a lot of people have great answers. I think it’s best to work with like a really good practitioner on this and also just do a quite a bit of self-experimentation. But the idea, I think, is to find out what’s at the foundation, like what’s driving it? Aaron mentioned it could be H. pylori. I think H. pylori, Aaron, and people who have H. pylori, there’s two things that I think of. I think of blood type because it’s linked hydrochloric acid levels. And I think of interleukin 6, the gene that we have listed on our site. I thought I saw something that you’d written about interleukin 6 and a greater predisposition to H. pylori.

Aaron: Yeah. So the stomach acid, it seems quite interesting. We looked at that diet originally, and it kind of didn’t really hold much water. But one of the interesting things was is that it did show that different blood types have different stomach acidity, and that can tie into the likelihood of having an H. pylori overgrowth in your gut. Obviously, there’s not much you can do about that. You can’t change your blood type. But it can give you a bit of information that said, “Well, maybe you might be at risk of developing this. Maybe you should take care when you think about your gut microbiome and trying to protect it as much as possible.”

The other one that you hit on, interleukin 6, that’s one of those cytokines that we talked about one of these molecules that’s released by cells to signal to other nearby cells and tissues, telling it to do something. And like you say IL-6 is an inflammatory one, it’s released to try and bring other immune cells in combat infection. But it’s actually been shown that if you have too higher levels of IL-6 produced, it can actually promote H. pylori colonization. So if you have this produced for significant amounts, you produce more of it and it’s released for longer periods of time. They can actually act to promote an H. pylori colonization.

John: It’s like the immune system can become a bull in its own china shop.

Aaron: Yeah, exactly that, yeah.

John: The immune system has some really great stuff, yet we have these mast cells, they’re basically the military sentinels of the body. They can kick ass when they need to and release some pretty powerful stuff and do an amazing job. But if they keep going and going and going, they actually start to weaken the organism that they’re trying to protect. And just to go back, because it’s pretty interesting, we alluded to blood type. This is research Aaron teased out, we basically were like, “Okay, does the blood type diet have any validity?” And there’s very little in the way of saying. If you feel great eating for your blood types, then I tip my hat to you. But there’s not like a whole lot in the way of studies proving it.

Although the thing that’s interesting is there seems to be a correlation between your blood type and the levels of hydrochloric acid in your stomach. So if you are somebody who has type A plus blood, like I do, and you have…which it would be the lowest levels of hydrochloric acid, theoretically, and then there’s also some kind of insult to the gut that further lessens the levels of hydrochloric acid in the gut. One, I think, avenue that some people could look at, which definitely will not apply to everyone, I’ll tell you that much but it could be one path to look down is low levels of hydrochloric acid, a diet that’s too high in animal protein, which is also a diet that’s high in histidine, maybe you’re taking a bunch of chicken and you’re making it Monday morning, like the bro diet. You know, you’ve got chicken, make it Monday morning, all the broccoli and then you’re just eating that every day. And you’re not digesting that protein. That protein is putrefying in the gut. It’s that process of purification is then creating bacteria that are then stimulating your immune cells in a way that’s sub optimal. Plausible, Aaron?

Aaron: Definitely. So when we looked into that account, I initially started looking at the blood diet, and that was just a load of nonsense. There’s not going to be any link between the blood type and your gut health. And a lot of the stuff that’s out there about it doesn’t hold water. But that idea of having higher or lower levels of hydrochloric acid in your gut and that regulating the pH and giving you a different gut pH, that will influence the microbiome, it’ll influence all sorts of things. And like, say, if you have another insult to that where you change the levels further, you can really drive your gut microbiome in a different way. And then all the stuff that we just talked about that, how that can affect intestinal health as well. So yeah, definitely. It’s something to consider. Again, it’s one of these things that fits into that whole picture of looking at everything together. It’s probably not the biggest piece in the puzzle, but it is still part of that puzzle.

John: Yeah, I guess my sense of things is that one person’s immune system is not going to react the same way, as you said, like you could have a twin. No two people are going to have the same immune system reaction. So for the person at home that’s interested in this and is like, “Hey, this might apply to me.” I think the thing to do is not to recommend any protocol because the protocol that I use or that you use might have absolutely no value for them. I think the thing to do is to say, “Hey, here’s a few places you could look with your physician and with a conservative protocol try to address and see if that helps,” because, again, we don’t want to set this policy of, “Hey, you know, I don’t want the person at home having already packed up half their earthly belongings in the back of their pickup truck based on the beginning the show and generate a move to whichever place.”

Even though this irony is that that might be ultimately what made them feel the best in some cases. What about the whole omega-6 versus omega-3 issue here? Aaron, can you speak to this whole thing of eicosanoids and arachidonic acid and basically these terrible disgusting vegetable oil fats that we eat and how they will stimulate the immune system downstream and then how this very high omega-6 count then starts to contribute to this inflammatory kind of histamine cytokine process.

Aaron: Yeah, so we’ve talked about it before, that difference, the need to balance omega-3 and omega-6 intake. And part of the reason for that is because, like you say, the downstream products and the omega-6 process and pathway can have quite strong inflammatory effects. And this has been linked to a lot of the sort of systemic inflammation that we see in the West. And that’s linked to a lot of quite serious disorders. So cardiovascular disease, cancer. A lot of the neurological diseases are linked to this high level of systemic inflammation. And that is going to be driving straight through the middle of that histamine pathway. They’re generating an immune response and inflammatory response.

Your histamine levels are going to be up as well just because that’s part of the immune response as well. And you’re going to get all of those other negative effects that we’ve talked about that occur when you have a high histamine. It doesn’t necessarily have to even be triggered. We’ve talked a lot of things here about intolerances and allergies triggering this histamine release. It can also be other, you know, systemic inflammation can also trigger the activation of histamine as well. So maybe it’s not the case that you need to cut a particular food out, it’s causing the allergy or this effect, it’s rather you just need to rebalance your diet, drop that level inflammation, and then you clear up the histamine release and clear the effect associated with that as well.

John: Yeah. Just to give the flip side of the coin too, you can also clear up the allergy. It’s not necessarily that the allergy is going to stay static either. And I think that’s a point that I probably should make because I haven’t made it to this point. Sometimes the allergy can be driven by some other thing that’s stimulating the immune system, and then the immune system is reacting to the allergens. And it’s not like the allergen is always the canonical issue either. It might not be. So…

Aaron: I mean, that’s a lot of what…you know, with quite severe allergies, that’s what people try and do is they try and introduce lower and…starting off with low levels of the allergen and try and introduce it and work it up and try and get your body to learn not to treat something as an allergen. And so when just because you’re allergic to something, doesn’t mean you necessarily have to be allergic to it your whole life. And that can be done in a sort of controlled way by the oral introduction therapy, I think is what it’s called when they do that. But it might also, like you say, it can be cleared up just by changing lifestyle. It might be the fact that you just need to change your lifestyle, change your dietary intake, and that might have a beneficial effect as well.

John: Yeah. So the two actionable tips we have, we’ve kind of outlined this issue that people have, that some might have, the first thing that you can try is you can start to really look at how does your body digest protein, you know, and how are you doing with your protein intake? Are you eating aged protein? Are you eating aged cheese? You know, certain types of fish, especially shellfish, white fish, any fish, frankly, that’s not fresh or that wasn’t frozen fresh or gutted rot very quickly after it was caught tends to be higher in histamine. As a practical matter, you know, most people aren’t going to have to take that step. But it’s something you can look at protein in terms of higher digesting it.

Omega-6 to omega-3 balance. And then we’re going to get into…there’s also a bunch of nutrients that can be helpful. Quercetin is a known stabilizer of mast cells. Taking quercetin on an empty stomach before eating can be helpful. There’s supplemental diamine oxidase that you can take, but it is derived from pork. So it’s not vegan for people…if we still have any remaining vegan listeners, then, you know, that’s not going to work for them. What else, Aaron? Like what are some cofactors for diamine oxidase that can help step up production of histamine.

Aaron: So there’s three cofactors directly. There’s copper, a mineral cofactor. So that’s essential for its activity. So if you can increase your copper levels in your food, that will maybe have a beneficial effect. And then there’s two vitamins. So vitamin C and vitamin B6. Again, both of these are cofactors. So the vitamin C, if you listen to this podcast, most people I’m assuming are probably getting enough vitamin C. That’s one of the relatively easy ones to get into diet. The vitamin B6 is probably the one if I was to target any particular cofactor, that’s the one I probably think about because that’s probably the one that people are more likely to be deficient in. And by improving the levels of all of these in your body, you can just maximize, ensure that your DAO, your AOC1 is acting at its maximal function.

John: So just one thing on vitamin C, the funny thing about…yeah, that’s true. Most people are getting plenty of vitamin C. Issue there is, though, is for people that are starting to awaken to this histamine issue, the citrus fruits are often known as high histamine liberating foods. In other words, if you’re looking to kind of explore with a low histamine diet, which you can do, citrus fruits are often ones that are kind of difficult for people to tolerate, who are in a stage in life where they’re having issues with histamine.

Aaron: Yeah, I mean, if you’re going to start trying to eliminate foods rich in histamine out of your diet, I think citrus fruits are probably one of the later ones, just because they have so many other beneficial effects. I think there’s stuff higher up there, you know, that personally that I would try and eliminate first just because, like you said, that those citrus fruits are so rich in other things that are beneficial.

John: I think we have a slight disagreement on that one, Aaron. That’s one where we have a slight disagreement. But…

Aaron: Or maybe it’s my understanding of what most people’s diets are like and what their big intake is. But when you look through the list of food that can be high in histamine, I mean you’re exactly right that citrus fruits are quite high or not high in histamine but they can generate your body to release histamine. The stuff that I would say is less beneficial is also high in levels. And that you can see and imagine would be high in quite a lot of people’s diets.

John: Yeah. I mean, for me, it’s just like I totally get what you’re saying. It’s just as a matter of policy. I mean, that the citrus fruits, it’s like how much benefit do you really get? I mean, there’s plenty of vitamin C in a sweet potato. You eat citrus fruit, it’s mostly just sugar anyway, it’s kind of satisfying, but the caloric value is very low. It depends case by case. At the end of the day, I think the important message, which is probably what you’re kind of wanting to steer the conversation towards is you can go on a low histamine diet for a little while, see how you do. That can be one clue that you might be at this stage in your life having an issue with histamine. It doesn’t mean you’re always going to have an issue with histamine. It could be the state of the microbiome, it could be protein intake, it could be omega-6 to omega-3 balance, all that stuff.

But when I wrote my blog is like I was having these issues and when I lived in Austin, especially. And you got to eat. So if you’re going to go on…people might take an interest in this subject and they’re going to go online and they’re going to read all these low histamine diets. Do what your dietitian says, do what your physician says. That Trumps any of the general discussions we’re having here. But I do think that the low histamine diets are so unsustainable for a long period of time because at the end of the day, Aaron just pointed out very eloquently, that there’s nutrients that are cofactors for clearing histamine. The last thing you want to do is start getting nutrient deficient.

I think it’s virtually impossible. I mean, if you start looking at the list of foods that you can’t eat when you’re on a supposedly low histamine diet is you can’t eat banana, you can’t can eat an avocado, you can’t eat cherry, you can’t eat citrus, some people say you can’t eat eggs because they have arachidonic acid, you know, poultry. You just go down the list, there’s like nothing left. You’ll literally have nothing to eat. So I think low histamine food lists are potentially helpful as a way of seeing whether you have the issue. But, man, I think it’s pretty tough to eat food…

Aaron: Yeah. And that restriction can also cause a lot of this…you know, if you’re sitting worrying about your food all the time, we know that stress and anxiety can trigger the release of histamine as well. So, if you’re spending all of your time worried about what you can and what you can’t eat, you might also just be making things just as bad as if you were eating whatever you wanted to.

John: For sure you’re causing yourself stress. What we want to do here is we want to…I think the person that we’re kind of speaking to is the person who’s like, “Man, I’m not sleeping that well. I feel kind of anxious. I don’t know why. Kind of having these issues and feeling stressed. And I can’t wait to wake up tomorrow to have my normal blue cheese and smoked salmon omelet with a side of avocado. And then, you know, have my glass of rose for lunch as I do every day.” And stuff like that. It’s like, you know, the big offenders that are going to get people in trouble with histamine are like aged cheese, fermented foods.

So it’s like, you know, as well-meaning as the person might be at your local farmers’ market who wants to sell you kombucha to heal your gut, if you have an issue with histamine or you’re having seasonal allergies, kombucha is not gonna be a good thing to drink like all day because you’re going to feel not amazing if you do. So it’s like, to Aaron’s point, you can just tackle the worst offenders first. And that’s what we recommend. I want to turn it over to Aaron here to talk about the panel of genes we look at in our nutrition plans to give people a histamine score to see if they’re going to be in one of our diet types that has low histamine. Because what we say that those people could do is they could just cut out the worst offenders, cheese, wine, beer, fermented foods, and maybe like pork or like super fatty meats, and just try that first. Don’t go down a rabbit hole of like, “I can’t eat food.” You’re not going to like your life if you go on a low histamine diet too strictly for long period of time.

Aaron: Exactly. Yeah, I mean, on our nutrition plan, the histamine is probably one of the ones that cuts out…or not cuts out, but suggests one of the most stringent, you know, reduction in certain food types. And so, wherever possible, we try and avoid going on to that. So the way that we weigh the nutrition plan, we’re trying to stop putting people on to that very low histamine diet because like John says, it can be really restrictive.

John: It can be really restrictive and…

Aaron: Possibly harmful as well. I mean, if you restrict literally everything that you read about as having high histamine, you’re not going to be in much variety of food.

John: Yeah, you have histamine circulating in your body, I have histamine circulating in my body. Everybody does. And all food has histamine, you know. So it’s like…just to take a little dig at some of the competitors that are out there, they’re actually not really competitors because they’re like 100,000 times bigger than our company. But some of the really well-funded nutrigenomic companies out there, they want to control the whole funnel. So they’ll be like, “Okay, we’re going to give you your sign diet type based on genetics, and then we’re going to do you a huge favor, we’re going prepare all your food for you, or we’re going to send it to you, meal prep.” Or just you’re using a meal prep service. Like that’s probably not a good idea.

Like following the Ayurvedic principle of basically like… What we say in our nutrition plans is like, “Eat fresh food. But make sure you’re eating food, but just pay attention to the freshness. So, you know, if you’re going to eat fish, see if it’s fresh.” I did a blog about the wild salmon that I’ve been getting from Bristol Bay. And I think one of the things that’s really cool about…the company actually interviewed the owners of the fishing operation in Bristol Bay, Alaska, which is like the last great place in the States where you can get like really high quality, wild caught salmon. And they’re gutting and freezing that salmon like very soon after it was caught. So that’s a very low histamine product. You can get some really nice wild salmon, you can get six months’ worth to have that at home. It gives you your protein, it gives you some omega-3s, and that’s a good way to go.

But meal prep services? Probably not such a great look. With that said, so, Aaron, in our panels, we’ve talked about AOC1, we’ve talked about HNMT. And unfortunately, for version four of 23andMe, they’ve actually removed a number of these snips. But what are some of the other ones that that you’ve identified and that you’ve included in the algorithm for the scoring for somebody who’s interested comprehensively and what their genetic predispositions are with histamine.

Aaron: So AOC1 is probably the major one. And like you said, unfortunately, a lot of the snips that can be quite informative of being pulled out of the later versions of 23andMe under the services like Ancestry, I don’t think they appear to the same extent as people with the earlier versions of the report like you where you can get a much clearer picture. So alongside AOC1 though, you’ve got HNMT. There’s one polymorphism and I wouldn’t say it is highly rated as the AOC1 snips but it can still have a significant effect that if you have the risk allele which is…so the polymorphisms called C3140. And the risk allele is the C allele. If you have that, then you’re going to be having poor histamine clearance. And that can have a lot of the issues that we talked about.

And then there’s just three other ones that we’ve talked about, really. So there’s IL-6 and IL-8, those two cytokines, interleukin 8 and interleukin 6, which had to release, recruit other immune cells. And like I said earlier in the podcast, I just went to the mechanism, they recruit immune cells, they generate inflammation, and they can trigger histamine release that way. And then each one of those is just a single polymorphism. And they’re more difficult to target unlike AOC1, where there’s potential cofactors and things like that with the IL-8 and IL-6. What we’re actually trying to do is actually just stop their release.

It’s not about the processing or how they’re received by the cells, it’s actually just trying to reduce the amount that the cells are producing. And that’s the bit more difficult to modulate than the AOC1. And then the very last one, it’s kind of one I think you mentioned briefly, it’s the acetaldehyde link, so how we process alcohol in our body. So when we drink alcohol, it’s converted to acetaldehyde. And that can have issues with generating histamine. So there’s one of the polymorphisms there which relates to how quickly we process alcohol and how we can clear it out and it’s often called the hangover gene. Because carriers of the risk allele which isn’t. In this case, it’s A allele of that snip, which I’m sure John will link in the podcast notes.

They process alcohol less well. It hangs around in the body for longest. Acetaldehyde hangs around in the body for longer and that can influence histamine. It can generate histamine in the body. So we’ve got that panel of five genes and multiple snips, AOC1 and for the other four genes is just a single polymorphism in each of them.

John: So, Aaron, question for you. So for the acetaldehyde, the function of alcohol is it’s when the body metabolizes that, produces that byproduct, which then stimulates the immune system in a way that we don’t want, is that also why alcohol blocks the production of the enzyme, the cholestyramine DAO? Or are those kind of two separate but parallel processes?

Aaron: They’re kind of separate and so they shouldn’t be directly linked. It’s not like they have a proper function against each other. It’s more just the downstream products of drinking lots of alcohol, have an inhibitory action on AOC1 function. So if you’re unable to clear the alcohol quickly or if you drink lots and lots of alcohol, then you’re going to be inhibiting your AOC1 function, and that’s going to be causing histamine to build up in your body.

John: Yeah. So it just goes back to the kind of the common sense stuff. It’s like if this is something that you’re starting to clue in, affects you, don’t turn first to the low histamine diet list. First thing you might want to do is just not drink red wine.

Aaron: Yeah, exactly.

John: Yeah. I mean, red wine is super high in histamine. Alcohol in general, unfortunately, it’s just going to be not a great look. It’s going to block DAO. And then, as Aaron said, it’s going to produce this byproduct which stimulates the immune system. And it’s going to be a broken record but I think it’s important to just keep saying issues with mold we had on Dr. Nathan. You know, I think sometimes in these conversations, it’s like the old saying, “If all you have is a hammer, everything looks like a nail. I think sometimes that happens with mold. I think everybody is like, “Oh, it’s mold, it’s mold, it’s mold.” You know, that happens a lot. And I think that’s partly because there’s this growing awareness that this is a big issue for people in buildings and stuff like that. It’s made some people very sick.

And I think it’s good to bring awareness to that, but I think it probably gets overplayed a little bit having said that. And some people, the issue that will be causing the histamine intolerance and also producing stuff like acetaldehyde is some lingering fungal issue. Whether it’s exposure in a toxic building that’s triggering the immune system, or whether it’s you’ve depleted your microbiome by taking a whole ton of antibiotics. What’s come to fill that void, as Aaron said, is H. pylori or some kind of pathogenic species of fungus. And the constant proliferation of that is continuing to be this irritant to the immune system that’s triggering this downstream issues of histamine intolerance. That’s something that that’s there too. So get rid of the alcohol. Maybe, you know, skip the gelato as well. What else, Aaron?

Aaron: All the good stuff, unfortunately.

John: Yeah. You know, not in perpetuity. And it depends on…Yeah. I mean, you know, not in perpetuity, but it’s good to cut some of this stuff out for a little while, see how you feel. And if you feel better then you have a clue that, “Okay, well, then in this case…” And the problem for me is, it’s actually a lot easier for me to cut out gelato because my basically two settings are like, you know, if I’m eating stuff like that, man, I can crush like, a ton of it. Just if that gets turned on to me, then I’m like cleaning out like whatever is in my past. So I actually find it easier to sort of like abstain from it entirely for stretches. Just with my family. And that’s kind of like a very boozy, you know, sugar-rich week for me. But that’s all good.

But while you’re doing this experimentation, just cut off from that and see how you feel. It could be something that could clue you in to be like, “Okay, that’s what it is.” And that way you can manage it. You know, what else? Is there anything else that we haven’t touched on in the show that we want to tell the people about the histamine genes? I think that hangover gene is really interesting. I hadn’t heard you mention it like that before.

Aaron: Yeah, I think we’ve hit everything on the head. I mean, one of the most important bits, and I’ve got a post about it up on the site is the confusion around the DAO and the AOC1 genes. So it’s one of these cases where it’s annoying that the gene and the protein name can be flipped, but actually relate to completely different proteins with completely different functions. So I think one of the most important things is just always check that you’re talking about the right polymorphism. And so we’re interested the histamine that’s AOC1, the gene. It’s not the gene DAO. So if you’re looking at the polymorphisms and it’s in the DAO gene, it’s not going to be related to histamine. I think that’s an important thing because you read a lot of stuff on the internet where people are talking about this.

John: Yeah, they’ll just use it. And some actually very reputable sites, they’ll just call it the DAO gene. It’s not the DAO gene.

Aaron: Yeah. Well, I’ve read publications, you know, peer reviewed publications that are talking about and they’ve got it wrong. And I think it’s people to split between the language. They’re talking about the protein. I mean, we’ve probably done it in the podcast. We’ve called it DAO and AOC1. It can get confusing fast. So just always double check and make sure you’re talking about the right gene.

John: Yeah. I guess another thing just to kind of throw out the histamine stuff. Like another thing I know people have talked about in terms of what we’re looking for these just like the root cause medicine. Another thing I think people have mentioned is metal toxicity. Metal toxicity can stimulate the immune system. I’ve seen that in some conversations. Tony Robbins of all people. Tony Robbins, the motivational speaker, the guy who… Have you heard of Tony Robbins, Aaron?

Aaron: Nope, nope.

John: Yeah, he’s been this motivational speaker in the U.S. for a long time. I heard him interviewed. It wasn’t related to mast cells, but he started developing really bad psychological symptoms. And he went and he’d been eating a ton of swordfish and tuna. And he went in and his doctor is like, “Hey, man, your mercury levels are off the chart, you know?” It comes back to the kind of the what we preach after every podcast episode is like, you know, try to get in there and get as much lab data as you have access to so you can have an idea with your doctor of what you’re actually looking at. So it’s like heavy metals. You can do a heavy metal test really well at home. The physicians, good allergist can run the serum tryptase panels for you.

You can do neuroendocrine labs at a place like pharmacy and labs and they’ll run your full spectrum of neurotransmitters in the brain including histamine, including glutamate, oxidative stress. Aaron said you can do an antihistamine challenge, you can take an antihistamine like Zyrtec. Does it calm you? How do you feel? Does that make you feel butter? Taking a week trying a low histamine diet? What does that look like for you? So there’s a lot of stuff. We did a post on L-theanine. I believe L-theanine is one of these mast cell stabilizers that we did not mention yet, Aaron, if you remember that post.

Aaron: Yeah, that’s definitely another one as well. That’s a quite a good one as well along with quercetin as well. That’s a good one.

John: Yeah. As far as my constitution, you know, everybody’s going to be a little bit different, I prefer quercetin quite a bit to theanine. And the reason why is because I’m just a little bit hesitant of the…I’m a little bit just cautious of these amino acid nootropic supplements that cross the blood brain barrier. Because I just…

Aaron: I think it’s more subtle, isn’t it? I think it’s a more subtle supplement that if you’re going to choose to take one.

John: Quercetin?

Aaron: Yeah.

John: Yeah, it is.

Aaron: You know, it’s probably easy to take in natural form because there’s lots of beneficial foods that are rich in it. And it is probably a subtle effect. Just absolutely using a sledgehammer to hit something.

John: Yeah. That’s how I feel about it. I feel, you know, theanines, I definitely get this nootropic effect and it feels good. But our conversation is about and even just doing research on some of these serotonin things like just how commonly people are like, “Oh, just go take 5-HTP.” So you’re taking 5-HTP or some of these amino acids that affect brain health, they cross the blood brain barrier. And I found it fascinating to learn that these amino acids are basically…these precursors to these neurotransmitters are all competing to get into the brain. So if you flood the brain with one, by definition, another one is going to get depleted. And I believe that’s true in the context of serotonin, right? Like if you’re taking 5-HTP, you’re sledgehammering your serotonin levels, that’s going to draw way down on your dopamine. Is that an accurate…?

Aaron: Yeah. I mean, you’re getting into sort of the pathways of addiction when you start down that route, as well. And you’re going to start oversaturating things. And then to get the same effect, you’re gonna have to take a higher dose.

John: Yeah, man, it’s just amazing to me. I guess. But we’re conservative on supplements on this podcast. We’re supplement advocates and fans, but I think taking the most conservative approach at the lowest dose is probably the best. With quercetin, they often pair quercetin with bromelain because it’s been shown to increase the bio availability. Based on the conversation I had with Chris on that dissenting opinions on supplements podcast, I’m not as focused on bio availability. So I’m just focused on quality of product.

And so, yeah, the most conservative play is basically vitamin C, maybe a little bit of diamine oxidase if you are comfortable with the fact that it’s derived from pork and some really good quality quercetin in small doses. And you want to always take a break from any supplement that you’re on to check with your doctor first. But the theanine also, one of the symptoms that people will have when they have…and do you know why this is, Aaron, why do some people that have histamine intolerance have low blood pressure?

Aaron: I mean, the histamine, one of the things is, you know, if there’s a dilate and it causes your blood vessels to widen, and that could lead to blood pressure, I don’t know why people…is that would be an effect that you would see long-term. But I guess it kind of makes sense that, you know, if your blood vessels are permanently dilated, you’re going to have reduced…you’re gonna have a lower blood pressure.

John: Yeah, that’s why I’m saying that because, you know, it’s like they say on the theanine front is that one of the side effects of theanine is that it will lower blood pressure. And some of the doses that you get in a lot of the pills are pretty high. So if you’re taking it all the time, it is going to change your brain chemistry, you know, maybe not in a way that’s actually going to be all that, you know, huge, but it’s gonna be case by case, it could lower your blood pressure. Having a histamine issue can lower your blood pressure. And I feel like that’s kind of like something where maybe just to play it safe, you don’t want to tread down that path. And a lot of nootropics have theanine. So it’s like, yeah, just some quercetin is something that you can look at or just, you know, Claritin and antihistamines. Okay, so, hopefully, that was a pretty comprehensive tour around the world of histamine. So what do you think, Aaron? How should we close this one out? Any final thoughts?

Aaron: I mean, it’s the kind of the same message we say every week, isn’t it? You know, if you’re going to try any supplements, take them in micro doses. If you’re going to start removing foods from your diet, again, don’t go the whole and just obliterate an entire portion of your diet, maybe take out one or two things and see how you feel after that. And I think the most important bit is that it’s always keeping that log of how you feel as an individual, you know, how does this make me feel? Keep that log so you remember it, and then, well, maybe that didn’t have an effect, I’ll try something else. And it’s doing that. That’s the really powerful bit for an individual. It’s keeping that record for yourself, looking at your genetics, looking at your environment, seeing what you can modulate and what’s the best way that you can modulate it without influencing or, you know, without causing harm in another pathway.

John: Yeah, I agree completely. I think I would echo that. Stick with the low-hanging fruit. You know, histamine is an interesting thing to have on your radar and getting it on…I think you can…once it’s on your radar, if it wasn’t there before, you can get a lot of benefit from the low-hanging fruit. Just understanding that as much as they’re pushing collagen and they’re pushing sauerkraut and some of these foods out there, if you think this is something that applies to you, start with the basics, you know, fermented foods, meaning no wine, beer, stuff like that. If you have to drink, maybe try switching over to something like, you know, a little bit of vodka on the rocks or something like that. So, good stuff. Well, thanks again, Aaron, for coming on. And we’re gonna look forward to doing future episodes with you sometime in the near future.

Aaron: No worries. It’s happy to talk to you always and I’ll speak to you again soon.

John: Thanks, buddy. Talk soon.

Aaron: See yah.

John: “The GeneFood Podcast” is our attempt to synthesize the latest developments in the fields of genetics, nutrition, and medicine, and offer you practical tips and stories you can use in your own unique health journey. If you enjoy this podcast, you can find more information online at mygenefood.com.