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Sulphoraphane: Gateway to Cellular Defence with Dr Christine Houghton

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Sulforaphane: Gateway to Cellular Defence with Dr Christine Houghton

What is sulforaphane? And what is the biochemistry of its actions within the human body?

Dr Christine Houghton returns to FX Medicine to discuss sulforaphane, its’ benefits and uses for various conditions, and why we should change the way we think about probiotics, antioxidants, and the overall way in which we approach treating our patients. She also succinctly breaks down the complex biochemistry of probiotics and how our microbiome affects our gut and immune system, including activating the Nrf2 pathways and priming our cellular defences. 

Covered in this episode

[00:50] Welcoming back Dr Christine Houghton
[01:52] Sulforaphane and its mechanisms of action 
[07:58] Not all sulforaphane supplements are created equal
[11:29] Preserving myrosinase in fresh cruciferous vegetables
[12:50] Limitations of probiotic supplements
[19:42] Lipoteichoic acid (LTA), dead probiotics and the effect on the immune system
[27:34] Prebiotics, fermented foods, and growing your own
[31:35] Polyphenols in the gut
[38:14] Supplementation vs dietary intake 
[42:32] Changing the way we think about antioxidants 
[50:59] Conditions that benefit from sulforaphane as a treatment 
[54:46] Thanking Christine and final comments

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook. Joining us on the line today again is Dr Christine Houghton. After practising nutritional medicine for three decades and holding a PhD in nutrigenomics, Christine has built on her extensive clinical experience to research, develop, and teach other clinicians clinically relevant strategies associated with nutrigenomically-active phytochemicals. 

Sulforaphane, derived from broccoli sprouts, was the focus of her PhD thesis, and she owns a nutraceutical company supplying these. Her recent research has culminated in the development of the G.E.M.M protocol, Gut Ecology and Metabolic Modulation, an approach that mimics the processes used by nature to re-establish homeostasis within the gut and with the consequent enhancement of cardio-metabolic health and reduction of a range of processes that contribute to chronic disease. 

Welcome back to FX Medicine, Christine. How are you?

Christine: Thank you, Andrew. Pleasure to be with you again.

Andrew: Now we're going to be talking about something that's very close to your heart and that's sulforaphane. And there's a lot of jockeying in the markets out there, but I think we have to go right back to the beginning. What is sulforaphane? And what's the biochemistry of the actions within the human body?

Christine: It's a tiny molecule which is lipophilic, which means that it slides very readily through cell membranes because of their lipid content. But it's probably the major reason that the vegetable broccoli has its health-promoting benefits, which are rather well-known. It's not the only bioactive compound in cruciferous vegetables, but it's certainly the one that's had the most research done on it. There's now over 2,000 published papers in the field.

Andrew: And of course, this is one of the glucosinolates, is that correct?

Christine: Well, actually, the precursor to sulforaphane is the glucosinolate. Sulforaphane itself is a breakdown product of the glucosinolate, and it's actually in the family isothiocyanate. Aren’t those words awful?

Andrew: Yeah, they are. So when we're talking about this isothio, this is the thiols we're talking about, correct?

Christine: Yes.

Andrew: Let's go into that a little bit. What are the purported actions of these thiols?

Christine: Well, the isothiocyanates in general are potent activators of cellular switches, one in particular, Nrf2, which if you like, is the guardian of the cellular defence mechanisms. So the primary and overarching function is that sulforaphane and its other isothiocyanate companions activate the genes related to cellular defences. So there are hundreds of genes which have already been identified in this context, and they are all turned on by this one Nrf2 switch, which is very convenient, isn't it, when you think about it?

Andrew: Mm-hmm. But it's interesting that there's this one switch. Well, the body's usually extremely elegant and it's got redundancy processes involved in things. So why is this such a one-way or a one-channel controller of inflammation and gene regulation?

Christine: Well, it's not entirely one way. There's another transcription factor that I think a lot of your listeners would be familiar with, and that's NF-κB. NF-κB tends to activate inflammatory processes. So when you switch on NF-κB, you're promoting inflammation. Sulforaphane, actually, downregulates NF-κB. So at the same time that it's switching on the protective defences, it's down-regulating inflammation. And there are all sorts of cross-talk reactions going on between Nrf2 and NF-κB.

Andrew: Okay. What about upstream processes then?

Christine: Well, when I talk about Nrf2 activating the cellular defences, what I'm talking about largely is a range of what we call “core upstream processes” that apply to the functioning of all cells. So these are functions like regulating redox balance. So this is the free radical antioxidant relationship, regulating inflammation, which is part of the immune system, regulating ATP synthesis as a means of outputting ATP as energy, and enhancing detoxification processes, which includes activating efflux pumps so that once you've detoxified the waste material, you can pump it out. So those are amongst the core upstream processes. But in addition to that, there are some other interesting ones. 

For example, sulforaphane via Nrf2 up-regulates the vitamin D receptor. And so, clinically what we found, although this is not published widely, is that in those individuals who seem to need to take very high doses of vitamin D, we'll often find once they activate Nrf2, they don't need such high doses of vitamin D. Because essentially, you've increased the receptor activity and now vitamin D has got somewhere to go.

Andrew: Now that's really interesting.

Christine: Yeah. So that's really interesting. There are other factors associated with inhibiting Substance P, which is related to allergen expression. So there's lots of different activities which are tied to the end of Nrf2 but those major ones I mentioned is the core upstream processes exist in every cell. And the beauty of something like Nrf2 activation is what you're doing to one cell in the body, you're doing to all of them.

Andrew: Okay. So we're talking about a biochemical process here, but then when we're talking about the intervention of sulforaphane, is there research showing that sulforaphane can indeed improve vitamin D levels, say in institutionalised elderly people?

Christine: Well, that's where no one's done the research, so... There's some preliminary research that shows that it upregulates the vitamin D receptors, and I'm only speaking from clinical experience in knowing that when you do that, people who've been dependent on the high vitamin D tend not to be to the same extent.

Andrew: So we should be serving broccoli sprouts and Brussel sprouts and kale to all of our elderly patients in institutions.

Christine: Yum.

Andrew: Oh, no, we could get them outside for sun as well. 

It was also very interesting what you were mentioning about Substance P as well. I mean, we've got a scourge of pain, so what about maybe enhancing the way that pain medications work or lessening the impact of the pain stimulus?

Christine: You should go into research, Andrew, because none of these questions has been investigated.

Andrew: I'm just a child.

Christine: We're on the leading edge of the new science, but truly, there are all sorts of interesting possibilities that haven't been investigated fully.

Andrew: Wow. Okay. So when we're talking about sulforaphane getting into cells, and we're talking about the gut interface. And it's the biggest interface that we have to intervene, and that's intrinsically linked to probiotics and digestive processes, and things like that. 

So what are the issues about, I guess, firstly, sulforaphane, as a given entity? You know, if you're talking about the broccoli sprouts or the foods, or indeed a supplement, when you're talking about drying out a cell of a plant and releasing things and changing things. Let's go through a few of these issues first with what happens at that gut interface?

Christine: Well, first of all, it's important to identify the differences between a whole broccoli sprout material, like fresh sprouts, and looking at supplements, because broccoli sprout supplements aren't all the same, and here lies the problem. There's no sulforaphane actually in broccoli. There is a precursor compound, glucoraphanin, and there's an enzyme myrosinase, and provided the two are kept intact, as soon as you bite or chew those sprouts, the enzyme will act on the glucoraphanin and that produces the sulforaphane. 

A large number of the broccoli sprouts supplements that have come out of the U.S., in particular, are actually broccoli seed extracts that have had the myrosinase enzyme deactivated. So what they are, is fairly concentrated sources of the precursor glucoraphanin. And when you challenge them, they say they're relying on the ability of the gut microflora to convert glucoraphanin into sulforaphane. What's not well known is that this conversion is only about 8% to 10% what you would get out of the whole sprout or a whole sprout supplement that retains both the precursor and the enzyme. 

So therein lies the trap, and some researchers like John Clarke in 2011 who published a paper, really flagging his concerns on this, because of the close link between cancer and cruciferous vegetables, people who had such illnesses go googling and they find broccoli seed supplements, and unknowingly will purchase one that's got no enzyme. These people are also likely to have a compromised microbiome anyway. And so they may get no conversion, or if they are getting some conversion, it won't be enough to reach the dose threshold to enhance gene expression. So it's a whole minefield of issues out there. 

The difficulty with the fresh sprouts is although they're going to contain a whole array of the vitamins and minerals and so on, including folate that you would get from a green vegetable, you don't know the seed source that you purchase. And so you may actually have a low glucoraphanin seed anyway. So I think if people want to grow sprouts for general health and wellbeing and green leafy vegetables, that's fantastic. But if you're looking for a measured dose that is known to enhance gene expression to a certain extent, then I think you've got to look to a well-characterised supplement to do that.

Andrew: So this is where, I mean, that the difference between food, which we should obviously always eat healthy foods, and any intervention where you want control.

Christine: It is. Yeah. And you can do both. And I often encourage people to do both.

Andrew: Yeah. Don't stop me eating my Brussel sprouts. No way.

Christine: And eat them raw if you can because that's what protects the myrosinase enzyme. Unfortunately, even a very small amount of cooking tends to destroy the myrosinase.

Andrew: Okay. But cooking is how we normally eat the brassica group of vegetables. So what about blanching them lightly, or maybe marinating them with some other type of protective herbal spice?

Christine: Well, you can't really protect them in that way, I'm sorry.

Andrew: Because it's heat.

Christine: Look, 10 minutes of microwave and 7 minutes of steaming has been shown to deactivate the myrosinase. And if you're cooking Brussels sprouts, I don't think seven minutes is enough to soften them.

Andrew: Hmm. This is bad news.

Christine: But you can shred your Brussel sprouts up in your salads. You can crumble your broccoli vegetable into your salad. You can toss any of those things into a casserole just before you serve it.

Andrew: Aha.

Christine: Little broccoli florets and shredded sprouts.

Andrew: We need to have recipes from you, Christine.

Christine: Yeah.

Andrew: Now, you were talking just before about the gut microbial milieu interacting with the glucosinolates, and you were saying this was ineffective. Let's talk about probiotics for a little bit because, obviously, these are the poster child of gut interventions. What are some of the issues around this approach?

Christine: Oh, there’s lots of issues in my mind. Anyway, firstly, the probiotic supplements typically don't colonise the gut. And I think there's been a popular misunderstanding for decades that you could take a probiotic supplement and you could recolonise your gut. But when you realise you've got perhaps a thousand different species in the gut and you can only have half a dozen or so in a supplement, that's unrealistic. You also don't know which ones you're missing, although you could do a microbiome analysis. But I think we're not colonising by taking a supplement. So there's the first problem. 

And I think a lot of the probiotic supplements are Lactobacillus and Bifidobacterium-based, and yet they make up a very small component of the entire microbiome. To a large extent, it's having these new DNA-based techniques, meta-genomic sequencing and such like, which has opened up to us the composition of what's really in the gut. And it's far more complex than we even knew when we were just using culture-based methods because so many of these bugs can't be cultured outside the gut. 

So everything's changed when we're starting to look at what's going on in there and how we can actually intervene. So there was a paper published just at the end of last year that also threw into question the value of taking probiotics after antibiotic intervention. And surprisingly enough, it showed that the people who were taking a probiotic supplement after they'd finished the antibiotics actually took five months longer for the gut microbiome to restore itself, compared with those who didn't take anything. So I think we've got to look very clearly now at what we expect the probiotic supplement to do.

Andrew: Yeah.

Christine: Now, things have changed in that light, but I'm not negating the value of probiotics. I'm not doing that at all, but I think we need to change our focus. 

So what we do know about probiotic supplements is there are specific strains which had been well-researched for particular effects in humans. Some of them, for example, might be beneficial for food intolerances, others might be beneficial for diarrhoea. And so it goes on, and there's heart and skin conditions, etc. There's a whole lot of research and it's rather good research, but what we do know about probiotic supplements is a couple of weeks after you stop taking them, it's no longer in trace in the stool. 

So I think what that's telling us is they are very useful interventions, but they don't have a long-term benefit. And I mean, that's no different from fermented foods. I mean, people who eat fermented foods, those bugs don't colonise the gut either. Except the difference is likely to be, if you eat fermented foods, you probably eat them as part of your dietary routine on a long-term basis.

Andrew: Yeah.

Christine: Whereas when you take it a probiotic supplement, you might take a bottle or two, and then you feel you're well, and then you don't take them anymore.

Andrew: This has always been the issue with probiotics. I know though with that paper you were mentioning, is it by Suez, and it was Post-antibiotic Gut Mucosal Microbiome Reconstitution is Impaired by Probiotics and Improved by Autologous FMT, faecal microbial transplant, which is really interesting. 

Christine: It is. It is.

Andrew: Now, I've spoken to a gastroenterologist, Dr Johan Van Den Bogaerde, and he was saying that even FMT, if it's not your own stool — which obviously it's not going to be because you're using it because yours is diseased — then even then you can get this, not a shortage probiotics, but you can get a restricted effect. Eventually, the patient's own microbiome, microbiota will return to what they were genetically imprinted with, let's say. Let's say it that way.

Christine: Yes, because we think now that there's this core fingerprint, which is your individual microbiome, and there's an overlay which comes and goes depending on a whole lot of environmental and lifestyle factors. But there's some horror stories surrounding FMT as well. And a big concern in my mind is there's a quest to try to find a healthy donor so that you can use their stool sample. Nobody really knows what we mean by a healthy stool or what a healthy microbiome is. And I think the risk is, even if they are healthy living in their environment with their genes, that doesn't mean that that sample is going to be appropriate for an individual with a compromised gut ecology anyway.

The individual who's accepting the FMT transfer may have all sorts of compromised and adapted biochemical processes that they have learnt to adapt over the years to whatever their particular condition is. Then you dump something that's healthy in one person, it can be reactive in another. And I think this is possibly what's at the core of some of these horror stories that we hear about. 

So there's something of a move now in some quarters is to say, if you know you have to have antibiotics, you should take yourself a little stool sample and store it appropriately so when you finished your course of antibiotics, you just re-inoculate your own stool.

Andrew: Oh, here's a Jeff Leach moment.

Christine: It is, isn’t it?

Andrew: I'm reminded by his blog when he said he propped himself up with his bum in the air with a turkey baster syringe which was filled with the faeces of one of the Hadza tribesmen. And he was doing a cycling, like a bike-riding motion to sort of "get things moving," wondering if he had done himself a service or a massive disservice.

Christine: He's a true scientist for doing it for the good of mankind.

Andrew: For the good of humankind. Yeah. Along that line, when we're talking live versus dead, we talk about LPS, a bacterial cell wall fragment from gram-negative bacteria. But what about probiotics? What about dead probiotics?

Christine: Well, if we just use Lactobacillus as an example, which we're all familiar with, Lactobacillus is part of the Firmicutes group and Lactobacillus is a gram-positive. So it doesn't have LPS on it's cell wall, it has another molecule, lipoteichoic acid or LTA. 

And the way we once thought that the main reason we were taking probiotics was to displace the bad guys out of the gut, it seems now there's lots and lots of signalling pathways that are going on that are quite independent of the displacement theory. Because you can have a dead Lactobacillus organism, and you can harvest the membranes which are rich in LTA, and you can use that therapeutically. 

So now that we understand how the signalling works, we know that LTA attaches itself to toll-like receptor 2, where the LPS bad guy, attaches to TLR4. And because LTA attaches to toll-like receptor 2, it initiates a process where the gut epithelium is communicating with the underlying immune network, and that is tending to activate a number of processes. So it's activating infection control, it's down-regulating prolonged inflammation, it's down-regulating a tendency to allergy, and it's also down-regulating autoimmunity. 

In other words, the modulation of immune response is coming about to a very large extent because these gram-positive organisms, dead or alive, which contain LTA, activate the natural processes used by nature. So if the person is eating fermented foods, be it kimchi or kefir or whatever, yogurt, there is an opportunity whether those organisms are dead or alive, to activate those defensive processes. It's pretty clever, really.

Andrew: Yeah, just a question though, regarding infection control, which one would simply think is stimulating the immune system, stimulating inflammation, versus dampening of auto-immunity, dampening the immune system, or at least the reactivity. Now, these are different parts of the immune system, correct?

Christine: They are. The way it works is largely this. When there is a need to control an infection and there are signalling processes that tell the cells, "Hey, there's a bug around here and it's going to cause trouble, switch on your defences." 

So when that happens, the cell generates the Th1 process. It generates large amounts of inflammatory cytokines and also natural killer cells and cytotoxic cells, and so on. So that kills the infection. The risk is, of course, when does the cell know where to stop? And that's the really clever thing about it because when LTA attaches to toll-like receptor 2, it's activating macrophages that produce IL-12, interleukin 12. Now, that's one we don't much talk about, but it has the ability to switch either way, and it's virtually capable, when the cell determines it's killed the bug, you can switch off your inflammatory responses, IL-12 now switches over and starts activating regulatory T-cells, which now produce interleukin 10 and TGF-β, which are anti-inflammatory cytokines.

So that slows everything down. And then Th17 is the Th cell that's associated with autoimmunity, and that is also suppressed. And so is Th2, which is the allergy component. So it's all about this really fine-tuning modulation that's going on in the gut-immune interface, and it's absolutely fascinating. And it really makes me realise that we have no ability to control those processes using single interventions that we want to use to push a pathway one way or the other. 

I think we have to step back and activate the gut-immune interface in the way that nature does. And these probiotic organisms with their cell wall LTA is one of the key processes that's used in that way. And when things go wrong, often what happens is that inflammatory process doesn't get adequately shut down. And so we need to really target this gut-immune interface in a way that ought to restore homeostasis to it, or maintains homeostasis if it's in existence.

Because I'd liken it to a racing car driver who's driving full tilt with one foot on the accelerator, we're going to kill these bugs, and the other foot is tipping the brake constantly. As he's getting feedback from what's happening, he's tipping the brake constantly to bring things into line. And it's on a moment-to-moment basis that this subtle fine-tuning is occurring. So when that gets out of control, we can have prolonged inflammation that doesn't shut down adequately, and we all know, I think that many of the chronic diseases are associated with long-term low-grade chronic inflammation. 

We can have other situations where we don't adequately mount control of the infection. So we really don't deal with the infection. We can have chronic low-grade infections which stay for a very long time. So there are all sorts of variations on how this fine-tuning can go wrong.

Andrew: Okay. So previously we've spoken about the probiotics, even though they're dead, they may have actions. Is this the issues of strain specificity here? Like, can you get effective species strains and ineffective species strains? I'm sure I've read ineffective studies on dead bacteria as well.

Christine: Yes, you can. They're choosing different strains for different reasons. So for example, there's quite a body of Japanese research that looks at Lactobacillus Plantarum. So there's a particular strain they’ve tagged HK L-137, which comes from a Filipino dish wherein they ferment vegetables and fish together. Now, the peculiarity of this strain is it tends to have a highly concentrated level of LTA on its outer cell wall. And so what they do then is they grow the live Lactobacillus Plantarum for long enough to maximise the LTA on the cell wall and also to maximise the number of organisms in the population. 

It turns out that both those things are around about 18 hours, and that's when they harvest the organism and they kill it using heat. So what they've done then is produced a standardised LTA content. So then when they use that in the clinical trials, they've got a predictable level of LTA in these supplements.

Andrew: Okay. So obviously we're talking about production issues here. You know, if you don't do it right, you haven't got the correct species, strain, level of LTA and that's got to be determined. 

So what about more, as you say, using nature to help us grow our own intrinsic microbiome, the prebiotics? There's a lot of work in this area.

Christine: Well, I'd like to talk about prebiotics, and I'd also like to talk about fermented foods that create their own prebiotics.

Andrew: Yes.

Christine: So let's just go back to your first question. So prebiotics, of course, are food for the bugs, but they're more than that. This is the beauty of symbiosis because when the microbes have “digested” the prebiotic fibre, they leave behind short-chain fatty acids of which butyrate is the best researched. 

So butyrate now signals through receptors on the intestinal cell wall and butyrate signals regulatory T-cells, among other things. And the regulatory T-cells are producing interleukin 10 and TGF-β, the anti-inflammatory cytokines. So that's one of the reasons that prebiotics are good for the host, as well as providing food for the microbiota. 

But when we talk about fermented foods, and I'm thinking of dairy kefir in particular here, if anyone's made their own dairy kefir, you start out with plain milk. You add your kefir granules to that and you wait about 24 hours and you have this thickened milk, which is not quite as thick as a yogurt, but perhaps more like a drinking yogurt.

Now, what's thickening that milk? What we call exopolysaccharides, and polysaccharides are prebiotic. So the dairy kefir is actually making its own prebiotic as it goes. So it's producing its own food supply. In addition to that, within that exopolysaccharides component, there's a particular molecule called kefiran. And kefiran has specific immune-modulating properties all of its own. 
So there are so many benefits from growing your own fermented foods. And I had to say growing, because you have to grow them in your own kitchen. The shop-bought kefir, for example, has half a dozen or so particular strains in it, which must be standardised by law for food products.

When you make your own kefir, you're in your kitchen, you've probably got 30 to 50 different species in there, which are constantly changing their compensation and their proportions depending on the conditions of your kitchen. Whether it's hot weather, cold weather, whether you bought this milk and not that milk, you have this seasonality within the food like kefir, and we'll encourage seasonality in selecting vegetables and other plant foods. And I think we can do the same thing by eating fermented foods. 

So the benefit of a fermented food is you're getting this multiplicity of different organisms, which is constantly changing and adapting as time goes by, and you are getting quantities, which easily match what you're getting in probiotic capsules. What you're not getting is a standardised dose of this particular species that you may need to treat your condition, your asthma or eczema, or whatever it is. So I think there's room for both.

Andrew: There's no point having a supplement without the basis of food. I was going to make the point that Élie Metchnikoff would probably be turning in his grave knowing that there was so much more than just Lactobacillus bulgaricus in kefir.

Christine: He probably would. I mean, there's even Saccharomyces boulardii in there. There's a whole host of different yeasts.

Andrew: Right. I know that's interesting. Now you were mentioning plants just before, and of course, they contain polyphenols. What about them as cellular defence mechanisms and indeed, at least helping to regulate immune surveillance and defence?

Christine: Well, there's about 10,000 different phytochemicals being identified in plant food, and we know a little about a few of them, which is a bit unfortunate. But what we do know is that polyphenols, which is the big bulky structures which make up a large proportion of the type of polyphenols that you see in foods like citrus and turmeric and ginger and green tea and grapes and red wine and that sort of thing. So they're very abundant. But because they're big bulky structures, very little actually gets absorbed. So about 1% of them is bioavailable. So there are two or three ways that they're beneficial. 

So, first of all, they're food for the microbiota. And certainly, it's been discovered that some of the newer, if you like, understood probiotic organisms like Akkermansia are fed specifically by certain polyphenols. So we have ways to manipulate which species we're producing. So that's one of the things that polyphenols does that we didn't use to know. 

We know that they have a direct-acting antioxidant effect in the gut. So if you have marinated your steak in red wine and there's extra virgin olive oil in there as well, any of the potential carcinogens embedded in that steak are going to be neutralised in the gut. What we don't get is an antioxidant effect being transferred into the systemic circulation because these molecules are just too large to get in.

The third thing that happens then is when the microbiota eat the polyphenols, they break them down into small fragments or polyphenol metabolites. And it seems now that those metabolites can get absorbed into the system. And this is helping us to understand now why these large polyphenolic molecules that we knew couldn't get absorbed intact can have beneficial systemic effects after they've been broken down.

The difficulty here is that depending on an individual's microbiota, a different combination of metabolites will occur from one individual to another. So we've got no way, really, of predicting what collection of metabolites is going to be absorbed into your system versus my system and anybody else's. So it's a whole new arena now of polyphenol research, which I think we're only just starting to explore more fully. But it has helped us to understand this idea of the metabolites being formed by the microbiota. It has helped us to understand how these big bulky molecules are actually systemically beneficial after all.

Andrew: And what about dendritic cell reading or sampling of those polyphenols and other...?

Christine: Yeah, so the dendritic cells are part of the antenna, if you like. So the intestinal epithelial cells push up these little dendritic cells up between the intestinal cells and they're sampling what's going on in the gut at all times. So for an intestinal epithelial cell and its underlying immune network to respond to its environment, it of course has to have a way of detecting what's floating around. So the dendritic cells are part of that signalling process. The toll-like receptors are also part of that process. So they're detecting what's floating by in the gut, learning and responding accordingly. 

And really, all functions of human cells tend to be in response to their environment. And that's why I think it's so important for us to protect the way we deal with trying to manipulate these conditions. I think in the past, we've sometimes been a bit aggressive in the way we manipulate that environment. And in fact, we're still doing it because I see a lot of anti-microbial plant compounds being used with a view to destroying pathogens and pathobionts in the gut. The problem is they're not selective, and so we're killing off commensals at the same time. 

So this is an example to me that we should really not necessarily think that because it's natural, it's better than using a pharmaceutical like an antibiotic. My approach is more to re-establish the homeostasis of the gut because those gut epithelial cells, and in particular, the Paneth cells right down in the bottom of the villi are capable of producing these defensins, which are very potent anti-microbial compounds. The difference is they completely ignore the commensals and they attack the pathogens and the pathobionts. And that is the beauty of letting nature do the work for you. If you can give nature her own toolbox, she'll fix it without us intervening too aggressively.

Andrew: Yeah. I think way too many — and I'll use this term glibly — protocols encourage a kill-kill approach to infections rather than supporting or nourishing the terrain, which is a far more naturopathic-type approach.

Christine: It is. Absolutely.

Andrew: And then once you've got the terrain set up and healthy, or as healthy as can be, then it's just nipping little buds off rather than this whole sale massive army going in of these things that can damage the good guys as well.

Christine: It's carpet-bombing the gut.

Andrew: That's right.

Christine: It really is. And one of the things that happens when you do that, is you kill off the weaker species first and you leave the stronger ones to proliferate.

Andrew: So it's a rat sack approach.

Christine: Yeah, you can say rat sack approach. I like carpet-bombing. But you'd make things worse. And this idea that it's only garlic, or it's only oregano oil. It isn't only those things. They're very potent anti-microbials, and we have to be careful.

Andrew: Yeah. And I think this is also the difference between cooking with one of these things and giving an absolutely massive dose that is way above what we would use in a dietary…like a Mediterranean style diet with lots of lovely flavours and things coming out and beautiful herbs being used and things like that. We've got to be careful into what we think is good and then saying more is better.

Christine: Well, I couldn't agree more with that. I mean, a sprinkle of oregano into your pasta sauce or whatever it is nothing like taking the concentrated oil, which comes from the seeds anyway. So I tend to take a view that if it's not possible to consume that quantity of bioactive from the food naturally, then I don't want to do it. Even 1000 milligrams of vitamin C is 16 oranges. Would I practically eat 16 oranges a day? I probably wouldn't. Should I be driving curcumin into my bloodstream when it doesn't naturally want to go there in that quantity? I don't have necessarily answers to those questions, but that doesn't sit right with me because nature has sustained us on this planet for millennia without doing those things.

And I'm more inclined to want to mimic what nature does because those mechanisms are there. Our modern lifestyle doesn't foster those mechanisms. In fact, it often destroys them, but they can be rekindled in most cases. And so I think the big guns, and I put these anti-microbial plant extracts into the big guns category along with pharmaceuticals. To me, they're reserved as an absolute last-ditch attempt when everything else I tried to do failed, and I might need to go to the big guns. But it's certainly not a first-line approach, from my perspective.

Andrew: Yeah. I'm winding back to sulforaphane here. So the sulforaphane that we're taking, that's in something that would be achievable with a food dose if we had access to it. Is that what you're saying?

Christine: Yes. So I can eat 100 grams of fresh sprouts and I can get 20 milligrams or 30 milligrams sulforaphane yield. Now, what that means is a lot of the clinical trials that have been done, have been done using between 14 milligrams and 40 milligrams daily. So we're in that ballpark.

Andrew: Right. And that...

Christine: So with a practical dose of the supplement, several capsules a day or whatever it is, we can get to what you would get if you were eating the 100 grams of fresh sprouts.

Andrew: Yeah. Can you tell us a little bit more about these β-defensins? You say that they ignore the commensals.

Christine: Hmm.

Andrew: Do we know about their mechanism of action about how they ignore commensals and how they attack...?

Christine: Yeah, well, it's tolerogenic processes that the gut has, which is recognised as different microbes. But the thing about the β-defensins, they largely synthesise down in the bottom of the crypt of the villus. Interestingly, that's where the stem cells reside and there are theories that say that the reason that they proliferate there is that they have to protect the stem cells. And those stem cells are differentiating, as in migrating up each side of the villus towards the top. So differentiating into the goblet cells that produce mucus and the enteroendocrine cells and so on. So that's where...

Andrew: Oh, that's interesting.

Christine: Yeah, it is interesting, isn't it? There are different defensins, not...

Andrew: β-defensins are not the only ones. Yeah. Right.

Christine: And so the stem cells have a life of about three weeks or so, the rest of the intestinal epithelium cells have a life of three or four days. What I like about that is that within a month, you can have say, 10 generations of intestinal epithelial cells that have passed by, so you can get a response pretty quickly when you're doing the right things through the gut. As you're nourishing them and feeding them, these cells are replacing themselves, and the new replenished cells are what's proliferating.

Andrew: I want to get onto enzymes, and not digestive enzymes, but biochemical enzymes. Before I do, though, I just wanted to clear something up because I keep going round as a quandary in this. The word antioxidants. 

Now, in a Petri dish, we know that there's an antioxidant effect. You spoke about the lumen of the gut and I understand that there's a well-defined antioxidant effect in the gut lumen. Well, once it's in the body, we should no longer be thinking about this term, about giving an "antioxidant." Oh, am I right there, or…?

Christine: You are correct, Andrew. And it's created a lot of confusion because until we understood this idea, that Nrf2 activates cell defences, we didn't really appreciate this. So the Petri dish analogy is a direct effect of antioxidants on free radicals, if you like. So when I said before that polyphenols in your red wine are having a direct antioxidant effect, that's what's happening there. 
Now, those direct-acting antioxidants are not the most potent type of antioxidant in the body. The cells of the body all produce their own antioxidant enzymes, which are literally capable of quenching millions of free radical species per second. They're very powerful. They constantly recycle, they last several days, so you continue to have this antioxidant effect within the cells. The trap here is that they are not activated by antioxidants. And now let me just explain.

So this Nrf2 switch that's in the cytoplasm has to go to the DNA to switch on the machinery that produces antioxidant enzymes. What tells Nrf2 to do this? It's actually a stress signal of some description. So the cell detects that it's under stress and then that activates Nrf2, and Nrf2 now produces a chain of antioxidants and other enzymes, including enzymes that produce glutathione. So the whole protective defensive machinery of the cell is activated when Nrf2 is switched on. 

If you just look at the analogy of exercise, when you go for a run, you're breathing in more oxygen. Part of that oxygen is converted to the superoxide radical. That is the signal that tells your cells that it needs to increase its defences because now we're loading up all of these processes and we will cause some sort of damage to the cells if we don't increase our antioxidant enzymes. That superoxide is a pro-oxidant. So we have this pro-oxidant signal that the cell detects, and that's switches on Nrf2 which now switches on the cellular machinery. 

The trap is if we take large amounts of direct-acting antioxidants at this time, we mask that pro-oxidant signal, which is the stress, and the cell doesn't know that it's under stress and, therefore, it doesn't switch on its protective machinery. That's the issue that we have now that seems to explain why the many studies done 20 or 30 years ago looking at antioxidants like vitamin C and E and β-carotene, and so on, had no protective benefit at all on reducing the likelihood of cancer, cardiovascular disease, and type 2 diabetes. And in some cases, there was indication where some people were actually worsened by taking β-carotene and vitamin E in particular. So it's changed the whole face of how we think of antioxidants.

And I know it creates a lot of confusion in the mind of consumers and clinicians as well, because it's totally the opposite of what we used to think. We used to think all free radicals are bad, all antioxidants are good, therefore we use antioxidants to knock off the free radicals. In fact, we didn't know at the time that those free radicals are the signals that warns your cell that it's going to be in trouble if it doesn't switch on its defences. So that's what these antioxidant enzymes are about. They are the powerful defences. 

Now, at the same time, we're switching on antioxidant enzymes, we're switching on detoxification enzymes and a whole host of other protective enzymes that govern this ability of the cell to take care of itself.

Andrew: Okay. But help me here because there's positive papers out there with regards to using interventions like N-acetyl cysteine, for instance. There's, for instance, a N-ICE trial, NAC, N-ICE addiction trial, and this is going on right this moment. We don't have the results yet, but this is really exciting uses of it. It's not just on an antioxidant "level." It's on a condition level. 

I'm wondering if the problem that we've run into is that we're thinking it's this electron, rather than a condition. But we don't think about, for instance, salbutamol for use for asthma. We don't talk about that as grabbing an electron. We think about that being a bitter agonist. So maybe we've got the vernacular wrong? We're not looking at the condition? Or is it the actual substance?

Christine: I would not put NAC into the category of a nutritional supplement anyway. To me, it's a pharmaco-nutrient so there's no doubt that it has beneficial effects in a whole range of conditions, mental health conditions probably being the ones that have lead the way. 

Andrew: Yes.

Christine: But we also have to remember that NAC was developed as a mucolytic and as a protective agent against paracetamol toxicity. But as a mucolytic, what's it doing to the gut? What's it doing to the mucus lining of the gut? Now, here's another area that needs research because there are some animals studies which show that it is mucolytic in the gut. We don't yet know what the dose might be that might affect humans, and if it affects humans in that way.

But I see it as one of those pharmaco-nutrients which we need to consider with caution. I don't think it's something we should just give everybody routinely. I think we need to think about it. If we're using it to enhance glutathione synthesis, then I think we need to ask how does Mother Nature you do that? Mother Nature increases glutathione synthesis by activating Nrf2. So assuming we have the precursor amino acids in place, which are available if one just eats a reasonable diet with adequate protein, then we will produce our own glutathione.

Andrew: Just mentioning enzymes really quickly, the elegant control mechanisms of the body, when we're talking about these, say the oxidative control enzymes or whatever, why don't we just give the co-factors? Like, for instance, zinc, B6, magnesium, or some selenium, things like that?

Christine: Well, you can look at those co-factors, and they will certainly be the little spark plugs that enzymes need to be up-regulated. And this is the megavitamin theory of the '70s, where we thought that that was the way we would drive an enzymatic reaction forward. And we can, but it's very limited to those enzymes, which need zinc and B6. So when you activate Nrf2, you've got 500 different genes, which are being programmed to increase their activity. So you're getting a much broader-spectrum approach. 

So I would suggest that you certainly need to have those co-factors in place, and that's what a reasonable diet will do. You don't need to megadose them, and then you're broadly affecting all cells of the body and not just those enzymes that need those co-factors that you mentioned.

Andrew: Got you. And just circling right back to sulforaphane, where we began.

Christine: Mm-hmm.

Andrew: What are the conditions that it's a hero treatment for? I know you've done research with metabolic syndrome, is that right?

Christine: Mm-hmm. Mm-hmm.

Andrew: Yeah? Tell us more about that.

Christine: There's a number of clinical trials. There are about 40 clinical trials now that have been published on sulforaphane. The ones that stand out, so type 2 diabetes, metabolic syndrome, so those were some of the earliest trials that were done. We've now got trials that have been done successfully on Helicobacter infection, and that's unrelated to the Nrf2 activation. 

Sulforaphane has other properties. One of them is that it's a urease inhibitor and Helicobacter and other gram-negative urease-positive organisms rely on urease to change the local pH. So in the stomach where Helicobacter burrows, the pH is uncomfortably low for it. So it uses urease to produce ammonia, which now raises the pH and makes Helicobacter happily able to raise its little Helicobacter kids in this comfortable pH environment.

Andrew: That's really interesting. Yeah.

Christine: So sulforaphane is a urease inhibitor. And so there may be some other benefits from Nrf2 activation, but specifically here, it's urease inhibition that's knocking off Helicobacter. And it does it quite successfully. I wouldn't suggest it's a long-term cure, but then I'm not necessarily suggesting that one needs to eradicate all Helicobacter anyway. I think it can live in a symbiotic relationship with us if the host is otherwise healthy. So there's that approach. 

Then there's been studies on asthma, emphysema. So those have beneficial responses. And I do know cases where people who are reliant on their asthma sprays can certainly, if not eliminate them completely, can certainly reduce the usage. So there's also psoriasis.

Andrew: What about things like IBS? It would seem counterintuitive because one would ordinarily associate the brassica group of vegetables with being a wind causing vegetable and therefore to be avoided.

Christine: Yes. And why do they do that? They do that because of the dysbiosis in that individual. So what we've found is when you get someone like that who says, "I can't tolerate this. Or, "I took your supplement and it gave me terrible gas and diarrhoea and whatever," we just slow that dose right down because sulforaphane is indirectly anti-microbial. It's up-regulating the defensins, you're killing off the pathogens, you're going to get all of the waste products from those pathogens, some of which will get absorbed systemically. People feel sick from it. You back the doseright off and creep it up slowly. It could be just as much powder that's on the sharp tip of a sharp knife blade that might be all they tolerate a couple of times a day.

Andrew: Gosh. Yeah.

Christine: And over roughly about a two week period, they'll get up to the full dose. You both detect the dysbiosis and you treat it using this. 

So yes, it's counterintuitive, but unfortunately, if you don't understand that process, most people will stop and conclude that this “Stuff disagrees with me, and I just won't do it anymore.” Until you understand what it's doing and why it's doing it, and then everything changes. You can do wonders for dysbiosis just using sulforaphane alone.

Andrew: Christine, I can't thank you enough for taking us through. This is the tip of the iceberg of the sulforaphane benefits and issues, but also for taking us through these responsibilities that we've got to have as clinicians. And you've really piqued our interest for a few points that we just take as an axiom that we do. We don't question what we do. 

And the way that your mind works, it really makes us wake up and question even the fundamentals that we think we've got right. So thank you so much for waking us up a bit. That's great.

Christine: Thank you, Andrew. It's always a pleasure.

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook.

Other episodes with Christine include


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