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Quorum Sensing with Belinda Reynolds

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Quorum Sensing with Belinda Reynolds

They lie in wait, biding their time until their numbers grow. Then suddenly, they strike and wreak havoc upon the harmonious community.

You'd think this is a story about revolution, but actually we're talking about the constant battle for supremacy which is being waged inside us. It's called quorum sensing, and it's a mechanism whereby micro-organisms silently grow in number while evading immune surveillance until they are numerous enough to sprout forth and cause an overt infection. They often do this by forming biofilms, which cloak their communities enabling them to evade detection - even antibiotics have a hard time penetrating these coatings!

Today, Belinda Reynolds will take us through quorum sensing, biofilms and how we can effectively rebalance our microcosmic communities using natural medicines.

Covered in this episode:

[00:53] Welcoming back Belinda Reynolds
[01:32] Introducing today's topic: Quorum Sensing
[02:44] What is Quorum Sensing?
[07:08] Quorum sensing role in antibiotic resistance?
[11:32] How is Quorum sensing initiated?
[19:14] What interventions can modulate biofilms?
[26:28] What other areas are relevant for biofilms and quorum sensing?
[35:16] Phytochemicals - harnessing the wisdom of plants
[39:48] Diversity in the diet is key
[40:31] Where to consider biofilms in the body
[45:12] Final thanks to Belinda

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook. And joining me in the studio today is Belinda Reynolds. Belinda is a dietitian with over 17 years experience in the integrative medicine industry. She's the manager of education with BioCeuticals, and she regularly presents to audiences throughout Australia and internationally. And she's well known for her practical and easy style, bringing complex biochemical processes, indeed those which she loves, into easily digestible formats with clinical applications for practitioners. 

Welcome to FX Medicine, Bel. How are you?

Belinda: I'm fantastic thank you, and thank you for having me back. 

Andrew: Now, Bel today we're going to be talking about something that really interests me but I don't fully understand it nor it's importance, and that's quorum sensing

So, I guess, to start off what the hell is it, and why do we need to know about it?

Belinda: So I first heard about quorum sensing during a TED talk that I watched with Bonnie Bassler. And the information that she presented was so fascinating and I thought I really have to understand this better. And she started off the talk by covering the fact that, as we all know, there's this emergence of super bugs and the problem of antibiotic resistance. And what we used to have at our disposal, in terms of antibiotics, now aren't working for a number of different infection types. And so, as a result of that researchers are trying to understand what other ways that we can manage infections, but also prevent and, of course, treat them. And so, what they've started to do is look into this process known as quorum sensing to see whether or not they can produce compounds that are able to interfere with this process. 

Now, what quorum sensing is basically the way in which bacteria communicate with each other. And the way they do this is by releasing what are known as ‘quorum sensing molecules’, and all of the bacteria will also have a receptor site for those quorum sensing molecules on their cell wall. And basically, what happens is that, as these quorum sensing molecules increase in concentration due to the numbers of bacteria increasing, that results in changes in gene transcription within the bacteria.

Andrew: Within each bacteria?

Belinda: Yes. So say, you might have Klebsiella bacteria there, for example. So, Klebsiella reaches a certain number within a particular area. And due to that high number, and the constant release of these quorum sensing molecules, the quorum sensing molecules reach a certain concentration, which is then detected by the receptors on those bacteria. And those quorum sensing molecules binding to those receptors ultimately triggers gene transcription and changes to gene transcription. And what that then does is turn on a whole variety of different functions, within that bacteria. And so, that can include the formation of micro-colonies, the beginning then of the release of a variety of different compounds that contribute to the formation of a biofilm, but it can also turn on the expression of a variety of different virulence factors. 

So it may mean that these...the quorum sensing molecules reaching a certain concentration triggers the release of certain toxins that contribute to a pathogen's virulence or the symptoms associated with it. Or it can also mean that you also have transcription altered to turn on the release of specific compounds that are able to degrade substances produced by the host immune system, in order to protect themselves from being killed off.

Andrew: So, not just protection by making, you know, let's say a force-field around themselves but also invasion of the local tissues?

Belinda: Yes. 

Andrew: So it's a double virulence… This is also a positive feedback mechanism, isn't it? It's not, you know, how normally we produce things to say, thanks very much I've got enough of it now, turn off. This is a positive feedback system where it's going, "I've got enough and I want more", "I've got enough and I want more and more and more." 

So, I guess, that's the, I guess the typical thing of an infection or an invader, do you want more and more troops to be able to effectively invade the country or the castle or whatever you're doing? Is that...so that's where we're headed now?

Belinda: Yeah. That's right. And so, we've basically gathered the understanding that these biofilms play a large role in protecting certain pathogens from the effects of the host immune system but also the effects of antibiotic drugs, for example. But now what we're also understanding is that quorum sensing is an essential step in this biofilm formation but also in that exertion of virulence, and also then their ability to compete with other local microorganisms as well for space. Because other factors that are released by bacteria will include certain enzymes which will degrade the quorum sensing molecules of other microorganisms.

So say, for example, if you have a pathogen which is trying to invade a particular area, they'll actually release substances which interfere with say, a commensal's ability to communicate and therefore their ability to protect themselves and adhere to a surface. And so, that's how they slowly will invade a particular area, particularly in an immune compromised individual.

Andrew: Yeah. So it's not just a way of protecting themselves but also a way of propagating themselves by bullying the ones that are already there. 

Belinda: Yeah. 

Andrew: What about with regards to antibiotic resistance, what's the relevance here of biofilms and quorum sensing?

Belinda: So one of the factors that contributes to antibiotic resistance can be that formation of biofilms that a microorganism is capable of. 

So, just to review what a biofilm is, what we know is that when we have a free swimming bacteria or a planktonic bacteria, it's incredibly susceptible to immune defences but also is very easily swept away. Say for example, if we're looking at the gastrointestinal tract a planktonic bacteria or a free swimming bacteria is very easily swept through the intestinal tracks with the fecal matter and is unable to attach efficiently to the intestinal wall, and then ultimately begin the process of multiplying. 

But what happens when there's the formation of a biofilm around a colony, this enables the colony to stick or adhere to the intestinal wall stopping it from being swept away. But what also happens is that first, there's like a slimy mucus layer that's produced around these micro-colonies and then the bacteria will start to produce other substances to form what's known as an ‘extra cellular polymeric substance’. So it includes polysaccharides, lipids, proteins, nucleic acids all of those different compounds are within these biofilms.

And what these biofilms are doing are protecting these colonies that are housed within them from the effects of the immune system and from the effects of antibiotics that might be prescribed. So sometimes you might find that the bacteria around the surface are susceptible to being killed off, but the bacteria that are close within the centre, they're very much protected.

Andrew: That reminds me of a swarm of fish, of sardines, the ones on the outside can get pickled off more readily.

Belinda: Yes, but the ones on the inside are protected. And often intentionally free swimming bacteria are released from the biofilm colony to try and spread the infection elsewhere or the biofilm itself will spread and attempt to invade other surfaces. 

But where quorum sensing comes in, is that it seems that the process of quorum sensing or this bacterial communication is essential in turning on the formation of these biofilms, and all of the other factors that come along with it. So, ultimately then, if we're able to interfere with this communication, we can essentially halt the formation of a biofilm or we can halt the progression of it, ultimately rendering these pathogens more sensitive to the effects of the antimicrobials we might be applying. Or it also means that these microorganisms are left more vulnerable to the effects to our immune system and gives the body more of an opportunity to clear this up before these biofilms are formed, but it will also silence their virulence genes so they're unable to exert their negative effects on the body despite their presence even if it's in high numbers. 

Andrew: Ahh…

Belinda: So there's a number of different ways that researchers are suggesting we may be able to interfere with this quorum sensing, and that can be by looking at drugs or compounds that can act as an antagonist at the quorum sensing molecule receptor. It can modulate the binding of the quorum sensing molecule to their receptor, it can degrade the quorum sensing molecules themselves. They may actually inhibit the release of them in the first place. 

I read one article and it was discussing the fact that hydrogen peroxide and other free radicals are involved in the turning on of the release of these quorum sensing molecules. And that's where antioxidants such as N-acetylcysteine have been noted as potentially helping to dampen the release of quorum sensing molecules from certain pathogen.

Andrew: You're really answering a question here that I had with Mike Ash, good old Mike Ash. Because years ago for sinusitis, to put Saccharomyces boulardii...a mixture of Saccharomyces boulardii and NAC up their nose on a cotton bud. Just wet the cotton tip and insert it into the nose. And then it can actually sort of help to degrade infectious biofilms from that point...or infections from that point. I'm assuming that there's biofilms in there? Notwithstanding that we think it's always bacterial, but there's a certain percentage that are fungally related. 

But, can I just go back a step, with regards to the initiation of quorum sensing. Do you need one organism? I mean, one organism divides obviously because they're bacteria. So does quorum sensing only start at a certain concentration like 10 or 50 or 64, whatever the division is. Or does it take a substantial amount of bacterial divisions to be able to say, okay we'll go from here, there's an aberrant terrain here that we can take advantage of so let's start doing this now, or does it just start from way back when it's two?

Belinda: My understanding is that it's a process that is consistently happening and may occur even when there are sort of very small numbers of these microorganisms there...

Andrew: So really it's a survival sort of thing? 

Belinda: Yes. So they constantly are releasing these molecules and expressing the receptors for themselves, and they're basically looking and waiting for these molecules to reach a certain concentration. 

What's interesting though, is that there's a variety of different quorum sensing molecules that can be released by a specific bacteria or fungi. So they'll release molecules that are specific to that same strain or species so that they will look to create the micro-colonies within themselves. But, they also will release generic-type quorum sensing molecules that are also detected by other bacteria or microorganism types. So they are constantly assessing their environment to a degree. 

But they've also identified that certain microorganisms are more of the eavesdropper-type, where they express a variety of different receptors but don't really release the same number of different quorum sensing molecules or there's the chatterboxes that release a lot of different molecules but don't necessarily express a huge number of different receptors. So it's...

Andrew: Wow, So there's a real bacterial racism then a bacterial multiculturalism with eavesdroppers and chatterboxes?

Belinda: Yeah. It's quite an interesting area of research. And, obviously, they're still trying to understand a lot of things about it but what...it is really interesting that, I guess, for certain pathogenic organisms, for example, they're able to detect the presence of competitor microorganisms and that is what potentially switches on the transcription factors that result in the release of the enzymes that will attempt to degrade the quorum sensing molecules of another species. 

So it's this constant battle ground, I guess. And that's where there seems to be a difference between your commensals and your pathogenic or potentially pathogenic microorganisms because the commensals seem to be, in a way, not all of them, but some of them appear to be in a way synergistic, where even giving a one particular species has been found to help with promoting...

Andrew: Another bacteria ....

Belinda: The colonization of others. 

Andrew: Well, we see that in the vaginal microbiota. Forgive me if I get the species wrong, but lactobacillus iners may be the first one to recover after bacterial vaginosis, and then it sort of hands on the banner to the next species, let's say it's lactobacillus jensenii. And then it progresses further and further until you get a normal microbiota restoration of the vaginal tract. So it really interests me this commensal stuff.

Belinda: It's interesting too that if we look at our immune system, we actually can facilitate the formation of biofilms in nonpathogenic organisms, but we actually inhibit the biofilms created by pathogens. 

Research has shown that secretory IgA or secretory immunoglobulin A which is naturally produced at our mucosal areas, that it is actually able to facilitate the formation of biofilms around nonpathogenic E.coli. I don't know if...

Andrew: Oh Really?

Belinda: Yeah. But on the flip side, it can actually inhibit the formation of biofilms around pathogens. 

Andrew: Enterotoxic. Are you talking specifically E.coli or all pathogens?

Belinda: Not specifically. Other pathogens, I can't say all, but definitely others. 

Then also in saying that, I've seen some evidence showing that probiotics or commensals actually hold the ability to penetrate pathogenic biofilms to then render them more sensitive to being broken down by aspects of the immune system. 

So we're often looking for these heavy drugs or other substances to try and break these biofilms down, but it's quite incredible that probiotics actually do harbour the ability to do that.

Andrew: So this is an interesting concept. If it can be shown that a certain species/strain has certain attributes of penetration of a pathogenic biofilm, could we then look at, down the track, pre-treatment using probiotics before antibiotics to make the antibiotic treatment more effective?

Belinda: Yes. And there is...

Andrew: Rather than after trying to clean up the mess that the antibiotics cause?

Belinda: And that's certainly been put forward as a potential option. That the use of... Obviously, there's a lot more research to be done but they do suggest that these probiotics have the ability to potentially assist in destabilising, I guess you'd say, these biofilms. 

But, in addition to that, if we're able to inhibit quorum sensing, we're able to slow the progression of the biofilms at the same time and having a healthy balance of commensals within an area actually inhibits by quorum sensing, simply due to the fact that it's controlling the concentrations of those molecules, and that's also something that's worth considering as well. 

But what's very interesting is that there's a huge variety of different phytochemicals found throughout our diet and also in herbs that we're currently using, that have been identified to hold the ability to interrupt with this quorum sensing. 

Andrew: So this is where I was gonna ask, is it always bacteria? Obviously not. I think it was David Hasse was talking to me on another podcast, and we consume 18 tons of food throughout our life, my wife would probably up that to 20 tons for me! 

But we've got a massive amount of information, of data, that we have to talk to, and some of that is immunologically active. So that's a really interesting concept. So what sort of phytochemicals or food aspects can help, let's say, modulate biofilms or quorum sensing?

Belinda: So there's quite a huge variety of them. 

I thought I'd touch first on N-acetylcysteine because you did mention it earlier on. So N-acetylcysteine has been shown to, not only hold the ability to interrupt the release of quorum sensing molecules, but it's also been shown to help with breaking down biofilms. NAC is not only an antioxidant and a precursor to glutathione, but it can assist in breaking down the mucus components of the biofilm. 

So it actually represents a really interesting addition to an antimicrobial type protocol, particularly if it's something that is known to be quite resistant. There has been some research where they've used it alongside the standard therapy for H.pylori infection, for example, to enhance the outcomes of the antibiotics that are used during triple therapy. In addition to the N-acetylcysteine...oh, actually I should point out too that the N-acetylcysteine has been shown to be really useful in Chronic Obstructive Pulmonary disorders

Andrew: Yes. Cystic fibrosis, things like that.

Belinda: Yeah. So not only is it able to break down the mucus, but it also is immune modulating to reduce the inflammation in the area but potentially too, because the standard or the types of bacteria that tend to infect individuals with cystic fibrosis tend to be those biofilm-forming, hard-to-treat type infections. The N-acetylcysteine could be useful there in helping with preventing or degrading the biofilms formed by those harmful pathogens. 

If we look at other foods... So there's a huge variety of different phytochemicals which have been noted to exert different types of effects on these quorum sensing. So as I mentioned before, it can be inhibiting the release of the quorum sensing molecule altogether, assisting in their degradation, binding to receptor sites or acting as an antagonist at those receptor sites or even modulating the binding of the quorum sensing molecules to those receptors. 

So, they include things like allicin from garlic, even curcumin, quercetin, sulforaphane, pterostilbene, resveratrol, the tannins or catechins found in green tea… There's a huge variety of different, sort of...I guess, phytochemicals that we consider to be ‘antioxidant’ tend to be quite useful.

Andrew: And it’s really sort of, opening up some questions in my mind about how we think these herbs work. 

For instance, we used to think that glucosamine got absorbed through the gut, went like a package to the knee joint and then opened up magically to be released into the the joint space and to regenerate cartilage. It's now known that it really is metabolised in the gut. 

You know, we can talk about polysaccharides and some people have said that polysaccharides aren't readily absorbed throughout the body. That doesn't mean they don't have an action, they can have an action at the gut then be read by the immune and carried systemically around the gut. 

So I'm wondering whether this plays, at least some part, in how these phytochemicals and indeed herbs might work. Are they reducing these inflammatory signals, these quorum sensing signals, from bacteria and maybe dampening inflammation at the gut level that's read systemically. I guess, the thing I'm thinking of here is centella asiatica - Gotu kola, commonly used for brain and also joints. Is it working on the joint or is it working on quorum sensing the gut?

Belinda: Yeah. Well, I mean, it's definitely a good question because, I mean, if we look at garlic, for example, or even berberine a component of commonly used antimicrobial herbs. Each of these have been shown to inhibit biofilms but also to inhibit quorum sensing. 

So is the mechanism of action actually via that inhibition of quorum sensing, that it prevents that biofilms formation or prevents the progression to ultimately leave the pathogen then more susceptible to the effects of the immune system but also the other anti-microbial effects exerted by that active within the plant? 

So I think there's probably a variety of different mechanisms through which these things are acting, but it is very interesting. Because, I think, we always used to talk about antimicrobial herbs and then we discovered biofilms and thought, oh, we have to target biofilms, and then now we’ve seen quorum sensing and, oh, we have to target quorum sensing. 

Andrew: Don't forget the old ways. 

Belinda: When you step back and have a look at the ingredients that are being shown to exert these actions it's what we've always been using. 

So, I think it's awesome that we're starting to understand it all better and we can take a smarter approach to treating persistent infections. And I think it's good that we're understanding that breaking down that biofilm, often if it is a resistant or persistent type of infection, that is a very important step, and if we might need to go in harder with things that are able to do that and that we know are able to do that. But, it's also interesting to just have that better understanding of how those phytochemicals are actually able to exert these functions. 

But it also emphasises the importance of having this plant rich diet, rich in prebiotic fibres, because the prebiotic fibres are gonna ensure that you've got a nice balance of commensals and diversity which is going to prevent the overgrowth of any one particular strain that could potentially lead to an infection. But you'll also ensure that you've got lots of those beneficial microbes that are able to compete with the pathogens. 

But, in addition to that, research suggests too that by consuming a whole variety of different phytochemicals such as those that are able to inhibit quorum sensing and prevent biofilm formation. It's a really good preventative diet, not just for the standard inflammatory chronic diseases that we often talk about, say, cardiovascular disease and cancer, it's also very useful for preventing infection within our bodies. Because it's far less likely that we'll develop these types of infections if we're consuming, on a daily and regular basis, all of these potentially beneficial compounds that are able to prevent those infections from developing. 

Andrew: Does quorum sensing and the formation of biofilms...does this sort of answer that question why some individuals might be more susceptible to reinfection? And indeed, what sort of conditions are we thinking about treating here? The obvious one in my mind is Helicobacter pylori. What are the areas of biofilms and quorum sensing relevant?

Belinda: So, I think, for most infections the quorum sensing seems to be relevant. They have demonstrated that quorum sensing across a huge variety of different microorganisms, and insects as well. 

So honey bees and ants use their own forms of quorum sensing in order to coordinate themselves for different things such as seeking out new hives when you're talking about bees, or seeking out new areas to create a home. So, I think, it certainly is something to consider for a huge variety of different infections. 

I know biofilms are quite commonly looked at when we're talking about persistent infections on medical implants and also urinary catheters and things, for example. But any sort of persistent infection that we tend to be aware of, we could always consider this quorum sensing and biofilm inhibition as being an important part of a treatment program. 

So Helicobacter pylori is an example of a condition that can be quite difficult to treat, and we are seeing the emergence of antibiotic resistance within this type of infection. So, I think, for patients who may have already undergone a Helicobacter pylori triple therapy treatment, and certainly...if their condition is persisting or seems to be recurrent, it certainly can be worthwhile adding in some ingredients that we know to be useful in degrading its biofilm. But also for quorum sensing inhibition in order to potentially improve the effectiveness of the anti-microbial therapy that we're using. 

In addition to that, when we look at common gastrointestinal infections or urogenital infections, Candida albicans, certainly utilises quorum sensing and creates biofilms around itself. So we certainly need to be considering that there. But again too, whenever we're looking at any sort of persistent infection, we need to be considering what else is going on in that person. 

So, for example, if we have a patient presenting with chronic candida, we also need to consider what other factors contribute to a candida overgrowth. So the first one you’d think of is chronic or a history of antibiotic use. So, of course, what's happened there, is you've killed off a lot of the beneficial microorganisms that would normally keep that candida under control. So you've often created an environment that is less acidic than it should be in order to deter the overgrowth of pathogens. So that's why you've now got an environment in which these pathogens are flourishing and having a great old time because the numbers of other bacteria have reduced, the candida is able to flourish. And due to then an increase in density of their quorum sensing molecules, they've switched on, they're exerting their virulence factors, they're creating a biofilm and slowly getting harder and harder to treat. 

So we need to be restoring the environment, so increasing the number of commensals. And that's where, if it's a vaginal Candida infection, for example, you may want to use a pessary. Because that can be a rapid way of restoring the commensals in the area. So a probiotic pessary because the lactobacilli that naturally inhabit that area will produce things like hydrogen peroxide, but also a variety of short chain fatty acids which can assist in trying to address that Candida infection. 

But in addition to that, there's other factors that we know to compromise our mucosal immune function. So a vitamin D deficiency, for example, will compromise the release of cathelicidin which is an anti microbial peptide released in response to a threatening infection or trauma on the mucosal surface or the skin. So if someone is chronically depleted in Vitamin D, they've also had a history of antibiotics use, they're not consuming a great diet, and they're potentially over cleaning the area because they're concerned about the Candida, they're constantly disturbing that delicate pH balance that's needed to prevent that candida overgrowth. And all of these things are contributing to a potentially chronic or recurrent infection. 

So, I think, we certainly need to be providing those substances that we know to be antimicrobial and are able to degrade biofilms, but we also need to be looking at the person. We also know, in women, that a high estrogen, low progesterone-type environment can also contribute to a greater risk of Candida overgrowth, and that's linked to alterations in the immune system. So what is happening within their diet or their lifestyle or their environment, which is contributing to this high level of estrogen? 

So just like normal, we need to consider a personalised approach and access that individual. But I think that consideration of biofilms and quorum sensing needs to be taken into account amongst all of that.

Andrew: But this has got to do with nourishing the terrain. And I think one of my biggest lessons years ago was I was zinc, zinc, zinc, for the immune system, zinc, zinc, zinc. 

I remember these ladies used to come in and just go, "Oh, some more probiotics. It's happened again. Thrush again. You know, I'd use bovine colostrum as a douche, if you like, or inserting it as a paste, inserting it overnight on a tampon. I would get evil looks if I told them not to wear a rather large surfboard, you know, a pad, because it comes out overnight, and they would look at me with daggers in their eyes. 

But the big lesson that I learnt was, don't forget the simple things like 12% odd of women are going to be iron deficient. Doh! dopey! And so, of course, in these recurrent women, part of the answer was to assess iron. And it's very well assessed, very cheaply assessed. And, low and behold, they were drastically iron deficient. So we corrected their iron deficiency anaemia, their immune system could pick up and low and behold they were fine.

There were other ladies that we had to use other sort of things. And there were some that just had recalcitrant issues. You know, post-coital irritation of the vaginal tract, of the vulval area, and they would get, not just a cystitis but they would get the itching and the cottage cheese and they'd get full blown thrush. And some of these ladies, it was just so frustrating to them. 

Now, that I sort of have a slight understanding of quorum sensing, I'm more mindful about, should I have been addressing this with doing the base things, nourishing the terrain, but also maybe looking further afield at what I could have been using, not just probiotics but herbs to maybe disrupt those biofilms. If that was what could have been the issue?

Belinda: Yeah. And I think that's really helping to increase the awareness of how beneficial these anti-microbial herbs can be. I'm not a herbalist, I haven't studied herbs, but I certainly wish to as my understanding of how incredibly beneficial the constituents within these herbs really can be. Particularly things like the allicin in garlic, even gingerols in ginger, the berberine, the incredible benefits that the berberine is being identified to exert throughout the body. So not just as an antimicrobial and a quorum sensing inhibitor, but also for its use in immune modulation and supporting insulin function, for example. 

So yes, I think we certainly need to go back and revisit herbs as a really useful way of addressing these persistent infections and using things like enzymes and probiotics, alongside those, to further enhance your treatment's ability to really get to those infections. 

Andrew: With regards to these broad plant-based phytochemicals, how can we maximise the usefulness of them from our diet?

Belinda: So I guess it comes back again to that holistic approach. 

So first of all, if we talk about the phytochemicals for a second and the reason why they're actually produced by the plants, it's suggested that the plants produce these in order to inhibit the quorum sensing of the microbes that threaten to invade and damage the plant itself. 

Andrew: When it's growing in the ground?

Belinda: Yes. So these plants have developed these phytochemicals that exert these quorum sensing inhibiting properties in order to protect themselves from, I guess, infection. And ultimately then, we're able to reap the benefits by consuming these plants as well. 

Andrew: Wow, Isn’t nature wonderful?

Belinda: It is. It's just incredible. 

Andrew: We just don't pay it enough attention. 

Belinda: No. But the interesting thing though, is that all of these phytochemicals aren't necessarily readily available from the plant. We actually need specific steps in the digestive process to yield these active. 

So if we take ellagic acid, for example. That's found in pomegranate. So not only has it been shown to be able to assist in preventing the formation of biofilms, in degrading pre-formed biofilms, is able to inhibit quorum sensing, but it also is noted as a natural antibiotic exerting similar activity to quinolone antibiotics. So it inhibits the DNA gyrase enzyme that halts the replication of E.coli, for example. 

So it's an incredible anti-microbial, it's also a biofilm degrader or inhibitor and a quorum sensing...

Andrew: So conditions, enterotoxic E.coli, food borne and UTIs? 

Belinda: So, urinary tract infections certainly because of the E.coli commonly being the culprit there. But there's a variety of different microorganism types that, at least in vitro, ellagic acid has been shown to be useful against. So Candida is another one. 

But the issue here with the ellagic acid is that certain bonds need to be broken to yield ellagic acid from the tannins in the pomegranate, and that requires tannase activity. And tannase activity is exerted by certain commensals within our intestinal tract. And interestingly then, when ellagic acid is further broken down it yields other components known as urolithic... I can never say it properly…

Andrew: Urolithic. 

Belinda: Yes, that's it. But they themselves exert their own benefits but then also work to feed microorganisms in the gut too acting as like a prebiotic. The pomegranate really does hold the potential to be incredibly beneficial, as long as we have the correct production of enzymes throughout our digestive tract in order to yield these beneficial substances. 

Andrew: And of course, if we go one step back from that, how do you prepare for digestion, and that is to create a nice little space around you where your parasympathetically dominant not sympathetically dominant. You're full of gratitude, you're going to ingest that food in a grateful way. Nourishingly chew the food adequately. And so there's all of this cephalic phase of digestion that we've gotta prepare for before all of this sort of stuff gets anywhere near our small intestine. 

Belinda: And then we all... I guess, we need to consider too that, say for example, if we were looking at a H.pylori infection or even SIBO for example or SIFO, where you’ve got the fungal overgrowth. Quite often you'll see hypochlorhydria in those situations, which can mean that you may be less able to reap the benefits of some these phytochemicals. 

So it's just important that we're paying attention to attempting to correct those digestive processes at the same time, in order to really get the maximal benefit. Because addressing, too, that hypochlorhydria is an important part of preventing re-infection as well. 

So yeah, there's a number of different things that we need to consider when we're trying to maximise the benefits of these but it really is, again, just taking a step back and looking at the big picture.

Andrew: Now, of course, when we're looking at food, we should always be looking at broad spectrum actions from a variety of foodstuffs. 

Can you go the other way and take too much of a good thing and therefore throw out the balance of the commensals, therefore damaging the terrain, let's say berberine or allicin? Can you take too much and therefore damage the terrain which will favour the future growth of biofilms? How careful do we have to be?

Belinda: It seems to be, though, that there's differences in the types of quorum sensing molecules that are released by different bacteria types. And it seems that the way the immune system responds to commensals versus potentially pathogenic microorganisms is quite different. Maybe that's down to the pathogen associated molecular patterns on the cell walls of these microorganisms but also the structure of the quorum sensing molecules themselves. 

We know that, for example, gram-negative bacteria, I think, primarily release protein-based quorum sensing molecules, whereas gram-positive bacteria tend to release lipid-based quorum sensing molecules. So there's a lot of variation amongst them all. So I'm sure that there is a way in which the berberine is primarily inhibiting the potentially pathogenic, but at the same time I can't be certain in that.

Andrew: Well, I've gotta say, you've certainly opened up a can of worms in my head, which is a horrible vision. But it's something that I think we really need to be cognisant of when we're talking about therapeutic approaches. 

To me, it opens up a mechanistic action of what we have often used but now we might be seeing it in a different light and we might be able to tweak it so that we can inhibit the bad guys, basically play them at their own game, while favouring our own commensal sort of populations. But not as simplistic as just give some bacteria and that will be the job. So this includes our diet and some selected herbs and nutrients, I guess.

Belinda: It really does just reinforce the importance of having that diversity in the diet. Because, as we have spoken about, different microorganisms release different types of quorum sensing molecules and each of those quorum sensing molecules or receptor sites may require a different type of phytochemical in order to be very effective. And so, therefore, we need to encourage a diversity of phytochemicals in the diet to be providing, I guess, that broad spectrum approach to attempting to suppress the development of infections but, and like you said, manage that terrain and ensure that there is a good balance and a good diversity in the area such as the gastrointestinal tract or the genitourinary tract. In order to prevent the quorum sensing molecules of any pathogen from reaching that threshold point at which those biofilms start forming and virulence is switched on.

Andrew: So any epithelial tissue, we can think about?

Belinda: So, again, upper respiratory tract as well, say for example, and even chronic ear infections in children, it's worth considering as well. 

Andrew: One last question. What about the issue...we know about biofilms in catheters and prostheses and things like that. 

What about biofilm formation internally, vascular system for instance, any issues there? I'm just wondering here about the actions of, you know, serapeptase or serrapeptidase, depending on the term you use, and it's possible action. We used to think it was inhibiting fibrinogen. I wonder if there may be some action on biofilms in the vascular system. We know that H.pylori can influence this.

Belinda: Well, I guess we are starting to discover pathogens in areas that we previously never thought they would be. 

Andrew: We thought they were sterile and... 

Belinda: Yeah. So, for example, in the vascular tissue in atherosclerotic plaques they've identified bacteria. And, I guess, in order for those bacteria to have been able to actually adhere to a surface where you've got blood constantly whooshing past, they must have the ability to form a biofilm in order to hold

Andrew: To resist the shearing force, yeah.

Belinda: So that's an important thing that I found really interesting to learn, is that it's that biofilm formation that really contributes to a microorganism's ability to hold on. 

So, of course, there's, say, E.coli uses its fimbriae that binds to certain receptors and they can hold on to a degree. But if they really want to attach, really stay there, those biofilms play a very important role. So it makes sense that potentially, yes, you'd have a biofilm there.

Andrew: Watch this space because we'll have to revisit this in a year or so and just see where the science has taken us, and indeed how we can apply the herbs and the repertoire that we have, as natural health practitioners, to help our patients and inhibit the biofilms or inhibit the quorum sensing to inhibit the biofilms and hence to help our patients. 

Bel, I can't thank you enough for your mind. I love the why that you take what could, and it does, confuse the hell out of me. You just digest these technical papers and then you bring them back to this simplistic sort of explanation, which brings it back into a clinical application to help people. 

So I really can't thank you enough for bringing your expertise to FX Medicine today. Thanks.

Belinda: Thank you so much for having me.

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

Additional Resources

Belinda Reynolds
TED Talk: Bonnie Bassler - How Bacteria Talk


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FX Medicine Podcast
FX Medicine is at the forefront of ensuring functional and integrative medicine gains the recognition it deserves and ultimately establishes itself as an integral part of standard medical practice. Hosted by Andrew Whitfield-Cook, our podcasts are designed to promote research and evidence-based therapeutic practises, acting as a progressive force for change and improvement in patient health and wellbeing.