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The Vaginal Microbiome with Dr Jessica Younes

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The Vaginal Microbiome with Dr Jessica Younes

What factors influence the terrain of the vaginal environment and its associated microbiota?
 

Today we are joined by Dr Jessica Younes, nutritionist, scientist and researcher in the areas of gynecology, urology, and women’s health. Jessica has a special interest and a wealth of expertise on the vaginal and urogenital microbiome. Today she shares with us the key influencers on these microbial communities, from sexual partners, biofilms, dysbiosis and infection, even the impact of an emergency c-section versus an elective ceasarean. 

Covered in this episode

[00:50] Introducing Dr Jessica Younes
[01:48] Jessica's career background
[03:10] What influences vaginal microbiota?
[04:31] The implications of sexual partners on microbiota
[07:09] Microbiota seeding in-utero and beyond
[09:20] Emergency vs. elective C-section can influence microbiota
[12:15] Understanding vaginal biofilms
[16:41] Commensals, pathobionts and pathogenic organisms
[19:12] Lactobacillus iners: an interesting species
[26:32] Strain specificity: mechanisms of action and function, not structure
[29:11] Mobiluncus: more research is needed
[30:08] Where do probiotics fit?
[31:53] Routes of administration
[35:18] The entero-mammary pathway: challenging beliefs
[37:27] The health implications of vaginal dysbiosis
[44:46] Microbiota sampling techniques


Andrew: This is FX Medicine, I'm Andrew Whitfield-Cook. Joining us on the line today from Amsterdam is Dr. Jessica Younes. 

She's a microbiome science liaison at Winclove Probiotics in Amsterdam. She combines expertise in the human microbiomes and probiotics with a strong personal interest in vulnerable patient populations, and making the microbiome accessible and understandable for healthcare professionals. 

One of her efforts to increase awareness and education about the importance of microbes resulted in womenandtheirmicrobes.com, an annual scientific conference, which facilitates awareness and communication of high quality research between scientific, academic and medical and industry stakeholders. 

Welcome to FX Medicine, Jessica, for the first of a series of podcasts on the human microbiota.  
 
Jessica: Thank you very much, Andrew. It's a pleasure to be here.  
 
Andrew: To introduce you to our audience, could you take us through a little bit of your career path and indeed what interested you in first becoming a PhD, where you took that, and where you've gone since then?  
 
Jessica: So, I started off doing kinesiology in my Bachelor, and I became fascinated with the human body. I wanted to go into medicine from that, very inspirational for myself. And I realised doctors didn't know enough about food. So I did a Master's in Nutrition after that. From there, I became in love with the microbiome and probiotics, and I was offered a PhD to do that in the Netherlands. So I crossed the ocean from Canada, came over to the Netherlands and that's how it all started. 

From there, I sort of came into contact with Winclove Probiotics at all of the conferences. We ended up finding each other when I finished my studies, and I've been working there ever since. So that's about three years now. So that's been my journey a little bit from academics into industry and also the reason why I did a PhD.  
 
Andrew: Well, I guess the first question I have to ask is going from Canada to the Netherlands, what about the language barrier?  
 
Jessica: A lot of Dutch people speak English, and very good English, so it wasn't too challenging. 

Andrew: Right. 

Jessica: But I must say I have learned Dutch. My husband is also Dutch. So, it's good to penetrate the culture a little bit more through language.  
 
Andrew: Gotcha. So today, we're going to be talking about the vaginal microbiota, and I guess on a rather intimate level. 

But I guess first, where do vaginal microorganisms come from? There's this pervading theory about that they, you know, populate the bowel and then move forward. But there's a lot of difference between the bowel microbiota and the vaginal microbiota as well.  
 
Jessica: Certainly, there is. And I'm really happy you brought that point up, Andrew. To answer that question, I think that we have to start looking at the two different niches. So the gut microbiota has multiple different niches within the gut, whereas, the vaginal niche is extremely dynamic, it's isolated, it has its own unique function. And I would say that the majority of the scientific literature does indicate that the gastrointestinal tract can be an extra-vaginal reservoir for these organisms. 

But it's also worth mentioning that the bladder can also potentially seed the vaginal microbiota. Sexual intercourse also has an effect, so your sexual partner. The oral microbiota has also been linked to the vaginal composition. But coming back to your question, I think it really plays a role, the host really plays a role here, in determining what species stay and what they do.  
 
Andrew: Right. So I guess the first question in my head there is when we're talking about sexual partners influencing the microbiota, you know, there's the common notion of, you know, after sex, try and void so to prevent any ascending urinary tract infection from irritation and stuff like that. 

There was also the issue many years ago about ladies with recurrent thrush. And they used to call it a ‘ping-pong infection,’ so that they'd treat both the lady and the partner. That's gone out of fashion and they just tend to ignore the partner now and treat the lady who has the issue. And I don't know why that is, if it's such an issue?
 
Jessica: I think there's a couple of things that play a role there. First of all, diagnosing correctly the type of infection that a woman has is very challenging. 

Andrew: Ahh, yes. 

Jessica: The point-of-care diagnostic tests that we have, are yeah, poor to say the least. I mean, to be honest, things haven't changed in 50 years. So that's a little bit discouraging. 

It's hard to differentiate without culture and you have to wait 24, 48 hours for a culture result. Candidiasis infection from a bacterial vaginosis infection from, you know, aerobic vaginitis. So, I think diagnosis is a key part of that. 

Secondly, the woman or the man, depending on which end you're coming from, has to convince their partner also to accept and undergo treatment. 

Andrew: Of course. 

Jessica: So, you know, there's multiple things that go in play there. But I think if it would be possible, there is data that shows that partners can be these extra-vaginal reservoirs for each other. There's a lot of species overlap between, for example, the vaginal and the seminal or penile microbiomes in shared sexual partners. So this is an important point you bring up.  
 
Andrew: Yeah. It makes sense. I remember, I think I wrote an article, I certainly read an article regarding, you know, the sharing of microbiota between pets and indeed families. It's like if you've got, in a familial environment, we will tend to share more of the strains than the same genetic offspring, if you like, that are living distally from us, who may or may not have the same dietary intake. I guess it makes sense when you've got a partner with intimate sharing of microbes. There's going to be similarities, but of course there's going to be differences as well because of the different types of acid or alkali environments that they're living in.  
 
Jessica: Certainly. I think it's related more to the life cycle of the woman, where she is in her phase of menstruation, reproduction, menopause, etc.  
 
Andrew: Of course. Can I just go back with regards to the seeding of the microorganisms? Even from birth, the entero-mammary  pathway, where's that concept sitting at now?  
 
Jessica: The entero-mammary pathway is an interesting one because there's a lot of suggestive data where we think we know it's been established, but it's not been definitively shown. 

I'm of the opinion that the scientific logic makes sense that the gut, the dendritic cells in the gut, select certain microorganisms, deposit them in the breast milk, and that is then transferred to the baby, or the infant, or the neonate depending on...well, I guess it wouldn't be a neonate if they're already breastfeeding. But breast milk is an interesting one, Andrew. 

We think that the gut select certain organisms via dendritic cells and the immune system, and then deposits those in breast milk. So, there's not very conclusive data in terms of the proof of how these bacteria travel throughout the body. But we can track the same organisms from the mother's gut into breast milk in the infant gut and so forth. So, there is some strong associations. But even stronger than that perhaps is the microbial colonisation of the uterus, the placenta, you know, the amniotic fluid during pregnancy that sort of prime the fetus to be tolerant to bacteria after birth. And we see that also in the meconium, I mean, that's the strongest piece of evidence we have that gut colonisation of the infant starts in-utero.  
 
Andrew: So, there are live bacteria in meconium? 
 
Jessica: So yes, there are live bacteria in meconium and the analysis of the microbiota shows low species diversity. It's usually dominated by streptococci and some unclassified species of enterobacteriaceae, so your E. coli, your Lactobacilli, your […inaudible…] and things like this. 

And, of course, bifidobacteria are definitely found in the meconium as early I think as three days, some of the data that I'm aware of. And this suggests, again, that the infant gut is immediately colonised within birth, or within the uterus.  
 
Andrew: Yeah. Wow. I didn't know that. So, you know, the previous theory was basically that the baby was smothered with the vaginal microbiota during birth from the birth canal. Is that still the pervading theory of colonisation of the infant gut?  
 
Jessica: I would say the literature is divided on this one, Andrew. But it's certainly interesting to hypothesise and sort of pick a side. And I… the side I prefer to pick, is it yes, the infant is sort of swathed in the vaginal microbes if the woman has a vaginal delivery. And these, you know, colonise the skin, they'll colonise the oral cavity, they'll colonise eventually the gut and each niche, of course, selects which organisms will stay and colonise and develop. And we also see differences between C-section infants compared to vaginal delivery. But yeah, this is an accepted route of colonisation for the infant. Absolutely.  
 
Andrew: Yeah. And, I guess, I've got to make the point. I know that caesarian-sections are, you know, way over-utilised and there's a real ethical issues around this, convenience issues. 

But let's say, a mother had frequent bouts of bacterial vaginosis, or even let's go one step further, what about herpes? And the obstetrician preferred, in this instance, to give the mother a C-section, so that the baby wasn't exposed to that infectious agent during birth. Is there any data, or experience even, to show that that prevents the infant from being infected from these microbiota?  
 
Jessica: I'm not certain of data other than comparing vaginal birth to C-section birth, which I imagine is what you're asking. 

Andrew: Yeah. 

Jessica: But I will also want to point out that there is a difference between an induced C-section and an emergency C-section. 

So, the woman might already go through some period of her labor, or some parts of it. And if you do a C-section after that, then the hormone cascade, the microbiome changes, have already started to occur. 

Andrew: Wow. 

Jessica: So, body-wide, basically, the mother's, well, her cavities, her gastrointestinal tract, her vaginal microbiome, they all change during pregnancy. But if you do an elective C-section then that last sort of piece doesn't per se, happen. 

Andrew: Yeah. 

Jessica: So, it would be more advantageous, if possible, of course, to allow the mother to go through a little bit of the labour. But, again, that's a risk assessment that each clinician and mother has to take into account.  
 
Andrew: So, let's talk then more about the vaginal microbiota. How's it organised? Because I've got to say, the more I learn about this, the more confused I'm getting. Particularly one species, which I'll ask about a little bit later. But, you know, with regards to, let's talk about biofilms, for instance.  
 
Jessica: Yeah, so I think you've had a podcast already on biofilms? So, won't really go too much into detail on the general aspect, but more on the vaginal biofilm aspects. And that's actually what I did a little bit of my doctorate work on. So it's a sort of a love child of mine. 

Andrew: Ahh, yeah. 

Jessica: And if we describe a biofilm, it's basically a community of microorganisms that are adhering to some sort of a surface. Right? And in the case of the vagina, they're actually on the mucosal layer that is attached and adhered to the epithelial layer of cells. 

So in a normal situation, an asymptomatic woman, who you could call healthy, tends to have a very loose vaginal biofilm and it tends to be dominated more by Lactobacilli or lactic acid-producing bacteria. Whereas, a woman with, for example, bacterial vaginosis, she would tend to have a rather very thick, adherent biofilm that also can degrade the mucus and come into a bit more contact with the epithelial layer. So, there is quite a difference in the biofilm, the nature of the biofilm in the vagina of a healthy woman or an asymptomatic woman, compared to a woman with dysbiosis or bacterial vaginosis, for example. 
 
Andrew: Can I ask a potentially really silly question? A lecturer, a naturopathic lecturer and I were discussing what is a biofilm compared to something like the glycocalyx? Is there a difference? Or is it just, you know, it's kind of like, you know, is a dandelion or herb or a weed? In that it depends who you are. If you're a gardener, it's a weed. If you're a herbalist, it's a herb. So, is there a difference in biofilms regarding pathogens versus commensals? Or, is it just a term?  
 
Jessica: So the glycocalyx, as you just said, Andrew, is more of the slime of the gut. Some people also consider it the coating surrounding certain epithelial cells, whereas, the biofilm is sort of the community, the geospatial architecture of the microbiome. So, that's the sort of apartment building where they all live in. 

Andrew: Yeah. 

Jessica: So, you have your microbes, and then you have the house that's established, the matrix that's around them, and that could be composed of mucins, that could be composed of extra-cellular DNA, fibrils, all sorts of things.  
 
Andrew: So, the glycocalyx is produced by us as a fence, basically, to keep them out. Keep them on the good, you know, the outside of the fence and talk to them through that fence. Whereas, a biofilm is created by them to survive, you know, the harsh environment of the gut. Would I be right in saying that?  
 
Jessica: Yeah. And then in the vagina operates in a similar way. So, as you said, if you want to think about it as a fence, then yeah, the biofilm in a way...it's actually the mucus layer would more prevent certain organisms from coming into contact with the cells that could have a pro-inflammatory effect, for example. 

Andrew: Yep. 

Jessica: And you can see even within discharge, you know, the normal sloughing off of cells and biomaterial from the vagina. Sometimes there are really thick biofilms there, and that's more indicative of an infection. But that's the natural sort of self-cleansing mechanism of the vagina. 

So, there's a couple of ways that the vagina controls and the host controls the type of biofilm. But, again, it's a synergistic relationship. So, if you look at the oestrogen that's produced within the vaginal environment that stimulates glucose and also the vaginal cells produce their own amylases, because Lactobacilli cannot actually digest glycogen themselves. They have to digest derivatives and metabolites of glycogen. 

Andrew: Ahh, yeah?

Jessica: So, there's a really strong host component in selecting not only the organisms that are there, but how they're assembled within the biofilm.  
 
Andrew: Right. So, what therefore, are the difference between, you know, commensals and, I've spoken about this before, the pathobionts, those things that are good but could be bad. Versus even true pathogens. And then, you've got other things like parasites. You know, what does this mean for the ‘normal’ vaginal microbiota? And I guess, again, on the second sort of hand, for diagnosis and treatment of disease?  
 
Jessica: Very good points. We have the commensals on the one hand, and we have sort of the extreme other end, the pathogens, your true pathogens, your parasites, and organisms that will cause disease if they're present. 

So fulfilling conscious postulates, so to say? And then in the middle, you sort of have your pathobionts, or your potentially pathogenic microorganisms. And I would say the difference between a commensal and a pothobiont would really be the presence of virulence factors, and also host vulnerability. And you could have, for example, a Gardnerella vaginalis, and he's considered, or this organism is considered a pathobiont. You have Candida subspecies, Prevotella, things like this, whereas we consider the commensals to be mostly Lactobacilli, so Lactobacillus crispatus, jensenii, iners, and so forth.  
 
Andrew: But, iners is very interesting to me, can that be a pathobiont?  
 
Jessica: The jury is out on this one. And if I have to be controversial on the air, I would say it's a pathobiont in my own opinion. 

Andrew: Yeah. 

Jessica: The data can support both ways. But to me, it's more suggestive that it's a really highly unusual suspect in the onset and transition between health and dysbiosis in the vagina. And it's also been shown to be, for example, offering less protection during vaginal dysbiosis and sexually transmitted infections. It's potentially a risk factor if it's colonising the vagina during pregnancy and things like this.  
 
Andrew: Oh, Really? 
 
Jessica: If you're interested, we can chat...yeah. We can chat a bit more about some of the small characteristics, but we could do a whole podcast on iners just on its own.  
 
Andrew: I know. Moira Bradfield and I were talking about this. And the papers that she was sending me after, I was just tearing my hair out, what little I have left. You know, what I thought I knew about it, I was just throwing away. 

But to me, is this then going for that point, or supporting the point that you spoke about regarding host resilience? Is this really something that takes advantage of terrain?  
 
Jessica: Yes. Yes, it does. And if we look at sort of the genome, just to jump in now that we're already on this track.

Andrew: Yeah. 

Jessica: Lactobacillus iners has a very uniquely small genome. It's unusually small for a Lactobacilli. Which actually does suggest on an ecological level that it's either a symbiotic or has a more parasitic, host-dependent lifestyle. Because it has some highly conserved genes. In other words, it's a one-trick pony or multiple-trick pony, but not as versatile as the rest of the other Lactobacilli, for example. 

So it adheres, for example, very strongly to vaginal epithelial cells, there's great persistence there. But what it does further than that, things that suggested it might be more of a pathobiont, it only produces L-lactic acids. So it can be in a high vaginal pH or low vaginal pH. It has very specific nutrient requirements, which it either produces itself or does it through cross feeding with other organisms. 

It's actually the only Lactobacilli species known thus far, or published, that encodes a poor-forming cytolitic toxin. Which means that it can punch holes through membranes of other cells.

Andrew: Whoa! 

Jessica: Which is usually a pathogenic trait. But, again, whether it's up-regulated or down-regulated, depends on the environment and epigenetics and so forth. So, there's some really unusual characteristics in iners.

Andrew: Yeah. 

Jessica: But we do find it in asymptomatic women. Of course, the prevalence differs between different populations.  
 
So, one more interesting thing from the epidemiology, Andrew, is that we've found that Lactobacillus crispatus and iners generally tend to be mutually exclusive. So, you find one dominating or the other dominating, but never both together. 

Andrew: Ahh, ok, yep. 

Jessica: And we don't really per se understand this. And there's a lot of people that are working on it all around the world. But it's also potentially troubling if they can go between each other. If your vaginal microbiome is dominated by iners it seems to offer less protection against the transition to bacterial vaginosis, for example, or dysbiosis or sexually transmitted infection. 

So, we're not sure what it means. My personal opinion is that it's a transitional organism that can become a pathobiont or at least parts of potentially the pathogenic form. 
 
Andrew: Given the terrain, yeah. 
 
Jessica: Yes. But that has to be still definitively demonstrated.  
 
Andrew: Right. So, maybe this is where I got previously confused. I was under the impression that there was a temporal shift basically, that almost like a relay team that the iners passed the baton to the crispatus in setting up a normal micro...or a recovery, a recovering vaginal microbiota. That the iners went in there first, set up house, and then handed over the baton to the crispatus. But what you're saying is that might not be the case that it actually might hand over the baton to an infectious agent given that there's poor resilience in that tissue. Is that what you're saying?  
 
Jessica: Yes and no. What you're saying just now suggests it goes from either one end or the other end of the spectrum. And I was only speaking of the infectious end of the spectrum. 

But it could be the case that it actually does also allow crispatus to re-dominate. If within ecology, you know, there's a lot of symbiosis and there's a of sort of goodwill, that could make sense. But I'm not certain about that.  
 
Andrew: And so, what about instead of giving Lactobacillus iners, because of that potential bad effect, that we shouldn't be using that. And instead we should be favouring the use of other organisms, including the Lactobacillus crispatus plus maybe some prebiotics to help the good guys to grow? Or some fibers or something like that to dampen, you know, inflammatory processes that might favour infections. Would that make sense? Or are we not there yet?  
 
Jessica: No. We're definitely there and that's sort of the general strategy behind administration of probiotics for vaginal infections. 

Andrew: Ahh, okay. 

Jessica: And there, I think, I would really caution, I mean, all of these effects, all of these mechanisms of action are really strain-specific. So, we could talk about Lactobacillus crispatus, but this is the sub-species, so there are multiple strains within that sub-species and some can, for example, be isolated from a woman who has bacterial vaginosis. So does that particular crispatus strain have the correct characteristics or the correct genes turned on? Has it evolved to only work within or only survive and colonise within a bacterial vaginosis state? Or can it also revert back to a more healthy state?  
 
So, this is why understanding the strains that are in a probiotic product and their mechanisms of action within the various indications that the product is being used for is essential. It's essential. 
 
Andrew: Yeah. I guess expanding on that, you know, when we talk about probiotics, we talk about does it work or not? You know, is it good enough or not? But there's other examples, for instance, E. coli. And we've got, on the one far spectrum, the enterotoxic E. coli. And then on other hand, way away, we've got the probiotic E. coli. And of course, E. coli is one of the major inhabitants of the human gut. So, you've got to have a vast spectrum there. Mostly, you know, we think about, as I said, you know, the good guys just being good enough or not. But then you've got this vast difference. Could Lactobacillus iners be this, kind of like an E. coli? You've got good and/or bad, you know, two ends of the spectrum rather than good enough or not.  
 
Jessica: You could be right there. I mean, it's interesting that humans are kind of a weird animal or mammal because we're one of the only mammals that's really dominated by Lactobacilli in our vagina. 

Andrew: Right.

Jessica: So, are we kind of a red herring among the mammals? Maybe. We are definitely an exception, but it's clear from ecology and of the evolutionary aspects of things that we have co-evolved with Lactobacilli. So that would suggest that there is a synergistic relationship. But, I mean, you mentioned E. coli in sort of the spectrum of extreme disease or diarrhoea-causing organisms to, you know... 
 
Andrew: Therapeutic agents.  
 
Jessica: ...a very innocuous therapeutic agent that is helpful. So, again, this strengthens and underscores my point about the strain specificity. And I think that's something that's a little bit lost every once in awhile when you think about probiotics. One probiotic strain that might be Lactobacillus acidophilus or a rhamnosus is not the same as another one.  
 
Andrew: I certainly understand that strain specificity is important, absolutely for scientific replication of studies and to determine the characteristics of that organism compared to one right next door, which may or may not have the same attributes, which we might favour. But then we have to make sure that it has all of the attributes that we favour. Because we're now questioning what we previously considered a probiotic, you know? It's like we better be damn sure about what we want.  
 
Jessica: I think, if I may offer, Andrew, another way to look at it. We should be thinking in mechanisms of action and function. It's not about structure. Structure determines function to a certain extent, but function is the ultimate goal we're looking for. 

So, is the vagina asymptomatic? Is the woman at risk for a sexually transmitted infection because of the type of organisms and what they're doing in her vagina? Is she more at risk for pre-term labor because there is X organism there? Yes or no, depends on what organism it is, and, again, as you said, to the landscape, the host vulnerability. 

So then a lot of pregnant women who are colonised with group B strep, the infant might not get sick from it, but he might or she might. So it's context, and there I would suggest that we think about it more on the level of a mechanism of action that's desirable for a particular health outcome. That fits within that patient profile, the clinical need or a situation that the patient's in.  
 
So, if there's a high domination of candida within a woman's vagina and you do a pH test, that's not really going to tell you much in terms of diagnosis, but perhaps you can identify it from discharge and things like that. But once you know anyways that there's a domination of candida species, then your brain should start to click, "Hey, okay. There's an immunocompromised situation here, which has allowed the overgrowth of candida. I have to think also about the nutritional environment. I have to think, potentially, are there other sources of candida throughout the body? Lactobaccili and candida can co-dominate…
 
Andrew: Nutritional deficiencies, yeah.  
 
Jessica: Exactly. So there, you're not per se looking just for strains that have evidence. But also you want to try and match the mechanisms of action from strains with evidence to the various niches and indications. And that's a challenge. The science from industry hasn't caught up there yet. And I personally think that's because diagnostics have also not been really pushed and developed as much as they should be.  
 
Andrew: Can I ask a question about mobiluncus? What's the clinical relevance of this species, or genus, forgive me?  
 
Jessica: Mobiluncus is an organism that's often found in the vagina, and it's quite often co-associated with Gardnerella vaginalis, especially in cases of bacterial vaginosis. 

What it does, what its function is, that's a little bit more of a gray area. It's sort of in the same category as Prevotella bivia. We're not exactly sure why it's there, what it does. We know a couple of its functions, but it's a bit hard to answer other than the epidemiology that we have that it's co-located or co-associated with certain other organisms. I know that doesn't really answer your question, but again, this is one of those situations where more research is needed.  
 
Andrew: Well, that's exactly right. I guess at least we can flag it for future research. 

Jessica: Yeah. 

Andrew: So, what about probiotics then, where do probiotics fit into all of this? Given that some of the questions, we’ve sort of, really got a question. I used to think why are we not giving iners, iners, iners as the premier, you know, let's say the person that goes in to set up household? Why aren't we giving that? I'm now really questioning the use of Lactobacillus iners given that we don't know about the terrain.  
 
Jessica: There's a couple of things I want to jump on here, Andrew. Thank you for that opening. And firstly, we need evidence-based probiotics. 

Andrew: Yep. 

Jesscia: So probiotics that have a solid safety dossier that are well characterised, you know, approved by the regulatory authorities. That's another issue as well. But that's the starting point. 

Andrew: Yeah. 

Jessica: From there, again, as I said before, we need to look for the appropriate mechanisms of action that also have been demonstrated in hopefully, clinical studies, that can help within the various indications. Because we're talking about multiple different types of infections here or situations within the vagina.  
 
It could be vaginal dryness that is experienced by a post-menopausal woman. It could be, you know, multiple bladder and vaginal infections that are just cycling in a premenstrual young girl. It could be a woman who is pregnant, who is undergoing antibiotic therapy for something, and then, you know, has a couple of infections that come up. 

So, we're all talking different clinical indications, and there, you need really to match the ‘super powers,’ if you will, of the bugs to what they're actually trying to do. And there that comes back again to the science, and sort of the quality of the company that'll be producing them. And the science that they have behind it to support their products.  
 
Andrew: What about the route of application? We spoke earlier about the entero-mammary pathway. And there's some indication that bacteria, are, either they're transported to some extent, or indeed, they might influence, let's say systemic systems, you know, like interleukins and things like that, to trigger a response in a distant part of the body. But what about route of application, like direct route of application, vaginal pessaries, things like this, you know, douches, all of that sort of application? 
 
Jessica: It's actually interesting you asked that because I talk with a lot of gynecologists, and I actually find that their opinions are completely mixed. 

So, in my network I have sort of a group of gynecologists that prefers local application. So a vaginal pessary, a capsule, things like this. And then there are other gynecologists who prefer the oral application, which is more of a systemic route, as you said, and then the bacteria will come and enter the rectum ultimately, hopefully, across the perineum, for example, and then enter the vagina and potentially the bladder as well, depending on what urogenital infection the woman has.  
 
Women themselves are also a little bit mixed on what they prefer. Some groups find a local application to be working better for them, or they prefer it because they think it's working faster. They prefer the lower dose, for example, and the less number of times they have to apply it. Some women prefer the convenience, more of an oral formulation. 

But, for example, as long as you have a product that can show that it can get to the place that you want it to get and do what you want it to do, whether it's orally applied or vaginally applied, I think that's the key. I'm not certain that there is a strong enough difference to really say one is better than the other.  
 
Andrew: We give an oral dose of a probiotic. You will inevitably get some sort of die-off in the stomach because that's one of the functions of the human stomach. But then it's got to survive bile, it's got to survive shearing forces, the mixture of chyle, fiber, what it's going to feed, what other bacteria it comes into contact with, and how those bacteria interact. And hopefully at the end of the anus, you're going to get that to move across from the perineum into the vaginal tract. That's a big ask.  
 
Jessica: It's a treacherous journey.  
 
Andrew: So, is that being demonstrated with oral dosing?  
 
Jessica: We've been able to track certain strains...I'm just going to speak about strains now. So for example, Lactobacillus reuteri RC 14 or Lactobacillus rhamnosus GR-1. 

Andrew: Yeah. 

Jessica: These are two particular strains that are often found together in formulations and there's some nice evidence that’s showing that these strains, when administered orally, can be found back in the vagina. 

Andrew: Wow. 

Jessica: We make the assumption, because nobody's ever studied this, but make the assumption that they go across the rectum, the perineum, and into the vagina. But, I mean, there's some very fascinating work coming out of France that suggests that there's also a blood microbiome..

Andrew: Yep. 

Jessica: And that organisms travel through lymph. So, I mean, let's go with the first route to the rectal ascension, but let's also not rule out the fact that there might be other ways that they travel, especially given our earlier discussion regarding breast milk. So, there is data.  
 
Andrew: When I first heard the entero-mammary pathway, and it was researchers at the Madrid University. Fernandez, Esther, Germanez, there's a few others. 

But I argued vehemently against this, because I said if you've got bacteria in the blood, you've got sepsis.

Jessica: No. 

Andrew: Totally being ignorant of the concept of being transported in an enclosed... what was it, a monocyte, wasn't it? It's engulfed in a monocyte and transported live through the blood, into the lymph and then into the breast milk. I mean, this is a wild concept. You've just mentioned before, an in-utero live bacterial colonies. You know, this would go against all sort of previous concepts of the sterile inner environment of the body.  
 
Jessica: Yes. And this is something that the microbiome world or the microbiota world is faced with translating the idea that these previously forbidden sterile niches are not sterile.

Andrew: Yeah. 

Jessica: And translating this to healthcare professionals, to the average layperson, the non-scientist, I should say. And that's a bit of a challenge because we've been raised in a world that says, "Okay, germs are terrible." Clinician’s always raise, you know, "The only good bacteria is dead bacteria," unless you're a gastroenterologist. 

So there's a lot of things that we're working against here. But, I mean, the microbiome is not the cornerstone of health, it's part of health. It's part of the story. And if you think about it on a just sort of all assumptions aside, if you think about it at a logical level, we are completely surrounded by microorganisms. So, if an infant comes out of the womb unprepared to meet all of these microorganisms, they're not going to be in a very comfortable position for either their short life or the rest of their life. So it would make sense that in some way they're prepared for this symbiosis or the potential threats or challenges that would happen throughout life upon exposure to organisms.  
 
Andrew: Okay. So let's go into some of these instances where they're not well prepared. You know, what can happen when you've got a vaginal microbiota that's way out of whack?  
 
Jessica: Yeah. If you had a vaginal microbiota that's way out of whack, it can have a lot of different implications. Not only for the woman but if she is of reproductive age and has children or is pregnant, then also for the infant. And I think the poster child here with respect to the microbiome and dysbiosis for infants would probably be necrotizing enterocolitis, or NEC. And we have some very, very nice data with respect to probiotics and reducing overall mortality with NEC that's directly related to sort of restoring or correcting this dysbiosis that occurs in the first, you know, five to eight days. But we could do a whole ‘nother podcast on that one too, Andrew. 
 
Andrew: Well, let's delve into that. And indeed, let's talk about the bacterial implications with neonates on another podcast. Because the other aspect I'd like to go into is vitamin K production, which really greatly interests me. Why humans have evolved to be vitamin K deficient at birth.  
 
Jessica: Well, from a nutritional aspect, I mean, you have multiple forms of vitamin K and one of them, I think it's vitamin K1, but…
 
Andrew: K1, yeah. Konakion. 
 
Jessica: Indeed. But that's actually produced by bacteria.  
 
Andrew: That's right. Why have we evolved?  
 
Jessica: Whereas, vitamin K2, I think, is more of an animal-derived source. But yeah, there is so much that our gut microbiota does for us. Vitamin synthesis, hormone synthesis, immune modulation, it's fascinating.  
 
Andrew: What about any wrap up topics, wrap up points that we need to make with regards to the vaginal microbiota? Can I offer one here? 

You know, if I had a lady who had recurrent thrush, I used to bomb it with a Betadine douche, which is iodine in povidone-iodine. So, used to try and kill everything, reset the landscape as if I was the god of the bacterial vaginal landscape, and try and re-colonise with probiotics. Admittedly, back in those days, we didn't have a lot of these commensals that we know about now: jensenii, gasseri, crispatus, etc. It was basically Lactobacillus acidophilus back then. 

How arrogant of me. But that's all I had. And I remember like we had some good recoveries in a few women, but there were other women that it just didn't do anything for. All we did was just, you know, scrape the landscape clean and not give them anything good to grow with. What should we really be looking at? How should we be intervening?  
 
Jessica: Ooh, that's a tough one. Caveat, I'm not a clinician. I think we said that already beforehand, but let's just keep that in mind. My answer will be a little bit more on the science side. And just one more word before I jump in is that science progresses, medicine progresses based on the knowledge that we have. And if we don't build on that, that's unfortunate. But if we use what we have at that moment, I think that's the best that can be expected of us. So don't beat yourself up for that, firstly. 

With respect to patients and handling patients, you mentioned thrush. We know with thrush there tends to be, as I said before, an immunocompromised state. And if you take a more holistic approach, you know, there are other signs potentially within the body that you can also identify, "Hey, is there something systemically I can do as well as locally?" 
 
I've come across gynecologists who tend to try and do that. Either with oestrogen therapy and then probiotics, antibiotics or antimicotics in this case are, yeah, a mixed bag in terms of their efficacy. 

Andrew: Yeah. 

Jessica: But again, it depends really what's in your guidelines. Not being a clinician, the scientific answer would say try to find out as much as you can about the patient and their symptoms and how you could address that. 

But we don't really understand from the microbiome perspective how we can influence the function, in addition to the structure yet. And that's coming, but it's a bit harder to really understand how to apply that to a patient at this moment. Because we know so little, especially about Candida albicans or glabrata and so on, those types of infections.  
 
Andrew: Can I ask though, a comment was made by gastroenterologist in Sydney that the previous theory of candidiasis was that the candida grew in the bowel, in the large bowel, and then moved forward because of, you know, irritation, or just locale and proximity to the anus and it moved into the vagina from there, given that you had a terrain that was going to favor growth. So, you know, whether it was the period of the cycle, whether it was local irritation, whatever. 

And yet, this gastroenterologist said they've looked at heaps and heaps of samples and they do not find candida growing in the colon.  
 
Jessica: Well, I'm not so much aware of the work on candida within gastrointestinal environment. I do know that it can be found in certain places. I would imagine based on current sampling techniques that's mostly in the proximal or distal colon. I'm not sure about the small intestine or the rectum, but within the vagina, it is a normal resident. It is a pathobiont or commensal potentially. 

And Candida is actually a really cool microorganism because it has two states, two morphologies. One is called yeast and that's its more reproductive phase, and it has also a state called hyphae and that's its more pathogenic, virulent phase. And it switches between the two. And, I mean, that's what makes it very unique because some antimycotics are targeting a protein that might be only up-regulated on the surface of hyphae.  
 
Andrew: You're right. 
 
Jessica: Whereas within the yeast state, it can hide... 
 
Andrew: It's dormant, yeah.  
 
Jessica: ...it can reproduce, it can grow and things like that. It can go dormant, exactly. 

And you asked also about the transport of this organism throughout the body. There's been some really cool rat studies that have shown that candida can actually leach on or latch onto other organisms within blood vessels and the lymphatic tissue and travel throughout the body. 

So for example, they infected these rats with...let me think how it was done. I believe it was a skin wound or they had an isolated sort of bolus within an infection model. And they found that these candida had migrated ultimately to the kidneys of these rats. 

Andrew: Wow.  
 
Jessica: So, there's some sort of microbial highway in the body that we're not aware of at all. And candida is a really fascinating organism, as I said, but it's also very opportunistic. 

Andrew: Yeah. 

Jessica: And in the vagina we find candida overgrowing when there's a lot of oestrogen. We find when there's low or high pH, we find it in multiple situations. So, we don't really know why, but we know when.  
 
Andrew: Yeah. I guess another question I have, I guess, to wrap up. Is, you know how we've spoken about the gut microbiome or microbiota and sampling that, but normally when we sample it, we have a faecal sample. Well, that's not sampling what's growing in the gut. That's what sampling what's coming out in the faeces. Is there any work, has there been any work done on direct biopsy of the microbiota growing at various places throughout the human gut?  
 
Jessica: There has been limited work and there's quite some work that's been going on that I'm aware of right now. The challenge, as you sort of alluded to, Andrew, is that the small intestine is really difficult to access.

Andrew: Yeah. 

Jessica: And there's, for example, a couple of companies that are working on technologies whereby you swallow this little capsule and, you know, it opens depending on pH changes or, I don't know, with some other signal and it will take a sample, and then you take it out and you can analyse that. 

Andrew: Wow, wow, yep. 

Jessica: Most of the data we have to this point is from surgical patients. So different biopsies that have happened or colon resections, things like this. So we have data from those types of patients. But I hope, I hope, that soon enough we'll have the technology to be able to really understand what's going on in those other sort of more hidden areas of the gut. 
 
Because as you mentioned, you know, a faecal sample, depending on how you take it, is not really representative of, not even actually the distal or proximal colon. There was a group, actually, I think it was in Belgium...no. But there's a group in Europe anyways that showed that there's mucosal layer surrounding feces by the time it comes right towards the end and gets deposited in the rectum. And they're sampling and analysis of the microbiota, suggested that there was very little exchange of microorganisms between faeces and the mucosal biofilm that was on the rectum, for example.

Andrew: Right. 

Jessica: Suggesting that, you know, at a certain moment faeces gets, the bolus, gets sort of encapsulated by this mucus layer and that’s that.  
 
Andrew: There's so much more to delve into and I cannot wait for the podcast with you, Jessica. But thank you so much for taking us through what you've taught us today. Really, really important stuff.  
 
Jessica: Thank you very much, Andrew, for the opportunity. It's been also my great pleasures to have this chat with you, and I hope we can continue in a couple of more podcasts. Also to explore and try to translate this type of science for the rest of the people who are listening.  
 
Andrew: This is FX Medicine, I'm Andrew Whitfield Cook. 

Additional Resources

Dr Jessica Younes
Winclove Probiotics
Women & Their Microbes Conference

Research explored in this episode

Jimenez E, Fernandez L, Maldonado A, et al. Oral administration of Lactobacillus strains isolated from breast milk as an alternative for the treatment of infectious mastitis during lactation. Appl Environ Microbiol 2008;74(15):4650-4655



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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.