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In this sixth episode, Ruairi speaks with Dr. Alan Walker and Dr. Jens Walter about pervasive myths in microbiome science. Dr. Walker is a gut microbiologist at the Rowett Institute, University of Aberdeen, and Dr. Walter is a microbiome researcher at APC Microbiome Ireland and University College Cork. Together, they dissect common misconceptions in the field, ranging from the novelty of microbiome research to the idea of a placental microbiome.

Dispelling Myths with Dr. Alan Walker and Dr. Jens Walter

Dr. Walker and Dr. Walter bring decades of experience in microbiome research, tackling myths that have misled both the public and scientific community. Their expertise spans gut microbiomes, the evolutionary principles shaping microbial communities, and the impact of diet and environment on microbiome composition.

Historical Context and Modern Misconceptions

Dr. Walker discusses the longstanding history of microbiome research, challenging the notion that it is a new field. He highlights significant contributions from early pioneers like Antony van Leeuwenhoek and Louis Pasteur, emphasizing that foundational research dates back over a century. Both experts stress the importance of recognizing past work to avoid underestimating earlier scientific achievements.

The Myth of Inherited Microbiota

One prevalent myth is the belief that a significant portion of the microbiome is inherited from the mother. Dr. Walker and Dr. Walter explain that while initial exposure occurs during birth, the long-term microbiome composition is influenced more by environmental factors and stochastic processes than by maternal inheritance. They highlight the complexity and uniqueness of each individual's microbiome, even among identical twins.

Debunking the Concept of Dysbiosis

The term "dysbiosis" often implies a simple balance of good and bad bacteria. Dr. Walter criticizes this oversimplification, pointing out the lack of concrete evidence linking specific microbial imbalances directly to disease states. Dr. Walker adds that the concept of a universally "healthy" microbiome is elusive due to the immense variability among individuals. They advocate for more nuanced approaches in microbiome research and treatment.

The Controversy of the Fetal Microbiome

Perhaps the most contentious myth is the existence of a placental or fetal microbiome. Dr. Walter recounts the debate spurred by early DNA sequencing studies, which claimed to find microbial DNA in fetal samples. Both experts argue that these findings are likely due to contamination and emphasize the biological implausibility of a fetal microbiome. They caution against sensationalist claims that divert scientific resources and public trust.

Conclusion

Dr. Alan Walker and Dr. Jens Walter emphasize the importance of critical thinking and rigorous validation in microbiome research. Their insights highlight the need to challenge misconceptions, ensuring that scientific progress is built on accurate and reproducible foundations. This episode serves as a reminder of the complexities of microbiome science and the responsibility researchers have in communicating their findings accurately.

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Full Transcript 

Ruairi Robertson: Thanks very much, Alan and Jens, for agreeing to chat. All about myths of microbiome science, because I think it's quite a hot topic in the field, and we're going to go through some of these kind of pervasive myths that really dog not only the general public's thoughts on microbiome science, but also us researchers as well, and we are sometimes the ones who perpetuate them. So let's just start off, if you could both kind of just give a little introduction to who you are and what you work on and how you got into microbiome science. So Alan, do you want to start off and tell us who you are?

Alan Walker: Yeah, thanks, Ruairi. So I'm Alan Walker. I'm a gut microbiologist. I've been working on gut microbiomes for over 20 years now. And I work up at the Rowett Institute at the University of Aberdeen. And we are mostly interested in how what we eat impacts the microbiome and then in turn how that impacts our health. But we also do various other research looking at how our microbiome protects against pathogens both in humans and in animals. And basically anything functional. We really want to work out what these bugs are doing. So, as well as sort of profiling using these modern sequencing approaches, we also do a lot of sort of in the lab based work with the bacteria to try and mechanistically work out what some of these little microbes are doing in our guts. So, yeah, varied research. Been doing it a long time. It's enjoyable stuff.

Ruairi Robertson: Right. And Jens?

Jens Walter: Hi. Thanks for having me. So I'm Jens Walter. I'm with the APC Microbiome Ireland and University College Cork, here in sunny southern Ireland. I'm also in this field for quite a while, like Alan. So I'm a microbiome researcher for probably now, we have 23 years interested in how gut microbes evolve. And I'm interested in kind of basic ecological principles that shape microbiomes. And then I try to apply this to modulate microbiomes. And I'm interested in microbial-based modulations like probiotics and FMTs, but I'm also interested in dietary modulations and using diet and nutrition and prebiotics and fiber to achieve some rational modifications to microbiomes. And this is probably where Alan and I overlapped the most and have also overlapped the most in the last, it goes back 15 years, I remember when we ran into each other on a conference where we had essentially the same post. So, yeah, pleasure to be here and to have that conversation.

Ruairi Robertson: Great. So, you're both kind of, I think, well-renowned for trying to bust a lot of these myths that persevere in the microbiome world, both in the public realm, but also in the kind of professional realm, I guess, if you want to call it that, within the community of science, of microbiome researchers. So we're going to run through maybe four or five of these more prevailing myths. So, Alan recently wrote a paper on this in Nature Microbiology, kind of going through each of these myths one by one and busting them, whereas Jens is well known for busting the myth of the placental or fetal or prenatal microbiome, which we'll touch on. So maybe Alan, I can start with you. The first myth that we're going to discuss is that microbiome research is a new field. We all like to say that to kind of make it out we're these big pioneers, you know, and we're doing something that's cutting edge and really new. But you know, microbiology research has been going on for years, you know, for centuries since Anthony von Leeuwenhoek saw microbes under a microscope and Metchnikoff discovered the role of some commensal organisms. Maybe you can talk us through that a little bit, the history of microbiome research and why that is a myth that it's very new.

Alan Walker: Yeah, no, definitely. So, I mean, you're quite right to pinpoint Antony van Leeuwenhoek. He's the first one to ever see a microbe down a microscope that was hundreds and hundreds of years ago. You know, microbiology as a field really kicked off with pioneers like Louis Pasteur, which people will have heard of, I'm sure. And, you know, just working out the roles that microbes played in disease. That goes back well over 150 years. I think if you look into something like E. coli, it was first isolated back in the late 1800s as were bifidobacteria, these very beneficial microbes associated with health and babies. And so, you know, this is well over a hundred years ago, people were doing very valuable, vital microbiome research. I mean, I'll be honest, it was much more of a cottage industry for a long time. And so when I was doing my PhD, back in the early 2000s, I think you got maybe one paper a month, lucky, and you know, even in the room in microbiome of the cow you were excited because at least it was a gut paper. And then I think I checked last year, it was well over 1000 papers every month. So, you know, it's undeniable that the field has completely gone crazy. You know, there's been a huge revolution, which is underpinned by modern molecular methods to study microbes. But it's not a new field. It goes back many, many decades. And I think The thing that really got my goat a little bit was when we talk about it being a new field, we actually do a disservice to lots of really, really nice work that was done before the advent of these modern sequencing approaches we use. So really it was just an attempt to correct record on that to pay homage to some of the really pioneering researchers that came before us. And just acknowledge that although we might like to claim a revolution race, like you say, we are standing on the shoulders of quite a lot of giants.

Jens Walter: Yeah, if I could add to this, you know, I've been as I fully agree, you know, and some of this is even real microbiome science, you know, I've just had to read up on early life microbiome for a review I was writing, you know, and so I read a few review papers, you know, that cited some of this early work by Tissier on bifidobacteria and formula feeding and, and it was him and also others, you know, they seriously already knew that formula fed infants have more diverse microbiomes, which is actually, I've just seen being presented in recent, I think even in titles of recent papers, as something new. So these guys with their microscopy, found this out 120 years ago. And I think, and then it continues on with all the germ free work, which goes back, I think to the 60s, where obviously this was designed causal role of microbiomes. And then we had nodobiology, where we put specific microbes into mice. Again, 70, 80 years ago. So this was real microbiome research and some of these findings stand and I'm actually sometimes fascinated and sometimes even embarrassed and I realized something that I thought is novel and I wrote in a paper and then I find out Rainier Dubois. I wrote on the evolution of lactobacilli, for example, and did a lot of population. genomics to figure out how these microbes evolve. And then I look back into an old Rene Dubois made from 60 and saw actually the final conclusion of my 10 years of work actually essentially being articulated there. So yeah, as Alan said, it's worth to look back, give these giants credit, but also we can learn something. And methods that they've used, microscopy and germ-free technology, they are still very, very valid. They are really not outdated.

Alan Walker: I totally agree.

Ruairi Robertson: How much of this is down to the fact that we now have a term for it? You know, this term microbiome is, you know, if you put it in the title of a scientific paper, that seems to bump you up in terms of how much it's read and the interest in it. But the same in the public realm as well. You know, people who have no interest in science before will have probably heard of the term microbiome, and it's mainly it's links with gut health. So is that the reason that we think that it's a modern science? Or what is it about this term microbiome that has created or fed into this kind of revolution, per se?

Alan Walker: Yeah, I would say, yeah, I think branding does help a little. I can't deny it, you know, I think. But I do just think it's a byproduct of just the increasing interest that comes from scientists. You know, it's... Nope. one paper a month to a thousand papers a month, you're learning a lot more, right, in that time. Now, okay, we knew a lot already, but you are exponentially increasing what is known. And every time something, you know, landmark happens and something exciting, it builds to that sort of snowball of excitement as it rolls down the hill. And so it becomes obvious, right? So I do think, you know, yeah, the branding helps a little and microbiome is something that I think the general public are able to latch onto as a concept. But yeah, I just think it's a virtue of just how much work has been done in the field now, you know, something you... is happening all over the world every day and it captures the attention. So I do think it's just it reflects the effort that's been put in there.

Jens Walter: And then perhaps, you know, modern technologies made a contribution. So as much as I still think microscopy and term-free work is in the microbiology is incredible, valuable, you know, it's that the fields. And I remember I'm that old that I remember the days where we really struggled, you know, with just, you know, characterizing communities, you know, where we did. denatured, ingredient, child electrophoresis, or cultured, you know, thousands of isolates. So I do think that the modern sequencing technologies opened a lot of doors also, and then, you know, a lot of researchers started applying them, you know. I think technology had a role in that.

Alan Walker: They're amazing technologies, I agree. I mean, they've unlocked so many doors to experiments that literally would have been impossible 10, 15 years ago. They are now routine, you know, people do them every day. So, I mean, yeah, you cannot understate. the impact that technology has had on the field. It has truly been amazing. But like I say, what we try and do is keep one eye on what's done in the past. And as Jens alludes to, a lot of these traditional methods, culturing for example, they're hugely important still today. I think if you rely just on sequencing, you can learn so much, but there are sort of biases involved in that. Yeah, there are limitations to what you can do with a sequence as opposed to having a bug in a lab you can do experiments with. So for us, We use a combination of both. We use the modern sequencing methods, but we also use the more traditional culturing and try and putting the two together to really elevate what we can learn.

Ruairi Robertson: Yeah, that seems to be an interesting trend now. So for people that are not in the actual research field, you know, previously to study microbiome research, you know, research would have to grow up all these microbes in the lab and in what we call culturing. And now with this DNA sequencing technology, which came about as part of the human genome project mainly, or at least the advances in it, that led us to be able to, you know, do all this work that you're saying, which is amazing, look at DNA bacteria and read them in that way. But interestingly, there's quite a few researchers now who are reverting back to what they call cultureomics, you know, of course, they have to brand it with a name as well. And kind of moving back to these older techniques, because they're still very valuable. and we still need to know how different microbes grow, which we can't learn by just reading their DNA, and we have to actually grow them. So there does seem to be a nice marriage of these more modern techniques and more classical ones that feed into this modern research.

Alan Walker: Yeah, absolutely. It's been quite nice. I mean, we've been growing bugs up in Aberdeen for decades now. And for a long time, we're quite unfashionable and it was hard to get funding and stuff. But nowadays it's come around full circle and I think people have realized, oopsies, maybe we do need those bugs in culture to do some experiments with them. So yeah, it's been quite gratifying to see culture come back into Vogue, yeah.

Ruairi Robertson: Okay, great. Okay, we're gonna move on to the second point or else we could hear for about three hours I think. So one of the kind of prevailing myths in the microbiome and I have to say I'm very guilty of having perpetuated this, I know Alan has mentioned that he has as well, Jens, I'm sure you have as well. I do, yeah. Is that we have a kind of 10 to 1 ratio of bacteria to human cells. And we're all guilty of probably not reading up on this enough and just kind of perpetuating a myth that we didn't have the evidence for. So Alan, I think you've read up a little bit on the history of this and where this figure came from. And then maybe we'll talk about what the real numbers might be.

Alan Walker: Yeah, I mean, I think it is a nice example of how mythology can get embedded in the literature. And yes, hands up, I also have used that quote, sort of unthinkingly repeated it. I've read it lots of times, so it must be true. And I think partly this is a virtue of the fact that there is so much microbiome literature now that no one can read a thousand papers every month. It's impossible. No one can go back and read every single paper that's been published in the microbes for the past 150 years. It's impossible, right? So we do rely a little bit on received wisdom from others. And sometimes that received wisdom is not always based in fact. And so in this particular case, there was a nice study done a few years ago now where they'd actually gone back and looked to see where that came from. And it was a back of the envelope calculation that some guy who very well meaningly had just done as a sort of estimate and probably did not intend for this to become dogma that was repeated. you know, literally ad infinitum around the world. So I think, you know, I don't, this is a problem just with microbiome science. I think it's a problem with any area of human endeavor. You can't literally go back and fact check every single little tiny detail. You just don't have time, but it does go to show that actually, you know, some things we think of as true may not actually always be the case. I think if you ask me what the actual number is, then it will vary from person to person, depend on how big you are. Number of cells you have in your body depends on how big you are. so much stool you have crammed in your colon. If you're very, very backed up and constipated, you could have up to a kilo of stool in there. If you're a baby, you're going to have very little stool in there. So the actual ratio will probably vary quite a lot from person to person. We now think it's closer to one to one or three to one in favor of the bacteria. But as I say, that will vary. But it certainly seems unlikely to be as much as 10 to one in most cases.

Ruairi Robertson: Yeah. And Jens, I suppose these calculations are all just based on bacteria. So there probably are very impressive numbers there if we did really want to, you know, compare our human cells to our bacterial cells. So, you know, first of all, what do we know about viruses, fungi, all these other microbes, which are less studied? And secondly, doesn't matter why is it important to know these numbers? Or is it just so that we can all use them in our first slide of a talk and to impress people?

Jens Walter: So to your first question, I'm not a virome person, but if I talk with my virome colleagues here at APC, I have a few of them. You know, they, you know, I think have good evidence that the virome outnumbers actually the bacterium, you know? So if you just wanna play a numbers game, you know, then obviously, and you use viruses, then you can generate ratios that are probably more impressive, you know, even than the 10 to one, you know? I have to say this is one myth that at least didn't get me going, and simply just because I used it a lot and I used it falsely, I also changed to more one-to-one, but the reason why it doesn't get me going is because the general message is still, because even in a one-to-one ratio, is impressive in that it just shows you the level of symbiosis that we maintain with microbial communities. And this is also where I use it in my early slide. So if you think about evolutionary, why do mammals maintain, touch a high amount of microbes? That's not necessarily, there are life forms that prevent microbes from colonizing, at least to a larger degree than we do. So obviously this has a biological reason in showing that there are that many microbes and specifically in the colon of humans. It's one of the densest, I think. microbial populations on earth. You know, that really shows you that this is a fundamental part of human biology. And this is where I used the message. And I think the message hasn't changed, you know, only because I'm going from 10 to one to one to one, it still means, you know, these microbial populations are, you know, playing important roles. So that's just one reason why it's one of the few myths that don't get me going because some, some do.

Alan Walker: I totally agree. It's a huge number. No matter how you can cast it, it's massive numbers of microbes. And as, as Yen says, of all the places a microbe can choose to live on the planet, our backsides turn out to be one of the most popular places, for good reasons, as Jens had said. It's a nice stable environment for bacteria, constant environment, pretty much constant supply of nutrients. If you're a bacterium, it's actually a really, really nice place for you to set up home. So yeah, I agree with Jens, the number is almost irrelevant. It's a lot. That's what counts.

Ruairi Robertson: Yeah. So we've kind of touched on the less dangerous myths to kind of get going and we'll move on to the more dangerous ones and more controversial ones. So kind of moving up the dangerous scale, I suppose, is another one you've spoken about in your research paper, Alan, is that the microbiota is inherited from the mother. So, I mean, this is of course, partially true. and we do inherit certainly in early life, but it's not as in any way as heritable as our genes. Maybe you can touch on that and what we know about heritability of a microbiome.

Alan Walker: Yeah, no, it's absolutely true. I put that into the article because it's an example of the nuance, which is quite often lost and isn't required when we talk about gut microbiomes. As you say, it's undeniably true, when the child is born, it will pick up some microbes from its mother. Anyone who's ever been at a birth knows it's quite a messy experience, bacteria will be exchanged. But what actually ends up sticking around inside a human's gut, particularly long term, is only to a very small proportion determined by that first exposure. Most of what ends up in our gut is established over the first few years of life. Interestingly, a lot of that seems to be kind of random. They don't quite understand where these bugs come from and how they assemble. It's one of the great unanswered questions in microbiome research. But every single human being ends up with a pretty unique combination of species in their gut. Now they're all drawn from a pool of bugs that colonize humans, but you end up with a sort of a subset of your own. Think of it as your own quite smelly fingerprint, I guess. So, you know, that process does happen via the mother, like I say, to some extent. It will also happen from the environment. The kids are exposed to very early in life. Some come from father, siblings, household pets. But even people, identical twins, grown in the same household together end up with a unique microbiome configuration. Same environment, same genes, same everything, and yet they end up with a different microbiome structure. Now, it's more similar to each other than to some random person off the street, but they are still unique. And so like I say, there's this kind of... pervasive myth, which I have to say is not normally in scientific publications, it's in sort of more public facing things that, oh, the baby gets its microbiome from its mother. It's actually not true. It gets some of it, but most of it comes from other sources. So that was just an attempt to sort of clear the record on that. And you know, that may have major implications for health of the growing infant and for the rest of their life, because that early window when the immune system is first exposed to microbes and is basically learning how to react as an immune system. may actually be very important. And so, so yeah, I think it's really important we do understand how microbes assemble in children. And yeah, and the mother is only part of that story.

Ruairi Robertson:: And Jens, do we know because there are a few bugs that have been studied in these, you know, big genetic studies, which do seem to be more heritable than others, they are dependent upon What do we know about them? And maybe from your perspective, from an evolutionary perspective, why is it that these bugs are the heritable ones and what role do they play in health?

Jens Walter: So, first let me mention, I think this is an example of just bad terminology being used, scientific terminology, because inheritance and heritability, they are scientific terms and there is a very strong... literature around them, you know how you determine again talking about goes hundreds of years back, perhaps 100 years, yeah, but heritabilities, you know, so it's an old, it's a very old concept, you know, just to throw this now on the microbiome, you know, it's just scientifically inaccurate, as Alan points out, yeah, in terms of there, you're right, you know, there are certain microbes, you know, for which you can detect heritability. There's also, you know, a certain influence of the host genome and then the composition of the microbiome that it samples. But this effect is remarkably low actually and I think it surprised scientists how low it was. I think if you now look into observational studies, it's something between 2 and 8% of the community in an adult can be explained by the host genetics and as Alan pointed out you know although monozygotic twins are more similar they are still almost as different as non-related individuals so they so I think ecology is more important you know than genetics probably and I think this is where the mother I think becomes quite important you know because it's all about you know where do you acquire these more organisms from and then to some degree also how does this I worked a little bit on priority effects, which I find fascinating. You know, that, you know, if, you know, if early colonizers, you know, have actually both an advantage for themselves, but they also shape then, you know, the trajectory of the, of the assembly, you know, so. there the mother becomes quite important because a lot of these early acquisitions are from the mother. It's very, very able, as Alan points out, because not every vaginal birth comes with a huge fecal inoculum. Obviously, we have C-sections and antibiotics used, so that brings in even more noise. But there's some good evidence now that strains that are acquired from the mother during a healthy vaginal birth actually stick around significantly longer than horizontally acquired strains. So there is some truth to it. And again, the mother is important, but it's just inherited is just the wrong scientific word for this.

Ruairi Robertson: Yeah, because I mean, I guess that's because there's such a strong environmental influence. So they're probably the right word is acquired and they persist. But there's nothing to suggest that they can't then disappear or, you know. be removed.

Jens Walter:Then the kind of the maternal influence on all of this, you know, and then you know, you have vertical transmission, horizontal transmission, it's probably even more complicated than this, you know, I'm having discussions at the moment around, you know, these terms, but obviously they are different and they actually influence different microbes, you know, a lot of... I think Hillary Brown did some really... you know, interesting work with Trevor Lawley, where they showed, you know, that a lot of the early vertical transmitted bacteria, they are non-spore forms, you know, so they are much more reliant on coming from the mother, you know, and if that is disrupted, it's probably a problem while then spore forms, you know, become dominant and diversify the microbiome later, six months, seven months, you know, they are, most of these species are actually spore forms, which already tell you something about the evolutionary strategies of these organisms and how they are shaped by the ecological you know, characteristics. All of this is fascinating. So, and this is why it's important, you know, not just throw it all out, this is inherited, you know, it's more complicated and it's more exciting than that, you know, and I think you have to figure out, you know, what exactly happens.

Alan Walker: I agree with Jens. You know, people talk about that we are, as a host, are almost selecting these bugs to pass on, but as Jens says, the microbes themselves have a role to play in what gets passed on too. You know, it's how they transmit, is kind of an under... appreciated and probably largely ignored aspect of how things are passed on to other humans from generation to generation. So I agree 100% Jens.

Ruairi Robertson: And do you think Jens that has changed with industrialization? You know, is our environment playing more of a role now than it did historically? Or how has that changed from your kind of evolutionary lens?

Jens Walter: If you view it evolutionarily, we have just introduced a lot of hurdles of essentially transmission of these microbes into modern life. Sea sections and antibiotics and formula feeding are probably the most obvious ones. But if you think about evolution, I did work in rural Papua New Guinea where the drinking water isn't really sanitized and everything. I think actually the entire ecological system of a microbiome has probably changed from, you know, a highly, you know, inter, you know, correlated, you know, meta community where microbes are quite readily exchanged, you know, which comes with a lot of disadvantages, I have to say. I don't want to, I don't want to, you know, romanticize this whole thing because that's why these communities have huge amounts of infections, you know, but, but that is still the, the context in which this microbiome is evolved. And probably actually when we talk about transmission, You know, probably maternal transmission might even be more important today than it was in these days, you know, because, you know, there was much more group exchange, actually, you know, between individuals, you know, now we're living in these highly sanitized, you know, environments and, you know, then there's a C-section antibiotics, you know, and then you have these, these large delays in microbiome acquisition, which we start to understand. some degree. So yeah, I think first, yes, it changed dramatically. We have some good evidence that this also influenced the prevalence of certain specifically highly evolved early gut microbes like this bifidobacterium infantis, which is lower in industrialized populations. And then this might well predispose us to certain pathologies, which we as well. It's hard to get causal information on all of this, but at least the The overall observational and evidence from epidemiological studies, I think, is quite strong.

Alan Walker: I mean, I think it really does worth repeating that point from Jens, because I think there's a lot of romanticization in urbanized societies that the older way was the best way. In the older way, people were dying off in their droves, usually as infants. The average lifespan of people, historically, is obviously way less than it is now. So objectively... The higher hygiene environment we live in now, on average is much, much better for health. We live much longer, we generally stay healthier for longer. The downside is of course that, you know, well, I guess, essentially everyone had worms. Do you want to walk around with worms in your gut? I particularly don't. I mean, I think most people would feel the same. You know, that's our ancestral healthy condition and it's not really particularly healthy, if we're being honest. So... I think the problem is, you know, with the sort of disappearing microbiota hygiene hypothesis type situation is that also we flip a little bit into a situation where our immune systems attack us instead, autoimmune conditions are, you know, through the roof in more urbanized societies. Ideally, you want that happy middle ground where you have the longevity of the health, but you don't have the autoimmune conditions. And I think, you know, we're not there yet and maybe we won't be there for a while, but that clearly that middle ground. is what we want to aim for, not the ancestral going back to rolling around in the dirt having worms in our guts, because that's inherently dangerous. People die from lots of infectious diseases. So yeah, that balance is important.

Jens Walter: But the nice thing is that the middle crown could in theory be achieved, because once we understand what are the drivers, and we are not there yet, we are not even close, but once we understand it, obviously, in the simple world, if it's really... infections and symbionts and we just interrupted both of them for the good and for the worth, then we can bring the symbionts back and I guess some research goes into this direction and even Ellen mentioned worms and parasites, there's even stuff going on in this area that people are looking at, larvae and things to bring them back and again I'm... It's all in its infancy, but you know, there is exciting stuff that's ongoing.

Alan Walker: Yeah, exactly.

Ruairi Robertson: Yeah, I guess the big question is, you know, where do we acquire all these microbes from? And we say the environment, but there isn't enough known about what is the contribution, as you've both pointed out. So we know that from these studies, maybe in the first few months of life, 10, 20% might come from the mother. The rest is a... you know, is it random? Is it depending on the environment? We don't know. But I was listening to some interesting research last week at the conference, we were at Alan, about studying children just before they go into nursery and looking at how the microbiome of these kids changes so rapidly based on this new environment they're in. And suddenly babies who've spent, you know, their first year or so of life or first few months of life just with their parents and close family, they're suddenly acquiring and sharing microbes with all these other kids. And their microbiomes become more like the children, you know, in their environment. They become more like the staff working in the, in that environment. And then they bring home and pass on some of these, these bugs to their parents, which, you know, some of which are good, but some of which, of course, is the reason that we are all getting sick. If you have young children, you know, because of the requirements.

Alan Walker: Yeah, norovirus outbreaks and things.

Jens Walter: Can I jump in here? I wonder if the term environment is actually good. Because it's not really environmental. If you think about all the microbes that are out there, we have soil and ocean and water and everything. That could be seen as the environment, but if you said they are going into nurseries, they are getting microbes from other humans. I think there is enough selection pressure. For example, in our Papua Nogunian study, as much as there are differences to Western populations, a fascinating finding was that actually 93% of all the the American controls and the Papua New, rural Papua New Guineans, that shows there was a massive overlap between the, so it's not that random. We do a sample of human microbiome and then obviously there's a lot of good work in my years that was done by Jeff Gordon, where they put soil microbiomes and then human microbiomes and then see how the rodent microbiome, when it comes in what happens. And the rodent microbiome replaces human microbiome in the mouse, you know, so if you think about this, so I don't think these are really, at least I wouldn't call them environmental microbes. Again, I think I like the vertical and horizontal transmission more and then again, of course, there is exposure to some environmental microbes, but to what degree... they then make a substantial part of the microbiome. I'm doubtful, you know, because I do think we are looking at primarily human or the human microbes there, you know?

Alan Walker: Yes, I guess. I agree. The human microbes in the environment, right? So yeah.

Jens Walter: Exactly. So what determines is that they're not, there are bugs you're saying that prefer to live in human guts than in other animals or, you know, on inanimate objects. So what determines whether I acquire those from Alan or Alan's acquiring them from me? You know, I mean, I would.

Alan Walker: Yeah, I mean, I think it's a good question. It's one that's not fully answered, but I think you just well, one has to be the chance to transmit if you and I are now. You're not going to give me your bugs down the end of this Zoom call. Right. So and I think, you know, an example of that is Prevotella. So Prevotella are very abundant in communities and more rural less urbanized societies. They're much less abundant in urbanized societies. And partly that's thought to be driven by diet, you know, the kind of food we eat. But actually I do wonder if that is just exposure to farm animals, because Prevotella are really common in ruminant farm animals, for example. And most people in an urbanized society are not in daily contact with the farm animals. You know, they just don't see them. So there's never that chance for that microbe to transmit to them. You know, if you look at, you know, rural communities like the Amish in America, they have far higher Prevotella than urbanized counterparts in the same country. And one of the major differences is that they are mingling with animals all the time. So one is that opportunity. If you're never exposed to a bug, you can't pick it up. But then two, as Jens has alluded to, is that background that bug is going into. And that founder effect, what else is there? And that's so important as to the chances of this new bug coming in, finding a place to set up home. And so if there happens to be a niche available, you know, there's a substrate that the rest of your microbes aren't breaking down. but that one can, then bingo, it's got its slot. This bug can find its home inside the gut. And once it's in, that's it, it can hang around. Most bugs that come in that are novel to your gut, your body will kick them out. You know, colonization resistance will kick in. And yeah, and this applies to probiotics too, of course. Most times when you consume a probiotic, your body will kick it out, just as if it was kicked out of a salmonella pathogen, because it doesn't belong to your body, and the rest of your microbes will outcompete it. So, I think opportunity is one factor and then the underlying baseline microbiota that's already there is the other major factor. But Jens, you may want to drive in on that.

Jens Walter: No, I agree with all of this, you know, but if you then also look into basic ecological literature, you know, they will actually tell you that a lot of ecological processes are just inherently stochastic. Yeah. You know, like priority effects, for example, but also others, you know, and then, you know, if you have... stochastic ecological processes that determine how your community looks in the end, you know, then this is probably one of the main explanations, for example, especially for the differences in monozygotic twins, you know, because at least in terms of opportunities, most of them have the same, you know, but then stochasticity still kicks in, you know, the early colonized. So, you know, when did you acquire which microbe? When did these microbes adapt? You know, microbes evolve, you know, over a short period of time. evolved through mutations, which are again stochastic. You know, I think there's a lot of stochastic, both ecological and evolutionary processes that then, and we look into this to something we in mice, you know, when you use germ-free mice and you actually transplant all of them the exactly same microbiome, they go off in all kinds of directions and we've published this and you can see them, you know, then within a cage, they're all quite similar, but between cages, they become different and between isolators, they become even more different. So think about this here. We have all the same opportunities. They have all the same exposure and these gavages work reasonably well. Doesn't matter. You know, the stochastic elements still kind of prevail and then you get this variation between animals. And I think it's very hard to predict this. And I would also say we don't understand it fully, but it definitely happens.

Ruairi Robertson: Yeah, well, yeah, those priority effects are fascinating. You know, the order of microbes that colonize and take that opportunity. Okay, so I think we're gonna move on to kind of ramping up the danger list or kind of the more controversial myths in microbiome science. One of them is around this term dysbiosis and the myth being that there is a balance of good to bad bacteria in... let's say the human gut. And that this balance is what determines whether we get sick or not. So Jens, I think you're probably the best person to talk about this at first anyway, thinking about ecology and balances of different types of microbiomes. Why is this a myth that this good and bad balance, why is that not true?

Jens Walter: Well, there's so much here to unwrap, you know, so and people are way more articulate than I have written about this. But I think it starts already with the term. So the term, you know, is dysbiosis. So meaning it tells you there is a dysregulated biology here somehow, you know, so it has a functional consequence. And in most cases. We simply don't know this, you know, because what we do is we seek when we compare, you know, a disease state with a healthy group, you know, and then we say, oh, there's an altered community. And then, you know, we speculate like crazy, you know, the lower diversity, you know, as you said, the good versus bad bacteria. Some of this makes a lot of sense, you know, but it is, it's in most cases not established that this is, in fact, in a dysbiotic state, you know, so it is really just altered at that moment. you know, you would have to do a lot of additional experiments, you know, to establish that it is actually causally implicated in the disease. So probably the main challenge that I see with the term, you know, that it's just, it's the move to assuming that it is actually causally implicated is just too quick in the microbiome field. And that's dangerous, you know, because... And now comes ecology, this dysbiosis might be a bystander. Some people who suffer from a certain disease eat very different, that will actually alter the microbiome. It might be a consequence of the pathology. It could be different reasons for this. So there is a lot of things that could alter a microbiome without actually having then causing consequences for the host. So the reason why this is important is, we are now starting mingling with this. We are starting to modify it. We are doing FMTs, which are really now used hundreds probably of different settings for which the so-called dysbiosis are detected. The question is what are we actually trying to modulate there or repair? So I do think that this comes with a danger to just do the wrong things. And then in terms of good versus bad, some of this is just very simplistic, and then also context specific. Obviously there are opportunistic pathogens. I think nobody wants a bloom. of Enter bacteria, which you see in a lot of these altered microbiome. But then there was other things, you know, actually think we mentioned Prevotella already, I think I can tell you 10 dysbiotic settings in which prevotella is enriched and 10 symbiotic settings or dysbiotic settings in which it's reduced, you know, so that doesn't tell us anything. What, what actually prevotella does, and it's probably even dependent on, you know, the situation in, in what that occurs. Yeah.

Alan Walker: I think my own take on it, Ruairi, is that the concept is quite appealing conceptually, right? It's a nice idea that, oh yeah, we've got this nice balance. It's just, it's pseudoscientific because what does balance look like? You tell me what is a balanced microbiota. I mean, I think in most cases, we've been searching for this for 20 years in the field. And what's a healthy microbiota? A healthy microbiota for me is one that's not making you overtly sick. And that's about as far as we can go. I think... Because humans are so frustratingly available in their content of microbiota, it's been almost impossible to find a signature that is always correlated with disease. I can't look at a microbiota profile and say you're definitely going to be ill. It's just not possible. You can talk about probabilities maybe, but nothing that has the required specificity for clinical use. And that's where dysbiosis falls down for me. You know, as Yen said, if I had higher entrobacteriacea in my gut, that's a pro-inflammatory group of bacteria, I could definitely see how that wouldn't be good. I could see how that might be triggering inflammation in my gut, which might in turn be reducing my diversity and all sorts of things, you know, but beyond that, you know, how do you treat it? We're just not there as a field, and I'm not entirely convinced we ever will be there as a field because, you know, because it is so variable from person to person. So applying a blanket treatment to every human being and expecting it to work is probably unrealistic. Jens' point about context dependence is absolutely bang on. You might have a bug in your gut, which might be super great at killing off invading pathogens, but might also be releasing something that gives you bowel cancer in 30 years time. So is that a good or a bad bug? Context is very much dependent. And so it's just really complicated, right? The microbiome is a hugely complex entity that varies hugely from person to person. So trying to distill it down. into this simplistic, oh, you've got dysbiosis, we can cure it with X, Y, and Z. That's where the danger comes from. It's balancing that promise of the microbiota with what we can actually deliver at population scale. And that's why I have some beef with dysbiosis as a concept. Yeah, it's almost pseudoscientific at this point.

Ruairi Robertson: Yeah, I remember doing my PhD and the head of the ABC Microbiome Institute where Jens works. at the time said we were all banned from using the term dysbiosis in any paper or any... So this is the individual I referred to in my first sentence. So what I'm kind of alluding to is, is a terminology thing. We have a responsibility to communicate both to other researchers, but also to the public that there are changes that are associated with disease and we're trying to adapt them, we're trying to intervene. How do we change that if we don't wanna use this term and how do we simplify our research to reflect that there's a change in this microbial community that is associated with the disease and might be causally linked to a disease if we don't wanna use the term dysbiosis and if we don't wanna say there's a balance of good and bad.

Jens Walter: I can come in. Probably first and then you can jump in afterwards. So again, I don't actually necessarily have a problem with the term dysbiosis. I have a problem with it using it for every altered microbiome, you know, that is out there, which is often the case. So again, I'm actually quite curious what Alan thinks about this, because I know he worked a lot on C. diff, you know, and so, but in C. diff infections, you know, I can live with the term dysbiosis. And the reason I can live with it is because I think we have good evidence. that the altered microbiome is causally contributing to the pathological state. So it is essentially, it is really a dysregulated kind of biosis. The reason why we know this is, there are different experimental design. I think Ellen was on a paper in MICE a few years ago that I liked quite a bit. But the definite proof for me is that fecal microbiota transplantation actually is hugely clinically beneficial. And this is quite well established and it actually repairs the altered status, good evidence that these recipients look more like a healthy microbiome in the end. So in this case, but this is years of research to establish these causal connections, then I'm fine with dysbiosis, but the struggle is this is probably almost the only example at which I'm fine with it, because in all the other cases this is just not established.

Alan Walker: I think you're right, Jens. I also don't use the term dysbiosis anymore. I turn to go for the equally really perturbations, but what does that also mean? Do you know what I mean? And so I do think terminology as a whole is a problem for the microbiome field. And if you allow me to go down a tangent in a second, I will. But I think it stems from trying to distill a very complex situation down into a simple sentence that can be understood. And as I tried to allude to earlier, there are very few simple stories in the microbiome where actually if you make a simple statement, it will be true in all cases. And so the example Jens gives is C. diff disease, when you've got a really perturbed gut environment, the pathogen takes advantage of that situation, causes disease. The way to cure that is to restore a complex microbial community. An undefined one, it turns out most fecal donors work equally well. So it doesn't have to be a set type of microbe. But again, it stems from that. that desire to take a complex thing and turn it into something a bit more palatable. You know, probiotic is another example. We use the word probiotic all the time. It's a meaningless term because probiotics include literally hundreds of different bacteria from completely different branches of life with completely different activities. And we branch them all together and group them together, sorry, into one word, probiotic. And, you know, we don't do that with any other type of intervention. We don't say... You know, I've got a headache, right? So I'm going to take aspirin. Oh, you should just take heroin. They're both painkillers. They're both exactly the same, right? That's what we do probiotics. Take a lactobacillus, take a bifida bacterium. They're both exactly the same. They're both probiotics. They're completely different organisms with different mechanisms of action, you know? And even down to the species level, you know, chihuahuas and rock violas are both dogs, but you're only picking one to guard your house, right? It's the chihuahua because they're vicious, right? But you know, it's... We do this all the time in microbiome research. We try and distill really simple complex things down into sound bites. And the sound bites very rarely are true. And that's the nuance that I repeatedly keep coming back to that when we tell the public microbiome stories, some of it is true, but most of it is nuanced and needs a lot more clarification.

Ruairi Robertson: Well, I'll try not to distill your using heroin as for a headache down into a sound. Yes, I do not clinically recommend that. I mean, it would probably work, but yeah, it comes to significant side effects, right? So, yeah, terminology is a problem in the field.

Jens Walter: Yeah, I think to answer your first question, it is a problem. Yeah.

Ruairi Robertson: OK, I think we should move on to the last example of a big myth that we're going to talk about and probably the most controversial. And I think I'll start with you, Jens. So there's a huge, well, there has been huge debate in the field, which I think you would argue is now settled. That humans are colonized with a microbiome prenatally before they're born. And therefore that there is a placental microbiome or a fetal microbiome. So maybe if you can start off telling us how this myth began from what science and why it's not true.

Jens Walter: So let me start with this statement that I think it's settled. So I was at Probiota talking about probiotics. I was at Probiota two weeks ago in Milan and they actually put a question up, room of 300, 400 people, a lot of commercial individuals, but still a certain scientific background. And they put up the big, it was the only question I think they put up in the entire conference. It was, are we colonized before birth? And I think that it was A, B, and C, and it was no, we are not. B was I don't know, and C was, oh, definitely, and microbes are everywhere. And that's exactly what it was framed. And guess what happened? 51% voted for we are colonized before birth. So it's depressing. That was funny because then there was, and that happened actually while there was a panel discussion where three of the scientists were actually in favour of not having a fetal microbiome. So as a meaning, it wasn't really that the audience was really kind of motivated to say this. No, I wouldn't say it's, I think scientifically it's settled for me, because I do think the evidence is overwhelming, but who am I to make a decision as a scientist... This is the idea of a scientific debate, you know, that you can't make that decision for yourself, you know. But to come back to what you said, so this is a... I got involved quite a bit and I think I wrote probably some four papers or so and sometimes I wondered, you know, why in the hell am I actually involved in all of this? Because I don't really work on it, you know, I don't do placental sequencing, I didn't do fetal sequencing. But the reason why I got involved is because I really, it really concerned me, you know, and it really... bothered me to some degree because I thought we've talked a lot about this acquisition of the microbiome early in life. So for me the fetal microbiome would change everything. Where do we acquire microbes? How do they interact with the immune system? The timing of all of this, the ecology of all of this, all of this would actually be different. Even down to... you know, mechanisms and anatomical features to prevent microbes, you know, from penetrating tissues and things, all of this would be altered, you know. So I think it's a really, it's something that really would change a lot of things how we see it, it would confuse people and it has confused people, I think, to a very, very large extent. So just to give you a little bit of context, we thought the people fetus was sterile and this became well-known scientific knowledge through actually the application of the derivation of germ-free animals in the 60s and then it continued. And then it was all challenged by these new sequencing techniques that we were just mentioning as being these massive breakthroughs. So obviously even they come with a downside because individuals were starting to oblige them. applied them without really the necessary controls and probably we didn't even know that they were necessary in the beginning. And then they found all of these microbes in placentas, in fetal samples, in amniotic fluids and that happened around 2014, 2013 probably the first. And then this field emerged, it was a field or is probably still a field with hundreds of papers doing the sequencing. sequencing studies. And then, you know, individuals like Ellen came in, you know, and other scientists, you know, who also did similar studies and they, you know, they said, look, we have contamination controls and we just don't, you know, we don't agree with your interpretations, you know, this is contamination. But that was never the main reason why it got me going, you know, because I'm not enough for sequencing guys. So the reason why I got involved is because I never believed it. And the reason why I never believed it, because again, it's actually historic, because I knew... 50, 60 years of history, you know, that you can generate germ-free animals. You know, you can, and this doesn't only work for mice, it works for rats, hamsters, you know, you can do it with primates, you know, with cows, with pigs, you know, this is in sheep, you know, this has been done. So meaning if you get a fetus in a sterile way of mammals, you know, this fetus is germ-free, you know, and this is a fundamental tool in actually microbiome science. This would really not be possible if the fetus is colonized. The other reason I had with it, you know that I think it's biologically implausible because if you think about this, if there is a mechanism by which the body would, and it's not only the fetus, it's also the brain or all these other internal microbiome. If there is a mechanism by which the body would allow microbes from forming complex populations there. Pathogenic microbes would have a ball with this, you know, because they are really good in evolving, you know, and there isn't a really good mechanism for the immune system to differentiate between them because, and if there would be, the pathogen would evolve just, you know, to be actually not recognized. You know, that pathogens are quicker than our immune system in terms of evolution. So the entire, as the entire... reality of us being able to maintain symbiotic relationships is actually to keep them at the healthy balance, to have anatomical barriers, mucus layers, defensines being produced at these mucus layers. And then you keep them, you wanna have them there because they provide you critical contributions, but you also have a lot of mechanisms in place to control them. And again, there is this... You know, that 70% of our immune cells are in the gut. And this doesn't even consider then all the defences, you know, and the mucus and all of these other mechanisms. So, having this idea of now suddenly having microbial communities in completely vulnerable places, you know, like the brain or a fetus, which doesn't even have a functional immune system, you know, just didn't make any sense to me. And this was really my main motivation why I started to get involved. And then I did team up with. contamination folks, you know, and then, you know, we did write a lot in this, in this area. So, that's sorry, a long story.

Alan Walker: Yeah. No, it's all right. I think your point is right, and you know, you know, microbes can get into the fetus, they can get into the brain, they can get into the blood, but quite often with quite catastrophic results, you know, and there's no such thing as a defined microbiome, a microbiota, defined microbial community that, you know, characterizes that environment, which doesn't exist. These invading bugs are rarities and or unfortunate infectious processes, as opposed to a true microbial community existing in sync with the body in these environments. It just doesn't exist.

Jens Walter: So I did some experiments in the day, you know, when this cell paper came out that claimed, you know, that for example you can find Staphylococcus in human fetal samples. So I actually sent this to Ruth Methi without telling her, you know, what my intention was with Methi is, you know, an expert in Staphylococci. And I still remember I got an email back with one single sentence. It said, if that's true, humans would never have evolved. That was her state. And again, she was not involved in the discussion. You know, she was just somebody knowing something about Staphylococci and you don't want them in your blood system. And you definitely don't want them in the fetus, you know, but the reality is they were never there because, you know, it was just... And Ellen said, you know, microbes make it into these systems, but very rarely, and it's often catastrophic. And again, in the Nature paper that we've published, you know, a year ago, we actually, we intentionally included medical microbiologists in there, which had no beef in the actual discussions, but they all said, look, if protective barrier are crossed specifically by large numbers of microbes, you are in big trouble. And again, the argument that this could just be beneficial microbes, I don't let that count, because there is no mechanism by which the body would pretend the pathogen from invading, because trust me, they are better at invading. They have stuff like cocci. They do have enzymes to lyse, to connective tissues and all kinds of things. So trust me, you don't want them inside of your body.

Ruairi Robertson: I think if we kind of come full circle, one of the reasons for that this has become a myth is partly because of these DNA sequencing technologies and people were relying on reading DNA in a placenta, in a fetal like meconium sample and saying, look, I found these bugs here. And it was kind of described quite elegantly in one paper as akin to finding blue whales in the Himalayas. whereby if you took any DNA, you know, you could, and aligned it to some database, it's possible that you could identify some sort of, something there that doesn't belong there. But really, if we try and grow these microbes and use these older techniques, or try and look at them microscopically, you know, they're just not there, they don't grow, or if they are, they're usually these things that cause infections. So maybe they're the ones that are associated with preterm birth. And I think some of the evidence from that paper, those papers show that the only ones that are truly identified once you account for all contamination, everything is probably these ones like the group B streptococcus and some other ones that can cause preterm birth.

Alan Walker: Which again, people already knew. You spent a lot of time and money confirming what was already known.

Ruairi Robertson: Why do we scientists want to believe? Or why did this become, before it gets in, we get into the public. Is it because it's that big, you know, big finding and a big shock to the field? And-

Alan Walker: I don't think it's that, sorry about it, Andrew. I think some of it is that, you know, as the field has got super busy, lots of people have jumped onto the field. And you know, this isn't the case for everyone, obviously, but some people maybe don't have a background in microbiology, so don't generally understand that what they're seeing is probably not of interest. So Bradyrhizobium is an example that I use. all the time in my contamination type rants. And that's a bug that lives in the root nodules of plants and fixes nitrogen for the plant, right? So why would that be in your brain? It's not fixing nitrogen in your brain. It's highly unlikely. So I just realized that level of just taking a step back and thinking, is this a whale in the Himalayas type you can take your analogy. Does it make any biological sense? And I think, There is a tendency for some, not everyone, you know, you crank your wheel of your analysis pipeline, you get some results out and that must be true. So you just stick it in a paper. And then that's what I found, you know, and that's your defense. That's what I found. But actually, you know, just applying a little bit of take a step back and just manually think about it. Does this make sense? If it doesn't make sense, then try and prove it with a different method, as you say, try and grow it in the lab and see if it's there. And that takes time, it takes effort, it's not as fast, and people are keen to move on to the next thing in life. And I think all of these things play into it. I don't think it's a case necessarily that people want it to be true. I think people just think it is true without actually applying that sort of stop, just have a think, does this make sense type approach.

Jens Walter: I think we- It still does puzzle me how this became then a debate, and it did become a debate over years. And then, big pushbacks and I was never involved on it but I had, you know, when we wrote the nature paper with 46 authors and I had quite a few of them that I had to actually convince to participate and I had to convince them because they said that they saw debates, you know, at conferences that became so hostile, you know, that they didn't want to be involved, you know, so I had to, you know, convince them they're going to be safe with me. Yeah, so. And I said, Ellen and I, we are big guys, you know, at conferences. You were in a good team there, you know, but no, I'm so I think I don't, there was still an element of it that I don't really grasp, you know, and why, why is it the fetal microbiome, you know, because it really became, is there a similar example in the microbiome field, you know, that got this contentious, you know, I'm, I'm not sure, you know, but it definitely did get contentious.

Ruairi Robertson: Well, there was a more recent example, which we probably don't have time to go into, but this theory of there being microbes within tumours and there was a big...

Alan Walker: For me, that's almost the same, you know, because it's at the same nature of things, you know. But you're right, that is very similar. You know, is it because there is so much implications of it? Because that's another example, you know, where... where it would have huge implication if it's real. And yeah, it was very contentious, the debate.

Alan Walker: I think that's one of the points that Leslie Hoyles and I made in the paper we wrote, the myths one. Some of this stuff seems, oh, it's fine. It's just scientific endeavour. But this is harmful. It leads science down paths that are unproductive at best. And science funding is finite. We don't have infinite amount of money to spend. And so money spent researching these things is actually money wasted that could have been spent researching other things. So I do think there are consequences to these sort of less well sort of rationally based type studies. And actually they have consequences across all microbiome science because simply we're doing less stuff. that might have been more productive and more useful.

Jens Walter: That was also the main reason for why I got quite active in this debate, despite not doing actual sequencing work. That was exactly that. It was not the only motivation, but it was the main motivation.

Ruairi Robertson: But I mean, on the point of the fetal microbiome, I think you offered it in your paper in Nature, Jens. Some of the metabolites the microbes are producing can actively cross the placental barrier and so may actively be important in the fetal. So I think what we're arguing is not that the microbiota is not important at all. for a fetal development. Actually, there probably is some really interesting science still to be done, but there's not a defined microbial community inside that placenta having a direct effect.

Jens Walter: So you've segued very naturally and nicely into the kind of second last point that I want to touch on is, we've gone through all these myths. So why are they dangerous? Is it just simply because scientists are gonna be distracted and pull down the wrong path? You know, wasting... science funding that taxpayers pay for, or what is the risk, let's say, for medicine or for correcting the record historically? What are the main risks to having these myths persevere?

Alan Walker: You don't want me jumping into this one, Yen. Sorry. So yeah, the point I've just made about wasted scientific funding, I think for me, one of the major ones is public trust. You know, for me, I think it's the most important thing. We've gone through a very traumatic period with things like the COVID and the public, a lot of them lost trust in scientists. Most scientists are very honoured people working their best under very difficult circumstances trying to address very difficult problems. And I think if you get a story in the newspaper one week, coffee causes cancer, and then the next week you get coffee cures cancer, all that's going to do in the mind of the public is just think these scientists don't know what they're talking about, they're a bunch of idiots. And I say most scientists are not idiots, they're very clever people. working on very challenging problems. And so the mixed messaging, I think, is a problem for public perception of science as a whole. And I think, you know, to some extent, that isn't helped by the fact that's just how science works. Science works by people independently replicating your findings. And if it's independently replicated enough times, so you know what, well, actually this is probably true, but that process takes decades, you know, whereas the newspapers work in a very different timeframe. I don't blame them that they work day to day. You know, and so those two timescales work on very different sort of levers, and it's very difficult to reconcile them both. So I think that's why right now at this point in time where people know the microbiome was important, it's undeniably important for across all aspects because it takes so long to get to concrete type of interventions. That is why I think as a field, it is incumbent on us to be guarded in what we say, to not overstate our findings. And if there's promise, indicate it. but really add that nuance and say, you know, we're a long way to go. And I think that's sometimes where as a field we fall down a bit, we get a bit excited and we get a bit carried away and we fail to apply that nuance and that guarded language.

Ruairi Robertson: Jens, anything to put on that, on the kind of the risks? Is it just semantics that we're talking for an hour here?

Jens Walter: No, I think, Alan, you know, the public perception and the public rep, the reputation of a field is huge, you know, but then I also, I would like to expand it. It's not only myth, it's also false claims. You know, some of them are not yet myth, they are just false claims, but they're both similar important in that they are generating. a false foundation of research. This means that the research that builds on it is actually bound to fail. Actually, this is not a microbiome specific thing. It's actually called the reproducibility crisis in science. You can read up on this. Actually, there was a huge... in cancer research actually, 10 years ago, they repeated, big companies repeated their landmark studies and found that they can, this were famous papers on which cancer drugs were based. And they, I think, found out that they can reproduce 17% or so, or 18%, so meaning one in five of these studies were false. And they started realizing that we are simply just not functional anymore. And I would argue that this is to something we does apply to the microbiome field. You know, if I could probably, again, I don't want to go into it, you know, and I don't want to give you specifics, but I could come up with a very long list of false claims that has kept the microbiome field quite busy for 15 years, and it has led to very, very little, you know? And so I think myth and false claims, you know, they are, the biggest... And this again relates also to wasting funding them, but it's more important is actually that everything that you do that is based on those, you know, is just fail. It will fail from the get-go, you know, which means your foundation of your research is flawed, you know, and that is just a very unproductive way of doing science, but it's not specific to the microbiome field.

Alan Walker: No, I agree that I think one final risk, which is again general, not just microbiome field is, you know, but I will talk in the context of microbiome is I think the general public appreciating the microbiome is important, right? I think you've talked about this at the start of this podcast, people get it. But there is unfortunately this vacuum at the moment, whereby people know it's important, but they don't really know how to treat it, or we can't treat it in a reproducible way yet. So that vacuum is filled. If you Google up microbiome treatments, the internet is filled with companies selling you microbiome stuff. Some of it has a decent scientific basis, quite a lot of it doesn't, to be honest. And so, again... that vacuum has been filled with things which probably don't have the level of support and scientific evidence you would want in a product. And so consumers waste their money, unscrupulous products get sold. So these things do have consequences beyond just us academics arguing about on a podcast.

Ruairi Robertson: So finally, how do we prevent these myths from being perpetuated? You know, it's probably a nature microbiology paper. You've got a podcast, you talk about it.

Alan Walker: Yeah, well, indeed. Yeah. No, you publicize it, right? The way is to try and get the message out a little bit. And I think, you know, like I say, most of it isn't malicious. People just have a result and they think it's exciting and they want to tell people about it. But just, you know, temper some of that a little bit. It would be my general advice.

Ruairi Robertson: Well, I guess you touched on reproducibility. Should we all should there be processes in place you know, big science find like that needs to be reproduced in across the world in different labs. Should we be more open to challenging researchers in a way on some of these findings like Jens or like you both have done? What will at least slow it slow that down?

Alan Walker: I'll say one thing I'll let Jens dive in. There was a nice, the conference I was at last week with you, Duri, actually, there was a nice point made by an editor of a journal where he claimed that, you know, any finding that was subsequently was turned out to be refuted or false, the same journal should have to publish the refutations by that, by that, by the other group. And actually, I think that would help a lot because quite often, you know, the big landmark stories are in the big high glamour impact journals and the stuff refuting it ends up in some little niche thing that no one ever reads. So that would help. But yeah, over to Jens, if you've got other suggestions.

Jens Walter: I have a lot of thoughts, you know, because we, we wrote a paper, you know, that we published in Cell, you know, about false, false claims and exaggerations in the microbiome field. And then we dive a little bit into this literature. There is a literature around this reproducibility crisis and about all the incentives that we have in science that are just not good, but that are really, really hard to tackle. As Ellen just said, you can publish the fleshiest thing in nature science and cell. And if it turns out to be you know, scientists who actually refute, you are going to end up somewhere in plus one. And the reason is because editors don't like negative studies, you know, and so and the field just moves on, you know, but it's just not a really, you know, productive. And there are actually modeling studies who show, you know, that if you model these false claims in science, they're actually, they are more successful, you know, they are because they are more spectacular, they get more citations, you know, and then it takes years. Fetal microbiome took now, I would say, six, seven years. And again, I'm not sure it's settled, but at least it took years for people to come around. So it's an entire, again, there's a lot written about it. And I love the idea with the journals have they have to publish it, but they would probably push back and would just say, hey, look, this is not true, because I've been in this situation where a journal just doesn't accept you. So they just stick to the. do their original paper. So it's probably also not that easy. But accountability and then the incentives in science are probably wrong. There are incentives to publish spectacular, fleshy science. And the critical stuff is almost, is actually reserved for the lower T journals for some reason. So. very hard to tackle. Probably has to do also with human psychology. I think we all love the big story. Nobody wants to listen to Alan and me about our nuances and how it's complex and how it will take another 20 years. It's way more exciting to hear somebody say, oh, I cured this thing.

Alan Walker: I think Alan mentioned before that the name of the theory is, but the effort it takes to...

Ruairi Robertson: Oh, Brandolini's law. Yeah. Okay. Yeah. Maybe you can explain that so, so I don't get it wrong.

Alan Walker: There's a tweet by, uh, I forget his first name, somebody Brandolini. Uh, the amount of energy required to refute bullshit is a magnitude of order higher than it is to create the bullshit. You know, you have to work 10 times harder to refute nonsense. It's pardon my French, but yeah, once that, once that liar, that false truth is out, the amount of effort it takes to try and disprove it, you know, for the, the whole, you know, firm, acute spectroide, he's cause obesity angle. That literally took 15 years. And. millions of research dollars and I think it's finally accepted now but the amount of effort it took to refute that is ridiculous on a global scale.

Ruairi Robertson: It sounds like you both have been working 10 times harder than other people then refuting off of it.

Alan Walker: That's certainly not true. One thing I do want to get clear and have this on the podcast is we come on and we say a little piece and it sounds really negative and there are negative aspects but science as a whole works. I think individual scientific papers can be wrong but they get corrected. I think one really important message to get across to the public is that science works. Sadly, it sometimes works on a slower time scale than we would like, but eventually the truth does out and problems get corrected, they get fixed and you end up at the truth. Science works. There's lots of brilliant microbiome science going on at the moment. We're highlighting a little bit of the stuff that we're less happy with, but you know. we shouldn't lose sight of the fact there is lots of amazing science happening right now and the field has progressed very, very fast over the last 20 years. So you need to balance that out, right? You know, it's, I guess, again, it's that nuance, right? So, you know, it's not all bad, it's not all good. Most of it is actually pretty good, to be honest. It's just, we need to be nuanced to make sure we're getting things right. And that takes time.

Ruairi Robertson: Well, we'll let the other guests in the other episodes talk about that amazing science that you've alluded to, but I think that's a nice positive note to end on. So thank you both very, very much. That was great.