Faeces and phages: Moulding the microbiome
Today, we're helping you to get to know your microbiome, and hearing why a better understanding of it viewed by some as the next frontier in helping us to live longer, healthier lives. First, we explore the co-evolution of man and microbe, and the suite of modern techniques helping to clear up the remaining mysteries of the intestines. And, later on, how medicine is mobilsing the microbiome to ward of antibiotic resistant bacteria using faecal transplants and 'good' viruses...
In this episode
00:54 - What is the microbiome and where does it come from?
What is the microbiome and where does it come from?
Ruth Ley, Max Planck Institute
The microbiome is an immense collection of microbial cells found on or in our body, but the majority of them are bacteria and reside in our gut. Despite the negative feeling the word ‘bacteria’ often evokes given their role in spreading some diseases, they are in fact crucial in allowing us to lead healthy lives: they help us digest things the body otherwise wouldn’t be able to, for example, and helpful bacteria outcompete “bad” bacteria within the intestine so they can’t establish themselves and do us harm.
But where do these bacteria come from and how did they become so suited to living in our bodies? I spoke with Ruth Ley, microbial ecologist at the Max Planck Institute, who’s been studying the co-evolution of humans and bacteria…
Ruth - When we're born, we're rather extraordinary in that we're an extremely large organism that is completely germ free. And this is an extraordinary thing to be because all large organisms are covered in microbes. But yet, when you develop in the womb, you're in this incredible protected space. Then, when you come out, you are colonised by microbes over several years, beginning at birth. But where these actually come from is your immediate environments. And what that really means is the people who are raising you or are around you as a child are the ones that are supplying you with the microbes that they have. And those microbes came from their parents and their families and your grandparents' microbes came from your great-grandparents and so on and so on. And then others, they might travel more widely between people and they might, for instance, spend time in water or in rivers and things like that and finally make their way into a human.
Chris - So they've evolved to be specifically part of our microbial passengers, then?
Ruth - It really does look like that. When you compare, for example, the microbes that we have to the ones that our great ape relatives have, you can see that there's a certain number of them that even share our evolutionary history. So, for instance, our closest relatives are the chimpanzees and then after that you have gorillas and orangutans and so on. We know how we're related to each other - who shares a common ancestor with whom and how far back that goes - and you can do the same for some of the species in the gut. So you can tell that they've been in our lineage so long that when we became human, our microbes followed us, if you will.
Chris - So it follows then that, if we have evolved to have this really close relationship with these microbial flora and fauna that come with us, that if they're not there or we upset the biological apple cart, we are presumably less healthy for it?
Ruth - Well, I think this is one of the questions. So we now know from recent work that when humans split off from our ancestors, with the chimpanzees, when we got the modern human lineages, a lot of them at that point were also lost. And so there's a lot that are in our great ape relatives that humans no longer have and that might be just fine because we have a different kind of digestive tract from them and a different kind of diet. And, we do very different things with our food: we cook our food. We might not need the suite of bacteria, for instance, that are good at breaking down the fibre in leaves because we don't eat as much leaf material as an ape, for instance. They're really folivores. So instead of relying on bacteria, we now rely on cooking and that's fine. We've culturally adapted to a new way of nourishing ourselves. But what's happening since we've taken that to a greater extreme is a little concerning. So what I mean by that is, with a more industrialised lifestyle and reliance on very fibre poor foods, it looks like we are losing even more. And that's where the concern's coming in.
Chris - I was gonna ask you because one of the words of the year that's going into the dictionary is 'ultra processed.' This whole field has really had a spotlight shone on it by Chris Van Tulleken writing his book about it. What impact does this modern ultra processed diet have on this assemblage of microbes?
Ruth - Well, I think it starves them. The biggest assemblage of microbes we have are in the large intestine, and they're there in order to break down fibre which is everything that reaches the large intestine. These ultra processed foods don't have any fibre in them at all. They're so highly pre-digested, if you will, that, when we eat them, we absorb sugars and fats and protein from them immediately. There's really nothing that happens in the small intestine and then there's no fibre left over for our gut microbes. The concern is that over time they disappear and then you can't get them back.
Chris - So what might be the health consequences of that?
Ruth - Well, I think this is what we're still trying to understand, but when you look at industrialised societies and their microbiomes compared to people who are living a lifestyle where they, at least with their nutrition, get much more fibre, they have a much more diverse microbiome, there's more species there and their species can do more things. There's a concern that we might be losing some of the beneficial functions that we take for granted, such as perhaps protecting us against pathogens, and being able to break down toxins that come in because we don't have those microbes anymore. Another one that's a bit more difficult to figure out, I think, is just how they interact with our immune systems and whether or not we are losing critical interactions with our immune systems such that then our immune systems might be doing things that work against us, such as the development of autoimmune diseases, for instance.
Chris - Researchers in Ireland in recent years have also shown that there may even be signals travelling between what's going on in a Mum's gut and her developing baby's brain. So could it be that by bending our microbiome through all the factors we're exposed to, we're not just impacting our own health, but we're potentially affecting the future health of a baby that hasn't even been born yet?
Ruth - That's entirely possible because when you look at what's in our blood, a lot of that is made up of molecules that are coming from the microbiome. And when you change the microbiome, you change this suite of molecules in the blood and those molecules do reach the developing baby through the placenta. That is the chemical environment that the baby then develops with. If that is radically changed because the mother's microbiome has been depleted, that can have knock-on consequences that we still need to understand but could be quite real.
Chris - So it definitely comes down to the saying 'you are what you eat,' I guess.
Ruth - You're not just what you eat, though. You are what you eat, and what your microbes have done with that. Yes.
08:05 - Identifying hidden gut bacteria
Identifying hidden gut bacteria
Alex Almeida, University of Cambridge
This fairly recent realisation of the significant health implications of a well maintained microbiome is all well and good, but if we’re going to help everyone reap the benefits there’s a lot of work to be done identifying and experimenting with the range of bacterial species that have colonised us. Working with DNA sampling technology, the University of Cambridge’s Alex Almeida is helping to reveal the many mysteries that remain in this field, and he spoke to our own James Tytko from his laboratory…
Alex - We can look at the microbes as individual organisms, so the number of actually microbial cells we have in our body. Current estimates sit at around 40 trillion microbial cells. Most of them are in the intestinal tract, that is clear. Now, if we take it to another level, so when we break it up to the level of species, in my line of work, the way that I classify what is known and what is unknown is based on whether we can actually experimentally characterise these species. So the way we do this is we try to isolate them and culture them in the lab first so we can actually work with them and perform experiments. Of current estimates of essentially the whole repertoire of microbial species that have been identified in the gut, 70% are unknown, so have not been cultured. That's a big limitation in the field and something that I'm looking forward to in my research to clarifying a bit more.
James - And we'll often hear that there are helpful and harmful bacteria that live within us at the same time. Help me to understand that a bit more. Can you provide some examples of bacteria that are good for us and ones that are not so good for us?
Alex - So this definition of good and bad bacteria is actually something microbiologists don't really like to use when classifying because whether a bacteria is good or bad is all about context: it's all about the interaction of that bacteria with the host, what are the other types of bacteria that exist surrounding it? How they all interact together. What I can tell you is that there are consistent trends in linking certain species with health or with disease phenotypes. One species consistently associated with health which has been quite extensively discussed as a novel potential probiotic is a species called Faecalibacterium prausnitzii (all bacterial species have Latin names.) It actually helps digest certain fibres and produces a compound that is known as short-chain fatty acids. Short-chain fatty acids have important roles in host inflammation which has been strongly linked with maintaining gut equilibrium, gut homeostasis and keeping things in check.
Alex - On the other hand, potentially disease associated species have been consistently associated with colorectal cancer is a species known as Fusobacterium nucleatum. What studies have shown is that colorectal cancer patients are consistently enriched in bacteria belonging to these species, and there have even been some experimental studies suggesting that the species is involved in tumour growth development as well. Obviously, there are more complicated species that have a bit of a mix of both being good and bad depending on context. The classic example is E. coli. Actually, E. coli is a normal commensal of the gut and is found in most individuals at the very low abundance. If E. coli reaches a significant level of abundance, that can create problems: it can lead to high levels of inflammation and even if certain strains of E. coli are able to translocate the intestinal epithelial, that can create problems because the bacteria can transfer to the bloodstream, transfer to other organs and that will cause problems for the individual as well.
James - This is why it's becoming an increasing priority within medicine to identify as many of the hidden bacteria in the gut that you spoke to earlier.
Alex - Yeah, exactly. So obviously the ideal scenario is to really find species that are robust and strongly associated with health and can benefit different individuals in different contexts in different health states. But we really need to first take a fundamental approach to understand what the biology of these species really is. What are they doing? What functions can they encode? This, before being too ambitious and immediately trying to use these species as potential probiotics.
James - And so this is where we come to your research and the tools we have are our disposal to identify more of these species.
Alex - So my research group is primarily a computational genomics lab. Genomics is the area that studies the DNA sequences of different organisms. In our field, for the microbiome world, we use what is called metagenomics, so it's beyond even genomics. It's actually looking at the whole genetic material of the community. So we do metagenomics on a traditional microbiome sample - usually what we work with are faecal samples to explore the intestinal microbiome - and we piece together these DNA sequences to make inferences about which pieces are there. So the DNA acts as a fingerprint, but since the DNA also acts as a sort of blueprint for what the bacteria is able to do, so what proteins it's able to encode, we can predict the metabolism and the function of these bacteria by looking at the DNA. We use large scale sequence data to really make inferences about what is the role of the microbiome, which species are there, what are they doing in different health contexts.
James - Tell me about some of the examples of species you've been able to link with certain diseases.
Alex - We have been looking at a wide range of diseases, some that are a bit more obvious such as inflammatory bowel disease or colorectal cancer, but we have also been looking at diseases that are not directly associated with the gut, like Parkinson's disease or multiple sclerosis. We definitely see a stronger link with diseases that occur in the gut but, even in cases of things like Parkinson's disease, there is definitely a strong link with the microbiome. The challenge is actually pinpointing when we find specific species linked to these diseases, why are they there? Is this just a correlation? Is the species present there as a consequence of the disease? Or is the species actually leading to a higher incidence of that disease? So we do find that there are some uncultured bacteria, species that we know very little about, that are very strongly associated with health in different contexts. I can give you some names but, to be honest, since these are uncultured, unknown species, their names are simply codes at this point. They carry very little meaning to people that are not directly in the field, but we are starting to see some good trends.
James - Highlighting there the difficulty with delineating cause and effect. What's the scale of the task there? How do we translate the work you are doing into medical diagnosis or treatments?
Alex - I think there are two levels we can think about. So, in the short term, the more perhaps realistic goal is to use certain species as biomarkers of a healthy or diseased state. And I think this could help with certain diseases where diagnostics can be quite invasive. If we think of things like colorectal cancer, obviously the gold standard diagnosis is doing a colonoscopy of an individual, but that's very costly, very invasive and carries some risk as well. So if we can develop a diagnostic tool as a method where, by analysing a faecal sample, we can identify specific species or specific compositions of the microbiome that clearly distinguish health and disease in an individual and we can use that information to identify individuals that are at greater disease risk, they could then be selected for further, in-depth screening. For a diagnostic purpose, this question of correlation versus causation is actually not as important because, even if the microbe is a consequence of the disease, it can still act as a good biomarker of disease that could be used for a diagnostic purpose. Now, obviously the field is becoming a bit more ambitious and thinking of how we can use the microbiome as a form of therapy to actually improve or protect against disease, and this becomes much more challenging. So in this case, we do need to establish causation. We need to identify species that directly protect or directly cause certain diseases. And then after we have that information, we can think about how we can enrich that particular protective bacteria or how we can reduce the bacteria that potentially is causing disease.
16:16 - Fighting antibiotic resistance with faecal transplants
Fighting antibiotic resistance with faecal transplants
Michael Woodworth, Emory School of Medicine
We’ve learned just how crucial the relationship between us and our gut bacteria is, so you won’t be surprised to hear that, when we do damage to our microbes, we could also be opening the door to health complications.
Antibiotics are used to treat or prevent bacterial infections. But while they can kill bad bacteria, they also do damage to good bacteria too, leaving people vulnerable to being colonised with a pathogen that could make them ill. This problem is often approached with the use of more antibiotics, leading to a vicious cycle with a progressively more deranged microbiome and bacteria that become increasingly antibiotic resistant.
Indeed, the superbugs that develop as a result are seriously bad news. Earlier this year, The UN Environment Programme called antimicrobial resistance a principal public health challenge and suggested as many as 10 million people a year could be dying from these infections by 2050.
So what can we do about it? Michael Woodworth from the Emory School of Medicine thinks part of the answer could lie in transplanting healthy bacteria from one person to another, and has just published some clinical trial results after performing faecal microbiota transplants in kidney transplant patients with established antimicrobial resistance…
Mike - We thought we would conduct a clinical trial to better understand if directly transplanting these whole communities of microbes from healthy people into people who are colonised with these resistant bacteria might be a way to try to reduce colonisation without using more antibiotics.
Chris - How did you do it? We dub this the 'transpoosion', don't we? The whole idea of recolonising people with the right stuff.
Mike - So I conducted this study with Dr. Colleen Kraft, who essentially helped to start the fecal transplant programme at Emory in 2012. We identified one of the stool donors for that programme who was very reliable and was very easy to work with and, in-house, manufactured a number of doses to transplant to kidney transplant recipients who had had a problem with a resistant bacterial infection. Then, we recruited and enrolled 11 participants who were randomised to either start with faecal microbiota transplant, which we call an FMT for short, or to start with an observation period with delayed FMT if they were still colonised with these resistant bacteria after a period of 36 days,
Chris - Just before you tell us what happened, how did you administer the transplant to these people? Did they literally have to swallow this solution?
Mike - That's an area that is still being evaluated. What is the best way to get these microbes in the right place? And in other studies, people have used colonoscopies, people have used nasal feeding tubes. In this study, we used enemas, so we directly instilled the material through patients' bottoms. And the reason for this was that we wanted to minimise the risk for the participants and we didn't want to subject everybody to colonoscopy or potential additional risks of anaesthesia.
Chris - So what happened once you've administered this? Before we talk about the transplanted people, in the people who were watched, did any of them get better on their own? Did they get rid of or kick out the resistant microbes and get back to a more normal microbiome?
Mike - We were surprised that in the five patients that were randomised to start in the observation group, that is, with a delayed FMT, that they were still positive. None of them were culture negative at their last visit. And we're expecting that we might observe a little bit more frequent decolonisation than this when just observing patients, but none of them were negative at their last visit prior to an FMT.
Chris - And how did that compare with the people that you went in at the get go and gave them the FMT. You transplanted the suspension of bugs in.
Mike - When we directly compared the five patients that were randomised to a delayed FMT to the six patients that were randomised to start with an FMT, four out of the six patients that started with an FMT were negative at their last visit compared to none that were randomised to start with observation. And because the dose of FMT that's needed to reduce colonisation is really not known, we set up the study to be able to offer patients a second treatment if they were still positive after one dose. And when we looked across all patients that got at least one FMT in our study, including those that had a delayed FMT after a period of observation, 8 out of 10 patients that were treated with FMT were negative at their last visit.
Chris - Do you know how it's working? Why should just shoving in more microbes into an environment which is already teaming with microbes displace the bad guys in the way that it did?
Mike - Well this is really the work to do. And we have ideas based on some of the analysis that was done in this paper. Some of it we think is similar to what we've seen in patients that have this problem of recurrent C. difficile infection that has been treated the most with FMT. And we think that some patients that are colonised with resistant bacteria really have a very abnormal microbiome. They're very disrupted and they really just don't have a similar amount of the healthy bacteria that we might expect to see in people that are walking around that are not colonised with these resistant bacteria. And those patients responded very quickly when we saw the bacteria from the donor show up in the data from the recipients. Now, on the other hand, there were a lot of patients that were in our study that actually seemed to have a milder set of disruptions in their microbiome. And for these patients it's a little bit less clear and there's more work to be done. But we do think that there are similar changes in what these microbes are doing after FMT that seem like they are doing more activities that are helpful for the hosts and also in reducing the virulence of other bacteria.
23:29 - Intestinal phage therapy for antimicrobial resistance
Intestinal phage therapy for antimicrobial resistance
But, as promising as faecal transplants might be for some people, they’re not a silver bullet for everyone with antimicrobial resistance. That means we need more treatment options in our arsenal, and there’s a strong sense that bacteriophages - viruses that exclusively attack bacterial cells - could be one of them. Tom Ireland is the author of The Good Virus: The Untold Story of Phages…
Tom - People have been studying the different bacterial communities in the gut for a long time, but there's actually another layer of microbe in the gut: the viruses that infect those bacteria. When we say viruses, we often think of bad viruses that make us ill, but actually the majority of viruses in our gut are viruses that infect bacteria. These are called bacteriophages or just phages for short. These can be really useful as a way to modulate and change those bacterial communities in our body. So if we have a particular bacteria that's causing a problem, we can then use a virus to kill that particular bacteria. This isn't actually a new idea, people have been using these viruses to kill off bacterial infections before we had antibiotics like penicillin. The idea has gone in and out of fashion over the years and it's just really starting to be taken seriously again because of the rise in antibiotic resistant bacteria that our antibiotics are just not effective on.
Chris - And is that the major advantage, then? You've got a way of fighting fire with fire. We're not giving drugs, we're not having to give other bacteria which might carry other risks, you're using something that's discreet for the bacteria and would be there anyway.
Tom - Yes. So we have trillions of these phages in our guts all the time. So having the right phages in our guts are important, just like having the right bacteria are important. The idea of using this so-called phage therapy is that we just give that immune system a boost and we make sure that the right phages, the right viruses, are in the intestines and they can kill the specific type of bacteria that we're looking to get rid of.
Chris - Would this mean then that, if someone has a particular class of antimicrobial resistance, would it be that we would have specific phages in a pot and if we knew someone carried those bacteria, we could administer these phages and they would go through them and hopefully wipe out the bad bacteria?
Tom - Yeah, that's the idea. There are so many different types of these viruses out there in the world that ideally you would have two or three different types of virus that can target that particular species. Bacteria can develop resistance to these viruses just like they can develop resistance to antibiotic drugs. But if you can hit them with two or three different phages, different viruses at the same time, then the likelihood that they can fight off all three of those viruses is absolutely tiny. But, it's taking a long time to get it into the hospitals and into clinical practice.
Chris - Is that just because we've got other alternatives that we regard as easier? Or is it just that people have found this a bit risky and they haven't invested hard enough in it, and it could be just a door waiting to be opened as it were?
Tom - Yeah, I think there's an element of we've just had antibiotics for so long, it's just the first thing that clinicians reach for when there's a bacterial infection. But using a virus in the human body as medicine, there is an inherent difficulty to that. When you think of something like dose, how much do you give when the medicine itself self replicates? If it works, it's going to replicate in the body. There's also all sorts of other complications to think of. You have to find exactly the right phage for the patient, which means doing some lab work for every patient. And there's a lack of a regulatory framework around this. So this is not something that doctors or drug regulators are used to using, so people don't know where to start. It's much more complicated than just giving someone an antibiotic and saying, take two of these a day for two weeks.
Chris - There are a number of other conditions as well, though, we call them non-communicable diseases, where your microbiome goes off kilter. Or, if you've taken certain classes of drugs, it can affect your microbiome and that can have knock-on effects for your health because, as people often say, your bowel bugs see your dinner before you do and, if you disrupt them, you do a lot of consequences for the rest of your body. So are there also grounds to consider using phage therapy to remould, refashion, to replenish, as it were, the normal makeup of a healthy microbiome in some people for other disease indications?
Tom - We're starting to hear people look at things like virus based probiotics. So instead of bacterial probiotics where you drink a drink that's got friendly bacteria in it and it seeds the colonisation of your guts with better bacteria, you could have the same thing but with viruses. So you drink some good viruses and that hopefully creates a healthier environment in your guts. There's also been some interesting work that combines faecal transplants with phage therapy. So if you've got a particularly nasty bacteria in your gut, you don't want your nice new poo to be recolonised by that bacteria, so you would combine a faecal transplant with phage therapy. So you get your new poo in your bowels and you have some phages so that any remnants of that bacteria that were causing the problem are wiped out by the phages. So there are lots of different ways that you can use phages potentially, not just diseases of the intestines and of the gut, but cardiovascular diseases, even neurological diseases, diabetes. It's a fascinating area and we know more about the bacteria in the gut and how that works, but we're only just starting to understand this additional layer.
Chris - Have we got a paucity of evidence at the moment then? Is it that we need to now start doing clinical trials? We know we can do this. We know it works in other situations outside the body or in animals, for example, but now we really do need to do some clinical trials and get some robust clinical data to really give clinicians the confidence that this is the way to go.
Tom - As I said, this isn't a particularly new idea; using viruses to kill bacterial infections. Getting good data from clinical trials has always been a problem. So, phage therapy can have really spectacular results on individual patients where you've matched the right phage to the bacteria that you want to get rid of, but if you have slightly different strains of bacteria among those different patients, it can mean that it works on some and doesn't work so well on others. The good news is, there's lots of good information that phages are very safe. There's been so many trials of phages over many years and very few of them ever report any side effects, and that's probably because we live with phages in and on us all the time. And there have also been studies using simulations of the human gut that show phages can be used to get rid of all sorts of drug resistant bacteria. It's just a case now of working out some regulations that allow for the unusual characteristics of a medicine based on a virus and designing some clinical trials that take these unique circumstances into account.