The Microbiome: Trust Your Gut?
When it comes to treating diseases, we often think of lifestyle changes, pills and procedures. What often isn’t considered is poo. But this week, the NICE guidelines - which recommend treatments for use in the NHS - were updated so people who have a recurring gut infection caused by the Clostridium difficile superbug are eligible to receive a transplant of healthy stool in a procedure called fecal microbiota transplantation (FMT) - sometimes dubbed a “transpoosion” - to aid their recovery. This procedure alters the balance of bacteria living in the gut, helping to hold the bad bugs in check and halt the disease. So, are microbes the new medication? We explore how much we known about our gut microbes and if altering can treat other diseases too...
In this episode
01:02 - What is the gut microbiome?
What is the gut microbiome?
Ben Mullish, Imperial College London
Julia Ravey is taking a look into what we know about our gut microbes and their role in disease by talking to Ben Mullish from Imperial College London, whilst also hoping to find out a little bit more about her own own inhabitants…
Julia - So I've been sent a health kit box, to better understand my own body pretty much. And here, there is the blood test that I have to do to look at the way my body handles processing fat. There's a glucose monitor, which I'm gonna wear to better understand how my body can deal with blood sugars. And then, there is the piece de resistance, a small tube, and a swab to collect a bit of stool sample mm-hmm yeah, we're going there because what our stool can reveal to us is a bit about the microbes that live in our gut. There has been a flurry of research recently that's linked the bugs that live inside us to our health and also disease. So I'm really keen to understand what bugs are living in my gut and what can that tell me about my health. And then also, just as a wider question, how much can the bugs that live inside us actually impact our overall health? To learn a little bit more about what is termed 'The Gut Microbiome', I contacted Ben Mullish from Imperial College, London, and he gave me the inside knowledge.
Ben - We probably have about a hundred trillion bacteria alone within our large intestine, within our colon. And in all, what we think is that actually bacteria outnumber us, that they are probably about 1.3 bacteria in us for every one human cell. So in other words, you might say that only about 35% of us are actually human with the rest of us actually being microbial.
Julia - So we're essentially carriers for the microbes?
Ben - Yeah, exactly. That's right. There's a sort of two-way relationship in one way, we provide a nice home for them. We keep the heating on, we provide nice temperature for these bugs, but they provide lots of functions for us. Roles they play in contributing to digestion of foods or chemicals they make, that we now recognize more than ever are contributing to a large number of different aspects to our health.
Julia - And how is this population established in an individual and what can impact what ends up in say, for example, our gut microbiome?
Ben - When a baby is born or the point of being born, it probably has very few members of its microbiome, but as the baby comes into the world, it's instantly exposed to a huge number of different bacteria. As babies are delivered through the delivery canal and exposure to microbes all around us in the world, instantly, or within a very short period of time, babies start to establish their own microbiome. And what we think is that in really early life, that undergoes a huge amount of changes before we really develop our fully flourished, final stable microbiome. But actually, as you say, what we also know is there are many different aspects that we are exposed to in life that might impact upon our microbiome and make changes to it. So one particular obvious example is antibiotics. We think age is important, it changes throughout life. Your diet is very important whereby we know that fiber and other prebiotic elements, so are things that are actually nutritional sources for our bacteria, or ways that can impact upon our gut microbiome and might have downstream effects. Whether a child is delivered a normal delivery or caesarean section, whether that child is breastfed or bottle fed. So there are different factors throughout the whole course of life that we are all exposed to that have pretty marked effects on what a microbiome is and what a microbiome is able to do.
Julia - How does the population of one person's microbes differ to the next person?
Ben - Each person looks different just as like, you know, we're all recognizable in some way, because we've all got faces, arms, bodies that look the same, but we all have very distinctive characteristics no one else has. So our microbiome is a bit like that as well. Whereby there is some overlap in terms of the sort of broad patterns but everyone has a very distinctive fingerprint, everyone has their own particular patterns. However, where it starts to get a bit more complicated is when you actually start to look at what the microbiome does. So though we might look at the composition and everyone looks very, very distinctive, there seems to be a sort of key number of functions of the microbiome that are preserved among healthy people that we can see.
Julia - The stomach, and the gut in general, is one of the most important entry points really to the body and so it's really important, I guess, in protecting us from nasty pathogens, viruses, et cetera. How does the microbiome contribute to our immune response?
Ben - This is something that's been a huge area of research over the past few years about actually how our microbiome might tailor and affect our immune responses throughout life. Lots of the work that we've been involved in at the moment has looked at people with hematological blood conditions and particularly people who have blood cancers like leukemia and people who have been unwell enough to require a stem cell transplants treatment for that. And we've found over the past few years, you can pretty accurately predict how well someone is going to respond to a stem cell transplant, or whether they're gonna have complications or might need further treatment actually based on the gut microbiome before they have the stem cell transplant and specifically what we call microbiome diversity. In other words, the degree of different mixture of bacteria and other microorganisms in their guts.
Julia - The gut also has this reputation of being called the second brain. Why do you think it's got this reputation?
Ben - I think lots of us have recognized for a very long time that how our gut works and how our brain and nervous system works are pretty closely connected. All of us have known that feeling, you know, before we've had an exam, for instance, when you feel churning in your stomach and a lot of focus on that has actually been nerves going from our brain or our spinal cord directly into our guts. But what we've started to recognize is that actually part of this communication between our guts and our brain is also related to our gut microbiome. For instance, if you look at the gut microbes of old mice who are not able to perform some neurological tasks so well, and you replace the microbes in the gut with those from younger mice, you can actually start to see changes in the structure and function of their brain. Again, just speaking from a clinical perspective, a lot of work that I do is working with people with advanced liver disease. And we've recognized for some time about a complication of advanced liver disease called hepatic encephalopathy, which is a pretty horrible confusional state. And we've recognized for a long time that the treatment for this is medications that impact upon the gut microbiota. So we give people lactulose, which is a sort of sugary medication that we don't absorb very well, but impacts upon the gut microbiota. And we also give them Rifaximin, which is a antibiotic that we don't absorb from the gut, so it stays in the gut and acts directly there. And they're effective medications and not perfect treatments, but they're effective medications.
Julia - Is it that the microbes are essentially talking to each other and releasing different messages and chemicals that are allowing them to chat, and then that is what stimulates the nerves that are sat around the gut and the brain is then getting signals from that?
Ben - Exactly right. So I guess the key question is if we think the gut microbiome is talking to our brain in our nervous system, what are the sort of messengers for doing that? And we think some of the key aspects of that are what we call metabolites - the chemicals that are either produced by the bacteria themselves - or the chemicals that are produced by us, but which the bacteria in our gut or elsewhere can actually impact upon change the composition on. And what we know is that these metabolites, these chemicals can transition from our guts up into our bloodstream. And in some cases, all the way to our brain and impact directly there upon aspects of how our brain functions?
09:41 - NICE recommends faecal microbiota transplant
NICE recommends faecal microbiota transplant
Ellie Percival & Nibil Quarashi, University of Birmingham
Normally the population of microbes exist in a balanced state it our guts that keeps us healthy. No one species of microbes dominates, and all of them compete for space and nutrients in the environment of the intestine. But not all of these microbial freeloaders have our best interests at heart, and if something happens to upset the apple cart - like we’re exposed to big doses of antibiotics - But when bad bugs outcompete the good guys, they can trigger a vicious cycle that can be hard to break. Ellie Percival had this happen to her. Clostridium difficile - or c. diff - is an infection caused by a bacterium that hijacks the gut and overgrows the normal microbes we rely upon for good health. When the density of bacteria increase, they secrete a toxin that injures the lining of the intestine, causing relentless diarrhoea and bowel injury. It is normally treated with antibiotics - essentially killing off the harmful bacteria and allowing the resident flora to respawn. But for 20-30% of patients, as soon as the treatment ends, the infection occurs over and over again, sometimes at the cost of the patient’s life. Thankfully, for these individuals, there is a treatment which has a whopping 90% cure rate: a faecal microbiota transplant, or FMT. Nibil Quarashi, clinical lead of the Microbiome Treatment Centre at University Hospitals Birmingham, explained to Julia Ravey exactly what FMT is…
Ellie - I'd say my quality of life was just awful. I think in the space of maybe six months, I had been admitted into hospital three times for a total of about two and a half months. And then the whole C. diff came about by literally just having a course of antibiotics due to a sinus infection. So every time the C. diff was treated with the antibiotics, which is just the kind of standard treatment that they'll give patients, I just felt completely paralyzed by the fear of it coming back. It's going to the toilet constantly, like 20 times a day. So it just completely drains you and another symptom of C. diff is your entire colon gets really inflamed and angry. So the pain from just having inflammation is extremely painful. So it's just really unmanageable to live with because I think I'd have about maybe an eight week period of being symptom free and then it would obviously come back again.
Nibil - What it is, is very healthy stool acquired from stringently screened donors, and it's processed in a lab and it's given either via up an NGI route, which is basically where you put a tube that goes through the nose, into the stomach, and it's infused directly into the patient's stomach or the small bowel, or it can be given either as enema or is given through a colonoscopy.
Julia - And what is the healthy stool actually doing there?
Nibil - It is potentially a million dollar question, because if you knew what the answer was, then if you wouldn't be using FMT anymore, you'd be using those components in stool that will cause the same effect that FMT does. So what you're trying to achieve here is you're associating a change in the gut microbiome with the disease. You're trying to potentially reverse that by changing the gut microbiome in very crude fashion, by giving them processed stool from a healthy screened individual, with the aim that if you change the microbiome, maybe the process that leads to that disease also changes. And therefore you're able to treat that disease that way.
Julia - Are there any other conditions where FMT has been shown to be potentially beneficial to patients?
Nibil - There are 80 or 90 conditions where FMT has been explored in clinical trials, but surprisingly, well not so surprisingly actually, none of them have been as promising as they have been for C. diff. C. diff is a very different disease though. It's where you get a field effect where the microbiome looks very different and there are potentially some mechanisms around bile acids, and them being abnormal links to C. diff. The strongest contender really is a condition called ulcerative colitis. This is a condition of the colon, the large bowel, which gets inflamed as a result of an immune mediated condition. Nearly 10 clinical trials have shown that FMD appears to be fairly effective in treating this condition. You've got a cure or remission treatment rate of about only 30 to 40%. And the treatment rate is not sustained. So over time, your microbiome in that patient with ulcer colitis returns back to their abnormal baseline and the disease comes back as well. So it's not a cure.
Julia - And a common condition that many people have is IBS. Could FMT potentially be used in IBS?
Nibil - The IBS is another condition that FMT has been exploded in. There have been at least four clinical trials. The problem with IBS, it's a very heterogeneous condition. So everyone's IBS is different. Some patients have got very mild IBS with a bit of bloating, whereas others will have debilitating diarrhea and abdominal pain. And because of this heterogeneous condition, what these trials do is they lump everyone together into the same group. Even though potentially they might be different syndromes on their own. FMT appears to be effective in some of these trials, but not in the others. There may be a role for FMT in IBS, but again, there might be a very small court of patients or a subgroup of patients in this massively heterogeneous condition.
Julia - What do you think the future of FMT is? Do you think we'll still be using this technique 20, 30 years down the line, or do you think research will allow us to find the components of whatever is in that healthy stool? And we can just give that to patients with C. diff instead, or other patients as well with different conditions and we can find the points in the stool that are the things that are doing the job and making things better for them?
Nibil - The problem with FMT is it's a very crude way of treating a condition. Every stool is different. Every stool we obtain from a donor is different. There's no way of standardizing FMT. So every treatment we give a patient is different. Unlike a pill in a lab where, you know, exactly know what chemical formula there is in the pill, you know the exact concentration and you know you can control it. And the other reason is there is no way scaling it up. Our donor pass rate at the Microbiome Treatment Center in Birmingham is only 5%. And if you think about treating chronic diseases where you have hundreds of thousands of patients suffering from it, you need to be able to scale up your donors. And you can't do that because donors are limited, which is why I think the future of FMT is outside treating C. diff. We are using FMT to understand what we are doing to a disease to disease mechanisms that leads to a favorable change, a favorable outcome. So if you are able to understand by introducing X, Y, and Z bacteria or metabolites in that individual with that disease, you're able to change that disease. Maybe the solution is we isolate those bacteria in a lab and grow them up. We can control the concentration, we can control exactly what strains there are. And then we do a clinical trial with those bacteria, or metabolites, to see whether they give you the same effect that FMT does. COVID made all the FMT lab shut down because we know we could detect COVID in the stool and you need to know the pandemic to stop manufacturing again. And for that reason, I don't think the future of FMT for treating chronic diseases is there. I think for C. diff it does have a role, but for other diseases the field is moving towards what we call next generation microbiome therapies.
Julia - And Ellie, who we heard from, had a faecal transplant earlier this year for her C. diff infection, and this is how it impacted her…
Ellie - The procedure kind of completely transformed my life as I'm now, I think, about eight months post transplant, and I've had no signs at all of the C. diff returning. It's just completely given my life back without that constant anxiety of it returning, and now I can actually enjoy life. So, yeah, it's nice. It was about three days later that I noticed a dramatic change in the symptoms. I think before I actually had the transplant, I was going to the loo about 20 times a day. And I think by day three, post transplant, I think I was maybe going three times. So yeah, it was a huge difference. Prior to the FMT, I don't think I'd ever seen such a dramatic change when I was being treated with just the standard antibiotics. I mean, obviously with COVID and everything, holidays have been delayed previously, but I've actually managed to go away and not have the fear of traveling and having to deal and manage all the symptoms. Yeah. It's just, it's not a constant fear. It's nice to live as normal a life as possible, which is great. I'd say FMT is just completely life changing and I'd a hundred percent recommend to anyone with recurrent C. diff.
20:03 - Do diseases have microbial fingerprints?
Do diseases have microbial fingerprints?
Andrew Page, Quadram Institute
Although faecal transplant can save the lives of people with C. diff infection, its application in other contexts has been slower to take off. A lack of healthy donors is one of the reasons. As Nibil Quarashi mentioned, only 5% of volunteers make the cut to become stool donors, and an application form online highlights why… To be regarded as “healthy”, individuals must have no history of gut problems, allergies, recent asthma, and even treatment for depression and anxiety. The reason for such stringent criteria is we are still unclear about how the microbiome contributes to all of these other conditions. Studies have begun investigating if there is a gut microbiome “fingerprint” for a host of different diseases - ranging from IBS to anxiety disorders and even Parkinson’s disease - to see if the gut could be used as a novel avenue for those next generation microbiome therapies. Andrew Page, Head of Informatics at the Quadram Institute which specialises in gut health, microbiology and food, told Julia Ravey about how we can find these fingerprints and why we still need to exercise caution…
Andrew - What people do is they do case control studies, so they look at someone with a disease or an illness, and then they look at people who are normal, maybe who live in the same area, same households, and they try and look for differences. So you get all the DNA from their poo and then you try and work out what species are in one and on the other. And it's only when you do this kind of on a large scale, you can start to see signals coming through. But it's a very new area and a lot has changed over the past few years. And I think it's gonna keep us occupied probably for the next 20 years, because there's so much inside us that we don't really know. If you take a normal person randomly off the street, they're probably gonna have novel species that we've never seen in the lab or grown in the lab and studied in depth.
Julia - So it sounds like it's very early days in terms of looking at if there are certain microbes potentially involved in different diseases, but so far, what diseases have shown some of these potential relationships?
Andrew - So people have said, okay, maybe Parkinson's disease has a relationship with the microbiome. This has been reproduced with multiple studies so maybe there's something there. But what we don't really fully understand is what's causing it. And is this just a signal of someone with Parkinson's has a different type of microbiome or is it something that's actually real and is there, and is a real signal. So when they've gone and done studies, they've consistently found signals where there's more lactobacillus and there's more bifidobacterium within the guts of people with Parkinson's versus not. But then the caution there is that lactobacillus is something that's very commonly found in yogurt. I can tell you now, yogurt that you buy in the supermarket is not gonna cure you of all your ills, but bifidobacterium is quite interesting because they've looked in other studies and they've found that it has a beneficial impact. So when they gave it to pre-term babies, they found that actually the rates of sepsis and other diseases like that have gone down simply by introducing some of these bacteria.
Julia - And so if we're looking towards many different diseases and trying to find a microbiome signature, how can you tell if the microbes that have changed is a consequence of the disease itself, or if it's causing the disease. Can you tell that from looking at DNA alone?
Andrew - Not from DNA alone, this is where you need heavy duty statistics and a lot of other experimental work. So if you just look at the DNA alone, the most common experiments people do is they look at 16S which is just a short region that's conservative bacteria. And they'll do a very high level and they'll say, 'oh, this genus is there. And it's in these numbers'. And then with a different person it's in different proportions. And that gives you kind of a high level overview, but that's kind of like trying to learn French by standing on the Cliffs of Dover with binoculars. You know, you can only tell so much. Genome sequencing allows you to go in further depth, but really the key is where you can pull out a bug, you can figure out how to grow it, and then you can actually go and do experiments on that individual bug. But then it gets more complicated because, within our gut, you might have hundreds of species living together in harmony, and each provide different things for each other. You're not just looking at one bug, you're looking at maybe 10 bugs in combination. And that's quite a difficult challenge. A lot of science is focused just on pathogens and things that make us sick, but it hasn't focused on all the other commensals, things that don't make us sick. And those have just been kind of ignored because there is no funding for research in those, yet those are the things that keep us healthy or keep pathogens at bay. And they make up the vast bulk of all the bacteria that are right there inside us. But we don't really know what they do.
Julia - So with DNA sequencing, do you think that right now, we're still at that phase where we're just trying to identify candidates and then get those candidates into a lab and try to understand essentially what they do before jumping into this is causing this disease? And this is how we're gonna manage it and treat it?
Andrew - Yeah. I mean, there's a lot of snake oil salesmen out there and they are jumping on this, like they've jumped on many other things. And they said, 'oh, you know, the microbiome is the latest, greatest thing. Give me lots of money and buy my cocktail and then will cure everything out there'. And, you know, I've heard a lot of crazy stuff. Unfortunately, a lot of it is gonna just turn out to be hype and then people have moved on to something else. What we do know is that actually, in some cases, if you add in a bacteria it can improve, say, how drugs are absorbed in the system, or it can improve other aspects. So there are definitely positive benefits there. So I think we actually have to figure out what is actually really impacted and what is not. And there's a lot of false routes that we can go down. So people have, say, found a microbiome in the placenta, but then other people have found that that's just contamination. But we absolutely do know that there is so much inside us that we don't know. And as we unpick it, and as we deconvolute all these complexities and how they work and what they produce, we'll find a lot more interesting stuff. And the goal is, in the future, that you can just take a pill with some bacteria in it, and then that'll maybe cure an illness or it'll make a drug more effective. It could lead to a whole new area of treatments for people to make you healthier and live longer, you know, in a much more healthier way.
26:24 - Could we use bacteria to fight disease?
Could we use bacteria to fight disease?
Amir Zarrinpar, UC San Diego
While efforts continue to identify more specific microbial contributions to certain diseases, it is important we have a way of (1) being able to test whether these bacteria and the products they make are actually involved in causing or contributing to disease and (2) if it turns out that they are, that we have a way to effectively deliver therapies to the gut in a targeted manner. Amir Zarrinpar, gastroenterologist at UC San Diego, believes he has found a way to do this using a modified form of the common bowel bacterium E.coli. We often regard E.coli as pathogen, but hundreds of strains have been identified - and many are more friend than foe. Amir explains why some of the current approaches for targeting the gut microbiome are challenging…
Amir - Microbiome is constantly fluctuating with the times of day with seasons. And it's hard to imagine what a therapy would look like that would work on all these different landscapes. What we noticed also was that each individual's microbiome seemed to be very well adapted to that person. And then this made us think that a lot of the approaches that people are taking to treat diseases with the microbiome use probiotics or bacteria that have never lived inside of a host. And we're asking that these bacteria now go into an environment in which they will have a great deal of surviving.
Julia - Yeah. And have you found a way to get around this then?
Amir - Yeah. So the way that we went around it was that instead of using a bacteria that never lived in the host, we went to in this case, a mouse and identified a bacteria that was already part of the microbiome of the mouse. And then we engineered that bacteria to express a gene that was potentially therapeutic or beneficial to the mouse to eventually affect the physiology of the mouse and even alleviate disease in these mice. And what was perhaps most remarkable was that these bacterias stayed in these mice for the rest of their life and were able to affect this change for months after this initial treatment.
Julia - And how did this expression of a new gene in a bacteria impact the health of the animals?
Amir - So we had done a lot of studies before where we were looking at the relationship between microbiome and obesity and diabetes. And we had come up with a list of bacterial genes that we had wished that we could always knock in to see whether it was correlational in terms of its relationship with animals' weight and blood glucose, or did it actually play a role in affecting these things? The first gene that we knocked in was a gene called bile salt hydrolase, which is a gene that changes the bile acids in the gut lumen. And what we found was that when these bacteria overexpressed this gene and actually modified the bile acids, they led to a decrease in blood sugars. And it seemed to show that insulin sensitivity of these mice improved. And this was just in regular normal mice on a regular diet. So we decided to then test this in a type two diabetes mouse model. So a mouse that eats so much that it becomes obese and diabetic. And in those mice, we saw a great reduction in blood glucose months after the mice had received this therapeutic bacteria.
Julia - Do you think that this type of bacterial tool could be used in other diseases as well? You know, say for example, in Parkinson's disease where there's been this potential relationship seen between certain bacterial species in the gut and individuals with the disease, can we use this tool to test if something is actually causal?
Amir - Absolutely. When we were thinking of this tool, we were thinking of it as, as I said, a tool so that individuals who are interested in the gut microbiome can actually knock in functions and determine whether things that they were observing in these multi omic studies that people do affect the host in the way that they think it does. But I think there's another potential science fiction version of what this bacteria could be used for, which is that many of our drugs are produced by E coli in labs and giant vats. And one of the things that we can do with these bacteria is engineer them to sense whether there is inflammation in the gut and thus express an anti-inflammatory whenever they sense inflammation, or perhaps if they can sense different things that are going on within our body, they can then express a therapeutic and create a world in which we don't really have to take drugs anymore because many of these drugs are produced by the bacteria in our gut.
Julia - And do you think then we could make these bacteria specific to different diseases? So if you found a relationship between a microbe in IBS and then you could then express the genetic component of whatever that microbe was doing to help people who didn't have IBS, you could then take that and express it in the E coli and then give it to the person with IBS.
Amir - Exactly. Now there are big questions as to what this would look like, whether it has to be a bacteria from that individual that is given back to that same individual, or whether there is a bacteria that we have found from a single individual that can then go to other individuals that have IBS. But that is exactly the kind of things that we were thinking. So for example, with IBS, there are many people who have been outstanding studies who have looked at the role of the gut microbiome, but before some of these synthetic biology experiments, including ours, there was usually only one way to change a person's gut microbiome effectively. And that was with fecal transplant, which may not last a very long time for someone with IBS who has a chronic disease. So the question here is will something like engineering and individual's native bacteria be able to affect a chronic disease on a much longer time scale, essentially functionally curing diseases. And that is the hope that we're striving towards.
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