From Surgery to Science: Dr. James Kinross on Gut Microbiome Research

Dr. Siobhan McCormack interviews James Kinross, a colorectal surgeon and microbiome researcher. James discusses the potential of robotic surgery and its precision, the link between the microbiome and colorectal cancer, and the importance of preserving gut health. They explore probiotics, evidence-based treatments, and the role of Fusobacterium nucleatum in colorectal cancer. James emphasizes the need for microbial conservation for disease prevention and offers practical advice from his book "Dark Matter" on diet and nutrition for a healthier gut microbiome. This conversation highlights the critical impact of microbiome research on the future of healthcare.

This podcast is brought to you in collaboration with the British Society of Lifestyle Medicine.

Disclaimer:
The content in this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your doctor or qualified healthcare provider. Never disregard professional medical advice or delay in seeking it because of something you have heard on this podcast.

Transcript

Siobhan: 1:00

Hello, I'm Dr. Siobhan McCormack and this is Microbiome Medics Podcast. Today I'm joined by someone I'd really like you to meet. He's a surgeon, a leading gut microbiome researcher and an author. His book, Dark Matter, The New Science of the Microbiome is brilliant, entertaining and hugely informative. I absolutely devoured it and I keep rereading it because, well, it covers so many aspects of this subject in such detail. So I'm both very excited and and extremely grateful that he's taken time out of his busy schedule to chat to us today. Hello there, James, and welcome to the podcast.

James: 1:38

Hi, thanks for having me.

Siobhan: 1:40

So I'd like to start by asking you to introduce yourself to the listeners.

James: 1:44

Sure. So my name is James Kinross. I am what is known as a reader in surgery, and what that means is I'm a clinical scientist. I'm a surgeon. I'm a colorectal surgeon, and I specialise clinically in the treatment of bowel cancer and I spend most of my day treating bowel cancer but I also have an academic life and I spend my time trying to understand how bacteria in the gut cause disease and how we can engineer them to treat disease.

Siobhan: 2:13

Okay, so that's really kind of a diverse range of interests you've got. So can you help me and the listeners understand how that looks in real life by, I don't know, describing a week in the life of James Kinross, how you balance these things up?

James: 2:27

Well, basically, it's a week with not a lot of sleep, is the bottom line. Because you're doing 100% of two jobs simultaneously, really. But what it means is that pretty much about 50% to 60% of my time is divided into treating patients. So that's being in clinics, being in the operating room, being on call. And the other half of the time, I'm running and managing a research group. So I have a laboratory and we do science in that laboratory. Laboratory, many of the studies and trials that we run, of course, overlap and align with my clinical practice. So for example, patients that I look after, we will often recruit into our studies and our trials, and we will sample them and study their microbiomes as we look after them. And it also means that I get to work internationally with lots of other scientists trying to solve similar problems. So I have this, you know, really lovely position to be in where I get to work with lots of collaborators from all over the world.

Siobhan: 3:21

Yeah. So if we sort of focus on your work with colorectal cancer and your work in theatre with robotics.

James: 3:29

Yeah.

Siobhan: 3:29

If I, this is not an area I know a lot about. I've never seen it done in real life. So if I were to attend a procedure and watch you doing robotic surgery on a patient with colorectal cancer, I mean, what would I see? How would it look and how long would it take?

James: 3:46

Well, surgery is undergoing a profound transformation at the moment. Surgery, if you like, has been performed for thousands of years in a data silo. It meant that there wasn't really a lot of information going in and out of the operating room unless someone recorded it with a pen or a paper or more latterly an Excel spreadsheet. And robotics is really transforming that. And what it means is that we can measure very precisely not just what a surgeon is doing, but also what the team is doing and how all of those instruments and devices within an operating room work. And the future of that is called digital surgery at least that's what we call it or computational surgery and it's how you apply ai in surgery so if you come into my operating room you will see a big robotic machine the typical machines that we have have a big series of arms that stand over the patient and i drive those arms by sitting at a console away from the patient and what that means is that I literally don't have to scrub and put my hands inside someone's abdomen. The instruments that are driven by the robot will do that. Everything is done in video so when I look at the video field I'm seeing everything in three dimensions and at least I get stereoscopic or depth perception in what I do and I use lots of robotic instruments to help me do that and I use increasingly computers to help me make better decisions for my patients and the microbiome sort of sits in that field really because it's about how you integrate the real-time analysis of biology in in the operating room and we're very interested in our research group in in how we do that.

Siobhan: 5:20

Sounds incredibly appealing, very futuristic, very sci-fi. And I think we're always attracted, aren't we, to progress and technology. And it makes me feel safe and that I'm in good hands and that I don't need to worry if I get colorectal cancer because there's this robotic surgery. I mean, is that how it is? I mean, what's the evidence of benefit and affordability for this sort of surgery going forwards well.

James: 5:47

I think it's definitely true that we must have innovation in all aspects of clinical practice but particularly in surgery if we're going to make it safer, and more precise and surgery is a dangerous undertaking still it still carries significant risk with it and a lot of that risk comes from variation between surgeons and difficulties in assessing technical performance and in making sure that we make the right decisions at the right time for the right patient and and certainly technology allows us to make really significant gains in that regard however all technologies need to be assessed and appraised and validated and trialed and of course there are unintended consequences of introducing machines in or any form of instrumentation for that matter into a high-risk clinical environment the operating room being one of them so so my job in part is to continuously appraise and assess these technologies we perform trials on them and we assess them and we and we appraise them that's one of the things that i'm interested in doing.

Siobhan: 6:40

So I'm curious so we have robotics okay it sounds new and big and futuristic and man-led and it contrasts with your interest in microbiomes so these collections of microscopic living organisms that have existed on the planet billions of years before we ever arrived on the planet so what have these microbiomes got to do with colorectal cancer?

James: 7:02

Well, I suppose the overlap, if you like, the common thread there is in what I call precision healthcare. So trying to make sure that we get the right treatment to the right person at the right time for the right reason, and that treatment is not just effective, but as safe as possible. And technology is one way of doing that. But understanding fundamentals of biology is another really important way of doing that. And the basic principle of the microbiome is that because it explains so much of the variance in biology between people, you can't really have personalized health care without an analysis or understanding, at least, of the microbiome. And bacteria, you know, have long been understood to be important determinants of operative outcomes. Outcomes if you come into my operating room although it's futuristic in many ways it looks you know we our behaviors and practices are still the same practices that have been followed for hundreds of years we wash our hands we scrub our hands we prep the skin they used to do it with carbolic acid and lister's time we use something a bit different but we still spend a lot of time focusing on asepsis and we drape our patients and we use sterilized gloves and that's because we're trying to fight bacteria and we know that pathogens can cause something called sepsis or infection. So many surgeons understand that bacteria are important in surgery. But the microbiome is so important because it gives us a completely different perspective within which to view that particular challenge. The microbiome is not just a critically important determinant of why patients get the diseases that I have to operate on, such as bowel cancer, but not not exclusively bowel cancer but it is also such a critical determinant of their treatment response and their outcome that might be through nutrition or diet or pre-operative strategies to try and prepare the gut and the patient for optimal wound healing or you know for improving their quality of life after surgery or increasingly for improving how drugs and other treatments of work in in their care because of course the treatment of something like cancer at the moment is what we would call multimodal it's not just one treatment that treats cancer it's usually usually multiple treatments so it's an operation with or without chemotherapy for example and the microbiome is important across the entire patient journey and across the entire lifetime of that patient.

Siobhan: 9:28

Okay so if we if we take a step back as we talk about the patient journey if we take a further step back so patients usually consider cancer is starting if you like at the onset of symptoms or when the doctor diagnoses them with a disease. But we know that these changes are taking place years or decades before this point. Could you start by just briefly talking us through the timeline of colorectal cancer so we can then place the microbiome on top of that?

James: 9:56

That's such an interesting question. We could probably talk for about an hour on that. And I'll try and be succinct. So I think probably most readers or listeners, at least to this podcast. Will probably be aware that we often do screening tests to detect bowel cancer. So that means we either look for the presence of blood in the stool and sometimes we do colonoscopies. And and those colonoscopies are not just looking to detect cancer they're looking to detect precursors of cancer what we call polyps these are typically benign growths that form in the bowel and sometimes they might have focuses of cancer change within them because if we can detect them we can not only treat cancer early but in some cases we can prevent it completely but the microbiome and cancer sort of raises some existential questions really about the role of microbes in causation of cancer and and it turns out that trying to prove the causation of microbes in cancer is really quite tricky and it's quite tricky for a number of different reasons the first is is that by definition as soon as you get a polyp or you even get a cancer the microbiome so the type of microbes that live on that polyp or live on that cancer change and we're not entirely sure that those that we're actually detecting on those lesions are in fact causative that they're there because that they cause the disease it might be that there are microbes that exist within the gut many many years before these things materialize that are the driver organisms the second challenge is that of course it might be bugs that live on the cancer or live on the polyp or live adherent to the bowel but it might also be microbes that live within within feces or within the lumen of the bowel that are very metabolically active. And the third challenge is that there are just so many microbes. The microbiome is just so massively diverse and it has a massive array of different functions. And that means there's an awful lot of complexity. So if you want to understand a condition like bowel cancer and cancer risk and you want to understand the role that the microbiome plays in it, it means that you probably have to go back many, many years in advance of that cancer materialising to really understand it. And increasingly in my group and in our group we are thinking actually you've got to go all the way back to the developing gut in infancy and you have to consider what happened to the gut over an individual's lifetime to try and explain causation and and that's so important particularly in young people because what we know is that young people now have a very significantly increased risk of bowel cancer compared compared to older people so the millennial generation have a risk of bowel cancer that is four times that of someone born in the 1960s or 50s and the epidemiology of bowel cancer is changing very very dramatically and we think that a major driver of that change is the microbiome and it's and to understand that you have to understand environmental microbiome gene interactions so so it's actually quite a complicated challenge to unpick.

Siobhan: 12:53

So that i always find that really alarming this idea of colorectal cancer in younger age groups now and i read that in your book about that four times risk.

James: 13:03

In the.

Siobhan: 13:03

Gen z generation so what what is happening there so if you say um you know you're looking.

James: 13:09

At microbiome.

Siobhan: 13:10

Related causes what changes have occurred that are affecting this gen z generation um that would account.

James: 13:18

For this so so i think one of the problems that we have as clinicians is that quite often we are only able to study a condition or a problem or a health challenge within our silo that we have expert knowledge and and so i think the first thing that i would say in answer to your question is if you want to understand why that change is happening you have to look outside the the sort of cancer spectrum and look at broader global epidemiology and what you see over a very short period of time is by which i'm sort of talking less than 100 years is a rapid rise in the global rates of conditions like obesity cardiovascular disease but also immune mediated diseases like allergy asthma atopy a massive rise in in mental health problems such as um anxiety depression and these sorts of problems that commonly afflict younger people more predominantly but also we We have a very significant ageing population and we have very significant social demographic changes. And I'm arguing that the commonality between all of these different changing paradigms is a slow but very steady destruction and change in our internal ecology. So it's not just a loss of the biodiversity of our microbiome, but also a dramatic change in its function. And that's just so, so critical. And the reason it's so critical amongst many things is because these microbes, they set up and, if you like, program our immune systems to function normally in a complicated and ever-changing environment. Environment and i'm arguing that actually that relationship has been fundamentally. Changed and altered but also that that change is generational because the microbiome is passed from parent to child that actually there has been a generational shift that's happened over a very very short period of time and we can begin to understand some of those environmental drivers and many of them of course are well established and well known so for example we know that we have a homogenized globalized diet that's very problematic we have urbanized populations we have more exposure to an external climate crisis which which we know shifts and changes risk of diseases but some of these things are much much more nuanced and more subtle so for example we are of the opinion or at least i'm of the opinion that antibiotic consumption has been a really, fundamental dry shit sorry determinant of microbiome changes across populations over in very short periods of time because we've just become addicted to it. We consume massive, massive volumes of them, but also pharmacy and medications more broadly. And the result is we're just trapped in a cycle where we have a transgenerational loss in these really important microbes that determine our health. And everything that we do to try and fix it potentiates that destruction. It makes things a little bit worse. So to get out of this, we really need a different way of thinking. And at the moment, I just don't think anyone's been able to really put an idea forward that allows us to break the cycle.

Siobhan: 16:31

I mean, talk about working in silos, and that is one of the problems, and that we're now, as we realise more and more, that we need a systems approach, and it's all kind of, you know, it's networks and everything connects. And you're talking about this sort of microbiome and these commonalities between all these diseases, whether we're talking about cancers or mental health disorders or cardiovascular disease, and this common pathways, including low-grade inflammation and various other changes. But are you unusual? because I don't know many surgeons who also do research. Is that unusual?

James: 17:07

Yeah, I think if you talk to my colleagues, they'll probably tell you I'm unusual. I'm not sure that I'm unusual. I think surgeons do do research, but we've had amazing surgeons throughout history that have done transformative work in this field. But I think surgeons typically like to do research generally, not always, but generally, that is practical and patient facing and related to the kind of technical art of surgery so you know performing surgical procedures like robotic surgery um but actually if you look at the really big innovations in surgery that have really shifted the dial and changes the way it changed the way we we you know that really changed patient outcomes they've not generally been technical so for example antisepsis you know joseph lips lister or if you look at you know um the the the creation of antibiotics, the creation of anesthetic, the creation of anesthesia, these things have transformed outcomes. It's not whether or not you can perform an operation minimally or invasively or not. And that's why to me, the microbiome is just so critical. Allows us to perceive human biology through a completely different lens it completely reframes how we look at human biology and it gives us a completely new set of tools and levers through which we can really impact on patient outcomes and when you when you sort of look at human biology through the microbiome instead of seeing a human being as a if you like a a biological organism whose health is determined by its genes and its genome and the environment actually what you see is a biological organism that is the composite of trillions or hundreds of trillions of bacteria and their own genomes interacting with our genome and actually we are sophisticated super organisms where we are complex uh a complex super organism that is the sum of all of those different microorganisms and and that transforms the way i look at my patients the way i manage my patients i'm much much more sympathetic to the microbiome and much more understanding that actually sometimes um killing all known germs bad or sorry killing all known germs dead is not necessarily the right the right strategy.

Siobhan: 19:19

Yeah that's why i wanted to bring you back or ask you about your colleagues because certainly i was educated in the medical school system you know on the background of the germ theory of disease and we had to get rid of them you know lots of antibiotics and all germs are bad they're a threat to human survival um and it really is a massive paradigm shift for the westernized health services to start thinking differently about microbes um and not only i don't know what the percentage of uh bacteria that cause are potentially pathogenic to humans are, I think it's between 5% and 8%. But most organisms, presumably microorganisms, are either disinterested in us or, you know, potentially beneficial. How do your colleagues see it?

James: 20:10

I think, you know, I've got some amazing colleagues who are very forward looking and think differently or who are interested in it. But I would say that the majority of my colleagues, I think, probably still mistrust microbiome science a little bit. And I think there's a number of reasons for that. And I think most of my colleagues are really just trying to deal with urgent health care problems. And they're just using the tools that they've got. and quite often the first tool in that armory is an antibiotic and and they use it um so so i'll try and sort of take just take a step back though and and answer your question a bit more broadly because um i think if you go back to like the 1900s the thing that was most likely to kill you was a pathogen you were most likely to die of pneumonia if that didn't kill you it was tuberculosis and if that didn't kill you it was probably cholera or a gi-mediated disease and and if you you like the the tremendous success of antibiotics and antisepsis meant that by the 21st century actually that is not the thing that's most likely to kill you um outside of obviously a global pandemic like sars-cov-2 but but um the thing that is most likely to kill people is actually cardiovascular disease. And cardiometabolic disease in fact stroke is the thing that kills most people in the united states but and but the bigger problem still is that these things don't actually kill quite often they maim or they reduce quality of life and they they entrap people in a standard of living which is very very costly for health care systems and very very poor for their own personal experience and and what we're arguing here is a not that germ theory is wrong of course germ theory is right pathogens still cause disease pathogens still kill lots of people around the world we have huge global problems in things like multi-drug resistant tb and malaria and hiv is still a problem these are still important pathogens that we need to address i'm no way saying that we shouldn't but what i am arguing for is an evolution of germ theory that says. Look if you don't treat your mutualists your symbionts the microbes in you that are there for your benefit well then you are at risk of non-communicable disease and what i'm arguing is that effectively germ theory has gone too far in one direction we've become if you like so efficient at killing pathogens that we have inadvertently damaged a lot of these innocent bystanders that we really really need and therefore we should move towards a kind of microbiome-based theory and microbiome-based theory says yep you've got to kill pathogens but you've got to do it in a very very selective and targeted way but actually microbial conservationism is in of itself not just an important prevention strategy to prevent non-communicable disease because actually that's what we should be doing but also as a therapeutic strategy in and of its own right. And that's just, I suppose, a nuance advance.

Siobhan: 23:00

Yeah, I mean, very complicated for surgeons, I suppose, because their greatest fear is surgical site infections. And I mean, just think about colorectal surgery and mechanical bowel preparations and oral antibiotics prior to colorectal resection surgery. I mean, where are we with that? And how do you balance the evidence? What's the evidence? And what does it tell us?

James: 23:22

So I think there's a really great example of how microbiome science is challenging clinical dogma. So in my business, I mean, I say this to all my patients, basically, I'm a plumber, I spent my time taking out dodgy sections of bowel, which are like a pipe, and then I've got two endy bits of pipe, which I joined together. And the medical name for that is an anastomosis. And surgical dogma always dictated that that join failed. We call that an anastomotic leak. That and when that joint fails and you have a leak it's a catastrophe it's not only you know very dangerous and you know patients are at risk of dying if that happens but it causes tremendous morbidity and it's it's it's a terrible thing to happen but surgical dogma dictated that those things failed because either the blood supply to the join wasn't very well performed or the join wasn't well performed or there was tension on that join and and despite the fact that the gut is absolutely loaded full of trillions of bacteria surgeons Biologists just assume that they had nothing to do with it. But of course, that's completely false. So what we have seen is work that has shown that actually it's the bacteria in that join that determine whether or not the join fails or not. And what they do is effectively particular microbes produce enzymes that break down something called collagen, which is the connective tissue that allows the join to heal. And of course, if you either target those microbes, you can prevent leak. But also, if you promote all of the important sort of mutualistic microbes in the gut around the time of surgery through better nutrition or various other strategies, you can also reduce leak. And so in my research group, at the moment, what we're trying to do is to take that one step further. So we believe that actually patients, by the time they come to have surgery, have such a profoundly abnormal microbiome, either because they've had an underlying disease or that they've been on lots of medicines and drugs that have further pushed it away from a state of health, that actually they just need a wholesale change in their microbiome to promote healing and to promote gut function and health through surgery. So we think patients now should move away from having what we call bowel prep where we give patients large doses of purgatives that gives them sorry not purgative large large doses of laxatives which cause awful torrential diarrhea to cleanse the bowel or even worse to give oral antibiotics to actually having a fecal transplant so we think we want to run a trial at imperial we're trying to set up a trial at imperial college where all patients will have if you like the the microbiome from a healthy individual placed into the gut well before they have surgery to try and promote healing and to promote the recovery from surgery. And we've got really, really good data in animals that this is an effective strategy. So we're really excited about that. And that will be a radical departure. Can you measure a microbiome in an individual before you operation? Can you define just how perturbed it is? Can you change it and put it onto a different healing pathway before the surgical intervention? And therefore, can you affect a better outcome? That's the question we're interested in asking.

Siobhan: 26:26

So, I mean, that sounds incredibly exciting. But again, when you talk about things like doing faecal microbiota transplants or even prebiotic and probiotic supplements, it still makes it feel as if the power lies with the medic and they will tell you what you need to do. Just while you wait for this research evidence to come around, it can feel like people sort of say, well, the microbiomes are relevant at the moment. We're waiting for the research to arrive. but I just wanted to ask you about practical actionable points you can use with your patients in the clinic now to prepare for the operation by optimizing their gut microbiome and sort of during the perioperative time afterwards what drugs you prescribe antibiotic use what patient eats can you sort of how do you explain that to the patient what sort of things might you tell them.

James: 27:17

I think you raise a really interesting point I'm not sure the power does lie with the medic i think actually in this particular space actually the power quite often lies with the patient and with the consumer and very often it is the patient that's rocking up in a clinic going hey i've had a consumer test on my microbiome what does it mean or i want a probiotic please what do you recommend and i think the problem is that many clinicians are on the back foot and just don't have an understanding of what those tests mean or they can't answer the question what what is the right probiotic for the right for the right treatment course um and but i i think that is changing um but i do think much of the microbiome revolution if you like has actually been patient driven i don't think it's necessarily being clinician driven um now the good news to all of this is that there are lots and lots of things that you can do which are really really important for your patients um and i you know i can give you a bunch of examples so the first would be. And obviously the most important thing is to not destroy it or damage it unnecessarily so if you are going to have to give antibiotics and there will be times when you simply have to give a sorry you simply have to give antibiotics it's, really you need to be sure that you're giving the most narrow spectrum antibiotic that you can that you're culturing and and giving antibiotic advice based on sensitivity results and keeping those courses of antibiotics as as focused as you possibly can um the second is you are going to give an antibiotic i think it is worth giving nutritional and dietary advice with it and also pro or prebiotic advice with it so for my patients what that means is is that i give them quite careful counseling on doing many of the common sense things that you probably already know and may even say to your patients so avoiding ultra processed foods shifting to a plant-based diet and trying to get to the magic 30 grams of fiber a day if they can it means avoiding refined sugars it means avoiding alcohol and it means it means having a diverse diet because a diverse diet improves microbial diversity so quite often i will recommend that my patients will take a fermented food with that For example, when it comes to probiotics, I am quite pragmatic. So our probiotics can be very very expensive. So either if there's a specific use case and, So, for example, a patient's got infected diarrhea, I will look to the literature and try and give an evidence-based approach. So, for C. diff, for example, Saccharomyces boulardii, it's got lots and lots of evidence, so I will go with something like that. But if there is no evidence and I'm not sure and a patient wants to try something, I try and make recommendations that are cost-effective, that are cheap and easy to use, and that will give the patient a good trial. So, I will recommend basically kefir. you can have water-based kefir if they're lactose intolerant and actually it's got lots of lovely probiotic strains it's got lots of prebiotic fibers and it's a pretty effective treatment i do my go-to is actually prebiotic fibers uh in the first instance because i think they're cheaper and easier to take and i will either recommend an indian or a glato oligosaccharide fiber and i try and do that in as a targeted way as i possibly can it's the final thing to say so I do sequence the microbiome as part of my routine clinical practice I appreciate that isn't going to be for everyone it's not going to be for every clinician because I think the challenges you need to understand a little bit about what you're measuring and I don't use consumer tests to do that I use a clinical a clinical analysis because I think the majority of the consumer tests are not fit for purpose kind of a long-winded answer sorry no.

Siobhan: 30:50

It's incredibly Incredibly important, actually. And it can feel because this, we, although microbiome science is a new science, it can feel like someone's invented it in their lab. Whereas actually, it's just incredibly important to remind people that these microbiomes, you know, existed long before we arrived. And we are, if you like, another surface to be occupied. We're walking ecosystems. systems. And I think people can often feel that if they want to enjoy the benefits of this newfound science, they have to spend a lot of money. They have to have costly tests and costly prebiotics and probiotics. Just wondered, Sheena and I try to really push this idea of frugal medicine, if you like. And, you know, it's this, you know, making it equitable to all that you can, the low-lying fruit with microbiome science at the moment is in these small changes on a daily basis. And these things are, you know, increasing your fibre and diversity of your intake of plants and vegetables, as you said. But also just you know trying to avoid antibiotics when you don't need them and the idea of fermented food if people did did that um do you feel that that is a significant inroads into optimizing your gut microbiome because everyone always thinks you know should i be doing these tests should i be taking expensive probiotics in healthy people yeah.

James: 32:17

Um so i think um And I think the joy or the value often in microbiome science is that it explains how well-established health prevention strategies actually work and provides a mechanism for it. If you like, it allows policymakers to make more robust decisions about how to maintain and improve health care, as well as offering new avenues of prevention, which I think is really important. And I do think, you know, microbiome science is a young science still comparatively. We've only been going at it around 20, 25 years really in any detailed way. And it's obviously a complex and nuanced science. And we don't have all of the answers and that data set is constantly emerging. The problem that we have is that many of these patients that come to see me particularly who are interested in the microbiome are often suffering terribly and they're often suffering from chronic diseases which don't have answers from traditional medicine and have been failed by typical medical therapy and they're desperate and the problem there is that the microbiome can can then be whatever you want it to be. And it's very open to manipulation and to misuse. So it's very easy for a social media person to say, oh, we've got this magical thing called the microbiome that just conveniently fills the gap for whatever nutritional supplement they're trying to sell. And as a result, I have a lot of people that come and see me that have been mistreated by nutritionists, who've been put on extreme diets, who have been given dubious microbiome-targeted therapy, and actually have come to harm from it. And so I think we do have to be very, very careful. I do agree with you, though, that microbiome consumer testing has basically been the Wild West and patients and consumers have not been well served. These tests are often very expensive. They often are not reproducible or standardized. They often actually don't give you very deep precision on the analysis of the microbiome and the computational analysis of it is very very variable and it's very difficult because it means that you can't really compare apples with apples and you don't really know often what you're measuring so i you know i do think microbiome analysis should be a critical part of clinical medicine like why would you not want to measure these communities of microbes if they're so important for your health we absolutely should be measuring them but what we absolutely also need is standardization better regulation and better quality control of these tests so that they become not just value for money but they become really, really useful to frontline clinicians because they should be really useful to frontline clinicians. When I use them in my practice it's very very helpful when you can show an individual the damage that a course of antibiotics has done and how to correct it you can use it to stratify nutritional and dietary strategies you can use it to stratify probiotic approaches you can use it you know to actually improve the efficacy or sorry to change the toxicity or effectiveness profile of individual medicines and drugs so you know it's a really useful tool if used effectively and I I think it is cost-effective if used effectively. It's just a shame that we've got lots of people out there selling these dubious products into the wellness industry, which, you know, which cause quite a lot of damage.

Siobhan: 35:46

Yeah, I mean, I have to say, I've never had an analysis done myself, but I do get people because they know that I'm interested in this area coming up and showing me these kind of, you know, lists of...

James: 35:55

Oh, we should totally do that.

Siobhan: 35:56

Oh, well, yes, yeah.

James: 35:58

Why don't you see if it's out of your microbiome?

Siobhan: 35:59

Well, you have to do Sheena as well.

James: 36:02

You should totally do that.

Siobhan: 36:02

You have to do Sheena. Oh, we'll do Sheena as well. I would like to, because I think it shows, okay, so this is my slightly lay person, if you like, because this is a whole new science view of it. I sort of think what's the point of having a photo, a telephone book of, you know, a list of bacteria, if I don't know what to do with it? It's not got a range like other blood tests, like the HbA1c, where you know what to do with it, and you won't know what's normal, abnormal. Normal so unless it's in someone's hands like yours where you're doing you know sequential tests for a specific purpose i don't understand how a one-off stool analysis could be helpful well.

James: 36:40

Okay, so let's answer that. And let's dig into that. And so the first thing is that you said to me that what we need is systems thinking. So and then what you've just said is, well, unless I get a linear test with it, which is either binary or, you know, easy to interpret, then I can't understand it. So we've got to meet in the middle somewhere and find a way that you can have a degree of systems analysis that is actionable and useful. So so i use a microbiome test in i suppose three or four key ways the first thing is that yeah because by definition the microbiome is is is vulnerable to change and shifts particularly through disease states or after medicational therapy that actually it's a longitudinal measure so a snapshot cross-sectional one time point microbiome analysis probably isn't as helpful as having multiple time points but actually having a time point when you're healthy and well is incredibly useful and beneficial because when you get that traveler's diarrhea when you get sick when you're on antibiotics when you when you become unwell you at least then know where your microbiome is supposed to be and that's important because our microbiomes are all so variable between individuals so actually have it even if it is a time point having that one time point is. Quite helpful the second reason it's very helpful is that it gives you a measure of the ecology of your microbiome so it allows you to measure not just the diversity but actually the resilience how strong is your microbiome in the face of change and how tough is it going to be if you do get sick or if you become unwell and also what do you then need to know to do about So actually, a microbiome analysis should come with a series of actionable interventions, which are invariably nutritional or dietary, which you can then make and then also see the effect of that change. So if you're making nutritional and dietary changes, you can then retest and you can prove that what you're doing is actually having a beneficial effect. Third reason why it's very very helpful is if you've got a good test and a good product actually it will give you strain specific information it should get all the way down to tell you very very specific members of the microbiome and invariably when you do it and i do it a lot is that you find occasionally some patients are carrying large abundances of microbes that just shouldn't be in the gut which you can then target and do something about or it will tell you that they're They're not carrying enough probiotic strains. And again, that is another, if you like, lever for sustained behavioral change. You can say to a patient, look, these specific microbes are missing and you really need to correct that. In the same way you say to someone, hey, you need to be making nutritional dietary changes for your cardiovascular, cardiometabolic health. Well, now you can say it for your gut health and you can do that in a really, really targeted way. And quite often you see changes that actually often relink or come back to causation. So for example i see patients that have um you know really terrible ibs and that ibs when you look at these microbiomes you see these poor people guts really really dominated by single players that just that are just profoundly abnormal and shouldn't be there and and and the problem is that no one's ever really looked and therefore they've just been going down endless cycles of care which are misdirected because people just haven't been able to see the underlying line problem so seeing that problem is quite is quite helpful microbiome analysis is in no way a panacea and it's not the solution to everybody's problem but it should be a tool in a clinical box that you're allowed to leverage that will give you insights into a critical you know mode of health what's very very unhappy unhappy unhelpful sorry is like a a uh you know a direct to consumer test that that renames all the bacteria you know colin and jeff and steve and sue and you know emily and doesn't really give you any detail that is not quantified that is not reproducible that is a black box technology uh and which isn't which isn't standardized.

Siobhan: 40:45

But the level of expertise that you're talking about, I mean, it's not available in the NHS, but you know, there's the occasional person like yourself, but I can't imagine. Is there medical students being taught about microbiome science? Have you got a new generation of medics who are aware of all this?

James: 41:05

I think that's a fair point. But I think that is changing. So we're seeing various initiatives throughout Europe and throughout the UK to try and change that to both, you know, standardize the kind of reporting and to make them easier to interpret. I think a lot of these tests are very variable and they use a lot of technical language and that's tricky. And yeah, we are seeing a very significant shift in what we teach medical medical students at medical school, and we're trying to give them the tool. If you're interested in this, you can go to humanmicrobiomeaction.eu. And there's a little bit there on one of the Horizon EU funded projects that will give you a bit of background into what I'm talking about.

Siobhan: 41:58

Yeah, I mean, I definitely would take you up on that offer. And I would definitely be coming from the sort of slight cynics point of view, which may maybe is helpful. You know, what do we do with this information, this idea that giving people data alters their health behaviors has got a question mark over it. Just giving people more and more data, whether it's data about their genome or their microbiome, and just sort of putting it in their lap and saying, right, there you go. You've got a, you know, and how it's associated with increased chance of various diseases. I'm just not convinced. It sounds very glamorous, but at the end, it's just numbers. And we don't do well with just give people numbers.

James: 42:40

Well, I certainly don't think it sounds glamorous. I mean, I think it sounds overwhelming and unhelpful. And I think that's why consumer tests have been really, really problematic, because the cart has gone well before the horse. And what you don't have is any kind of standardized way of explaining or communicating these results. And I think if you look at what happened genomics, in human genomics, it's taken them a very, very long time to get their house in order. So the nhs now has guidelines on how you communicate a report and share results we now have kind of national uh genetics mdts we have you know clinical geneticists that are able to explain that data and i think the microbiome science is a long way is a long way behind that but but but i do quite strongly feel that um you know having used microbiome analysis in my my clinical practice that it very often changes my clinical decision making and um it's a tool and if we're saying that the microbiome is a key determinant of human health why are we not interested in measuring it why are we not measuring it it makes no sense to me uh we have to well.

Siobhan: 43:55

Certainly your arguments are well made and and convincing and i am i'm thinking about them so if If we take something like colorectal cancer again, something like Fusobacterium nucleatum, which is associated with increased risk. So are you saying, presumably, is that found in people's normal microbiome to a small degree or is it absolutely always an indicator of increased risk?

James: 44:22

Yeah, it's a super interesting question. So for those of you who are listeners that don't know, Fusobacterium nucleatum is typically an anaerobe found in the mouth. And it's a common commensal. It's a normal microbe. We're supposed to have it in very low abundances. And what we find is that this bug turns up in lots of different cancers, actually, not just colorectal cancer. It turns up in upper GI cancers, in fact, breast cancers, a lot of solid cancers. And it seems, excuse me, to get there through the blood. And we're not entirely sure how that mechanism happens. There's been some very interesting work that's been published just this year that's identified that actually there are very specific subclades within Fusobacterium nucleatum and we're beginning to identify particularly these clades. And there are two things that are relevant perhaps for your listeners to know. The first is that you can significantly improve the accuracy of colorectal cancer screening tests if you look for these microbes in the standard tests that all GPs do, which is something called a FIT test or faecal immunochemistry testing, which screens for blood in poo. So we can take those samples, we can sequence out the microbes, and if you find those microbes in them, the test becomes significantly more accurate. There is also something helpful in knowing this piece of information that because it seems that when you detect the Fusobacterium nucleatum clades in the mouth and in the gut, so when it transitions from going just in the mouth to going into the gut, that's the moment when your risk of colorectal cancer changes. And we're getting to a point now where Fusobacterium nucleatum is actually, i think probably going to have its status changed and i think it will likely be one of the first bacteria that we have labeled as really being oncogenic we see it as an intratumoral bacteria so we find this microbe in cancer cells we find this cancer inside metastatic cells so cancer cells that are spread to different organs we understand that fusobacterium changes the behavior of cancer it makes it more aggressive and it also changes treatment response to cancer so we know that it can drive resistance to particular chemotherapeutic drugs and we know the mechanisms through which it happens so fusobacterium nucleatum is an important kind of example i think of of how how microbiome science is making really actionable changes to a common condition like bowel cancer.

Siobhan: 46:50

So we're talking about you know microbiomes involvement in diagnosis and risk stratification um we talked about sort of some aspects of perioperative care and how important it is we haven't talked about how it can improve your response to chemotherapy and reduce your chances of toxicity but if i can just go right back to the beginning when we talked about this.

James: 47:09

Timeline that.

Siobhan: 47:10

Was years or decades before that person was diagnosed with colorectal cancer so i'd just like to because again we can you know i i we sort of talk about germ theory Then we start talking about bacterias being oncogenic, which they clearly can be. But if we go to the prevention and how your human microbiomes, particularly the gut microbiome, can benefit you and keep you safe and protect you from cancer. Can you explain how that could be?

James: 47:42

Sure. So what we know from really, really good epidemiological studies with many hundreds of thousands of patients from multiple different groups across the world is that if you have antibiotic use, so regular antibiotic use when you're young. Your risk of bowel cancer changes. It goes up, particularly in women. The risk of adenomas go up. What we know is that pregnant women who are obese and who have an abnormal microbiome are more likely to have children at higher risk of bowel cancer and these two pieces of information are important they tell us that bowel cancer risk can be determined in early life and that the microbiome is quite likely to be a key part of that story it may not be everything but it may be part of it it might be that your gut is colonized with drivers so these bugs like fusobacterium nucleatum that we know are kind of directly causative it might be that the microbiome is set up for metabolic signaling that slowly changes your risk over time so for example it might change the way your bile acids metabolize it might reduce your way your kind of short chain fatty acid metabolism there might be a number of these different pathways all at play and so the way that i think about it is if you want to understand cancer risk you have to understand that probably four or five events maybe three or four events have to happen in an aligned way to lead to a risk of cancer the first is that the maternal microbiome signaling if you like needs to be disrupted or abnormal in some way the second is that the microbiome set up in very early life so from birth basically it's about the age of five is disrupted and that's really really important because it means your immune system your gut may not be set up to be quite as robust. Third is that you have an event where actually you have a long-term sustained environmental, risk interacting with that microbiome now that might be a poor diet for example you might be living in an urban environment with a very very westernized diet and we know that that drives colorectal cancer risk the fourth is that eventually you get a polyp that that precursor lesion that we talked about or you get a cancer and then the microbiome again takes over and it shifts the trajectory of that cancer so i think about it in a very very time dependent way and i think about the microbiome if you like influencing cancer risk it it kind of different levels it might do it at the kind of the intratumor level it might just be in the lumen of the bowel.

Siobhan: 50:14

Look i'm going to move on to your book okay so dark.

James: 50:17

Matter the.

Siobhan: 50:18

New science of the microbiome it's amazing and i've read it several times each time i read it it's i just there is so much in In fact, it kind of makes my headache. Each chapter has got so much in it that every time I read it, I don't remember reading certain paragraphs. So you just go so wide. I would expect someone who's a surgeon with an interest in colorectal cancer and the microbiome to just stick within that remit. But you go, I mean, you go huge. You start at the beginning of time. you take in evolution, ecology, microbiology, planetary health, plastics, climate change, food systems, ultra-processed food, emulsifiers, antibiotics. I mean, the list goes on. What were you thinking and how did you do this without going slightly crazy?

James: 51:04

What were you thinking? Yeah. Well, look, I mean, I think that there's a couple of things. The first thing is that I wanted to write, I wanted to produce a body of evidence that would convince people that microbiome science is not just highly credible, but that it is so, so important for the future of humanity and for the future of human health. And to do that, you've got to write broadly. The main hypothesis that i'm really reaching is that we are experiencing an internal climate crisis and in the space of around 70 or 80 years we have decimated these very very precious biodiverse ecosystems within us and their destruction is right is causing this rise in non-communicable disease that we've discussed over the last hour and to provide a compelling body of evidence to support that conclusion you've got to go wide and and i really want people to understand that the microbiome isn't just something that affects us when we get old and we're worrying about non-communicable diseases. It affects how our organs develop, it affects how our brains develop, and it affects so many of these really, really critical processes that define us and define our health. That might be your sex or your gender, it might be how you think and how you feel. And you can't really make that case, at least I believe you couldn't really make that case unless you talk widely. And that was what I tried to do.

Siobhan: 52:35

Yeah, I mean, it's, if I can just, you know, one quote, the human microbiome represents the most important new therapeutic target that we have for treating the greatest threats to human life in the 21st century. That's a kind of, you know, bold statement. You really feel it's that important.

James: 52:54

Yeah, I do. And, you know, I think what science will continue to do is to biohack the microbiome and to try and bypass it, right? Because ultimately, it's much easier to bypass it. But the problem is, is that doesn't get us to where we need to be, which has to be disease prevention. What we can't have is a healthcare system that is reliant on incredibly expensive, drugs that manipulate our immune system, which keep us in a very, very expensive you know chronic disease state and which don't cure us the drugs that are making the most amount of money for drug companies at the moment are all biological therapies that regulate the immune system to treat conditions like rheumatoid arthritis to treat conditions like inflammatory bowel disease and these diseases are preventable and i'm asking the question why are we accepting the fact that our kids are more and more exposed to this why aren't we interested in trying to solve the problem of causation. And unless you understand the microbiome, you cannot prevent these conditions. It is completely unsustainable for us to be living in a society where we have inflamed, obese, unhappy, stressed, anxious kids constantly trying to fix their problems with more medicines and more drugs, which keep us and trap them in a perpetuating cycle. And the only way out of this is exactly like the only way out of climate change like we can't solve climate change. With you know technology alone we have to have system solutions and we have to have a different way of thinking and we have to have a different way of preventing disease and that has to come through some form of microbial conservationism i'm completely convinced of that and that's why i think it's so important so.

Siobhan: 54:40

Towards the end of your book um after talking about incredible credible potential manipulations of the microbiome going forward, you did sort of list some really very sensible, actionable points. But sometimes when you say common sense and sensible, it makes it sound less potent than it is. Can you sort of go through, if you were giving, advising people, I sort of feel that these things done daily have potential to be very influential on people's health. You know, could you sort of talk through the nutrition things that you might, you know, advise the general public to do?

James: 55:18

I think, you know, it is much like climate change. And most of us, you know, understand that if we want to reverse climate change. We all have to take a little bit of responsibility and do little things on our own. And just to do them repeatedly whether that's recycling or you know perhaps thinking about the way we travel and I think the microbiome is just the same so you know nutrition and diet so a couple of simple things again like you will have heard of all of the things I'm going to say I'm not going to say anything radical but it is very much firstly about de-westernizing your diet so it means trying to really stay away from ultra-processed foods pre-processed pre-packaged foods but it also means really deleting your food delivery apps those uh you know are really not great for your gut they're really not great for your gut microbiome and it's much much more important that you go and go to the supermarket yourself you have a diversity of food that you have control of and more importantly that you get a bit of exercise when you're going to and from the shops and you know the next thing that i would really say is is social eating and social consuming is so important so the microbiome is defined of course by how we share microbes between us and we are increasingly lonely and eating alone is you know something that many of us do but actually if you can eat socially it really will be great for your microbiome we know that social people have more diverse microbial ecosystems and they're more likely to have robust and resilient microbiome systems i think cooking and preparing your own food is really really important so we We often think about nutritional content. But we don't think about how we cook it. And I think that makes a very big impact on your microbiome. And I think taking responsibility for how you cook it is also really, really important. My big one, of course, is just to get more fiber in your diet. So don't overcomplicate it. But if you can have at least 30 grams of fiber a day in your diet, your risk of cardiovascular disease, your risk of diabetes, your risk of stroke, your risk of cancer, everything will go down and you will live longer and you will live happier. So please do that and you'll feel much better. The challenges, of course, is that the modern gut really struggles with fiber. So many of my young patients who come to see me feel like they bloat and have discomfort when they eat vegetables. So if you're one of those people do work with a dietitian they are worth their weight in gold love dietitians but also if you can't afford a dietitian you don't have access to one, just go slowly you can make those changes but make them really really slowly every period of months and your gut will adapt to it and you'll be surprised at what you can what you can tolerate.

Siobhan: 57:50

Yeah i mean i second you about dietitians i'm back at university doing a master's in nutritional medicine and oh my goodness it's so complex and these these dietitians and the knowledge these they have is is incredible and so important you've also just reminded me dennis burkett when we're talking about surgeons who do research of course you know the legendary in the 1950s 1960s so so for any listeners who aren't aware this is a i think it was an irish surgeon who then did missionary work in Africa and ended up in Kampala, I think, in Uganda and did lots of incredible epidemiological work on the connection between high-fiber diets and low- very low rates of um colorectal cancer in in the the populations in uh in uganda um and he was sort of you know one of the first people to make this big connection i'm sure he's he's almost certainly someone who's uh who you've uh studied um but i i love his work just thinking about robotics because he did this wonderful work i think he retrained or got some training from an orthopedic surgeon And he went back to Uganda and he literally went to scrapyards and found bits of metal and wood to make prosthetics for amputees, amputee children in Uganda. So I love this idea of going back to your robotics, just, you know, sort of doing all those things and connecting. You know, I think I think in your book you said you've got a brain that fizzes with ideas. And um i think that's fantastic because all these things connect and one thing really influences another and again i suppose what you're doing is you've got a systems approach to your work that you're being influenced by all these different areas um and it's it's fantastic to see it's fantastic to listen to you james you've you've been more than generous with your time i've learned so much i have so much more to ask you but i want to thank you for your incredible contribution, I mean, to this wonderful new science of the microbiome, your work as a surgeon, as a researcher in the field, as an author in this book, which we haven't nearly given enough time to, I urge everyone to read it because it is for all of us. And it's a really beautifully written book. I love your turn of phrase as well as the, you know, encompassing this whole area. It's, you know, absolutely wonderful. So I definitely recommend everyone read that. So, James, thank you so much.