#625: Does Changing the Microbiome Actually Improve Health? – Prof. Harry Sokol

0:00Prof. Harry Sokol: Hello and welcome to Sigma Nutrition Radio. This is episode 625 of the podcast. My name is Danny Lennon and you are very welcome to the show. Today we're going to be talking about a range of topics that relate to the gut microbiome and health and specifically taking a look at some of the common narratives we hear in this area, seeing is there evidence behind them, and then based on the evidence, how we should assess that, what types of outcomes are actually meaningful that we can draw conclusions from, where does that leave us? And then some of the new avenues in this field that might be more promising if we can get the quality of evidence that we are looking for.

0:41Prof. Harry Sokol: And so to go through all this, I'm going to be talking with Professor Harry Sokol, who is a professor of gastroenterology at San Antoine Hospital in Sorbonne University in Paris. He's also an internationally recognized researcher in the field of inflammatory bowel disease, gut microbiota, fecal microbiota, transplantation, and not only has done really interesting work in some of these specific fields, as well as developing some potentially innovative treatments that we'll discuss, but has also been very clear to publicly talk about the excessive hype that can sometimes come in this field when headlines that we see are drawn beyond what the evidence can actually conclude, as well as when we base certain beliefs or conclusions in this area on the types of evidence that can't really demonstrate those things, at least in a causal manner.

1:35Prof. Harry Sokol: So we're going to try and discuss a variety of these issues as we go through this episode. For those of you who are premium members, of course, you will get a set of detailed study notes to accompany this episode, which you can click through in the description box or over on the website when you go to this specific episode. For those of you listening on the free public feed of the podcast, if you're interested in getting more out of this podcast learning, using this more as an educational resource that you can learn a bit deeper from, that you can revise over quicker, that you can pull information from, and then translate into your either own learning or your own content, etc., then check out what we offer with a Sigma Nutrition premium subscription.

2:18Prof. Harry Sokol: all that will be linked up in the description box where you're currently listening and of course you can also click through to the episode page there as well and i'll give some more related resources to this particular episode so with that out of the way let's dive into this conversation between myself and professor harry socker

2:49Prof. Harry Sokol: Professor Harry Sokol, thank you so much for taking the time to come and join me on the podcast today. Thank you. Very happy to be with you today. The pleasure is all mine. I've been really intrigued to put a number of questions to you, because as we'll get to, this is an area that there's been a lot of interest generated. But I think still there's a bit of confusion, given how sometimes some of the claims might outpace some of the evidence. But before we get to any of that, maybe for people listening and to give them a bit of context, can you give them an introduction into your academic background, your research interests, the work you do, anything else that might be relevant for our discussion today?

3:29Sure. So I'm a gastroenterologist. I'm professor of medicine in Paris, in St. Antoine Hospital in Sorbonne University. I have clinical activity seeing mostly patients with inflammatory bowel disease. I'm also coordinating the Center for Fecal Microbiota Transplantation in the Paris area. And I have a research lab focusing on host microbiome interactions, really trying to understand these interactions between the host and the microbiome with the idea to turn this science into medicine, either new drugs, new biomarker, and this type of thing. And maybe something I want to disclose is that I co-founded a company based on my research to really develop one bacteria as a drug.

4:16And this is something currently in process with several clinical trials now ongoing.

4:22Prof. Harry Sokol: And we'll certainly get into that. And there's a few different areas that I want to touch on. And we'll come back to them at different time points. Because as you note, some of this work is really at the cutting edge of really interesting and intriguing research. but maybe to get a broader overview for people listening because i'm sure they've heard a whole range of different claims when it comes to the microbiome and then how things that we can do can interact with that probably a place i like to start is with the concept of what we might refer to as a healthy microbiome because there's much debate about not only what that is but even how we go about maybe defining that in a clinically useful way.

5:04Prof. Harry Sokol: So for you, how do you conceptualize something that we can term a healthy microbiome? Or is that even a useful place to try and start getting definitions? So that's a very good question, a very complex one. And actually, at least for now, there is no good answer. We cannot define what is precisely a normal microbiome. Actually, there are very good reasons for that. The microbiome science is relatively young. We are studying really in depth this field since maybe 20 years, 25 years. And many very important functions of the dead microbiome are still unknown. So if you do not know the normal function, it's very difficult to describe what is normal and what is not normal.

5:53The other aspect is that usually we are working and describing the microbiome in terms of its composition. So what bacteria are here, what bacteria are not here, their abundance, the diversity, and so on. But the more we work on this field, the more we understand that basically the name of the bacteria is not so important. What is important is what they are doing, and many different bacteria can do the same job. So the field is moving from what we call a taxonomic description of the microbiome, again, what are the bacteria here, to a functional definition. So what are they doing? What are they able to do?

6:41And I think that if one day we are able to describe what is a normal microbiome, it will be with this angle.

6:48Prof. Harry Sokol: One of the areas that I'm sure that you've seen people maybe get confused is look at various headlines that we tend to see maybe in mainstream news, on social media, etc. where maybe they've taken a study that has shown some association between let's say a certain type of microbiome found in a healthy group or and then compare that to another group that has some type of disease and seen a difference in that microbiome composition and then from there jump to conclusions about what that may be driving that disease and it has to necessarily be connected and of course for many people that's an easy trap to fall into can you maybe explain the things that people might need to be on the lookout for and how we can be how we need to be careful in maybe some of the interpretations we see of that type of associational work that shows differences at that type of level and maybe a difference in an outcome like a disease and what we really need to do to understand And are these microbial differences driving that disease or not?

7:55Yeah. That's a very important aspect. This is basically the difference between correlation and causality. So when you compare a group of people who are healthy to a group of patients, they are different in many ways. And if you start describing their microbiome and see differences, this is only a first step. And actually, the differences you see in their microbiome composition can be related to basically the role of the microbiome in their disease. But they can also be related to the disease itself acting on the microbiome. This is what we call reverse causality. And that's why it's absolutely not sufficient to conclude that the microbiome play a role in the disease.

8:44So just I can give you a very simple example. Let's say you get, unfortunately, a gastroenteritis. You will have quite strong diarrhea. You will have abdominal pain. And if you analyze the microbiome at this time, it will be altered. And it's not because the microbiome in this disease plays a role. It's just because you got a virus, you got some kind of inflammation in the gut, and this is leading to alteration in your ecosystem. So if you see alteration in the microbiome associated with a disease, and you want to evaluate whether this alteration may play a role in the disease itself, you have to follow different steps.

9:24One step, one possible step at least, is to move to animal experiment. And you can try to transfer the microbiome of patients into germ-free mice, so mice that are raised without any microbiome and actually any microorganism. And you can do the same with the microbiome of healthy subjects. and then you can see whether transferring this microbiome leads to the disease you are studying or at least worsens the disease you are studying. So this is one step. But still, this is not sufficient. This is mice. And obviously, mice are not humans. Even in the field of drug development, tons of drugs that worked in mice did not, unfortunately, work in humans.

10:07So this is an important step, but this is not sufficient. Really, what is necessary to conclude that the microbiome is involved is to make an intervention in humans and to modify the microbiome and to see whether this modification leads to some kind of changes in the disease itself. And for that, you have, again, many different possibilities. One of them is to do fecal microbiota transplantation. So taking the microbiome of healthy subjects, transferring it into patients, and evaluating whether this modification will have some changes in the disease severity. This has been used in many different diseases now and has been very helpful.

10:50But this is not the only possibility. The role of, for example, of antibiotics can be also evaluated. If when you give antibiotics, you see some kind of effect on the disease, this is a clue, at least, that the microbiome may be involved.

11:05Prof. Harry Sokol: one thing that you just mentioned around microbiota transplantation and one of the areas and again you can correct me if i'm wrong that has traditionally shown really convincing results is around for recurrent clostridium difficile and we have really strong results in there from looking from the outside of the field and again you can clarify the exact evidence base we have right now for some other outcomes the interventions have been maybe a bit more mixed in some cases or haven't been as consistent in that case. Why are we seeing differences there? And can you maybe give us a live land for this type of intervention?

11:39Prof. Harry Sokol: Where do we see the most promising interventions in terms of those outcomes? And maybe for what other outcomes have we yet to see a positive signal? Yeah, so recurrent, multi-recurrent clostridioid as difficile infection is a very specific disease, which is almost fully related to an alteration in the gut microbiome. This is related to a bacteria that is present in the environment and may also be present at very low level in the gut of healthy subjects. And in a situation of microbiome alteration, most of the cases is following an antibiotic treatment, this bacteria will have the opportunity to bloom and take the space available in the gut and lead to an inflammation of the colon.

12:26And this disease is really almost fully related to this alteration in the microbiome. And this is probably why acting on the microbiome is so efficient. And fecal microbiota transplantation is, I have to say, almost magical in this disease. We are doing this type of treatment several hundreds of times every year in my center. And this is really helping people. However, in many other diseases in which the microbiome may be involved, it is far from being the only actor in the pathogenesis, in the disease process. So if we speak, for example, about inflammatory bowel disease, Crohn's disease, ulcerative colitis, clearly the microbiome is involved.

13:12There are many reasons to say that. And one of them is the fact that actually fecal microbiota transplantation have shown positive effects in multiple studies and well-done clinical trials. However, the result is far from being as spectacular as in clostridioides difficile infection. So in multi-recurrent clostridioides difficile infection, the success rate is 80 or 90%, which is really, really high. For IBD, mostly ulcerative colitis. If you do FMT to induce a remission, so in this disease, patients have inflammation in their gut, diarrhea, abdominal pain. If you do FMT in these patients, the success rate will be around 30-35%, meaning that this patient will enter remission.

14:01Their disease will calm down. They will not be cured, unfortunately. After some time, in most of the cases, the disease comes back. probably because the microbiome do not stay exactly the way you transfer it. But this is still a positive outcome, but far less than what you get with clostridoridus difficile infection. Many other diseases in which we suspect the microbiome may play a role, the results are not as good. So let's talk, for example, about irritable bowel syndrome. So this is a very frequent condition. This patient has abdominal pain, issue with transit, either constipation or diarrhea.

14:43And the gastroenterologist who is going to do all the tests basically will not find any lesions. It does not mean that it's not a disease and that the patients do not have anything. Far from that, they have something and it's called irritable bowel syndrome. It's mostly related to alteration in the sensitivity in the gut and also microinflammation. but the usual tests say nothing. It has been shown that the microbiome is altered in this patient or at least in subpopulation of patients, not all of them. But until now, the fecal microbiota transplantations that have been done and published are globally negative.

15:23There is no good rationale today to use fecal microbiota transplantation in this patient.

15:29Prof. Harry Sokol: For one moment, I want to talk about some of the potential dietary interventions because at least they get promoted quite heavily as something that could be used. And again, I think this is one of those areas where when you look at some of the dietary intervention work and connecting that to some type of benefit for health outcomes via the microbiome, sometimes, again, things get a bit mixed up here on that chain, that causality chain you mentioned a bit earlier, in that we can see maybe someone publishes a study where a certain type of diet was followed or a certain type of dietary intervention.

16:03Prof. Harry Sokol: Following that, some type of change in the microbiome is noted, and that then is said to be positive because there's some association with that being a good thing. Maybe people talk about greater diversity or a certain type of bacteria and so on, as opposed to a kind of clear clinical outcome. So when it comes to some of the dietary recommendations that tend to be promoted on the basis of quote-unquote feeding the microbiome or being beneficial for our health via the microbiome. How can we start to distinguish between things where we actually have really good evidence for versus some where maybe there's some hypotheses around it, but again, we're not actually so sure in terms of causal evidence?

16:47So first, what you mentioned is crucial. And in the microbiome field, unfortunately, most of the endpoints that have been studied regarding, you know, therapeutic intervention are related to the microbiome itself. And as a physician, to be honest, I don't care about the microbiome diversity. I care about the health of my patients. Does he feel well? Does he feel healthy? Can he, you know, work? Can he has relationships and so on. And that's really one of the issues we had in the field in the last decade, is to focus on microbiome readouts as they are, you know, the most important thing, and they are not.

17:29Clearly, the field should focus on hard outcome, health outcome, like for any other therapeutic intervention we are studying. Regarding diet now, diet is a very, very powerful way to act on your microbiome. From my point of view, it's mostly important in prevention for healthy subjects wanting to remain healthy, and that's the majority, obviously. For therapeutic intervention in patients who already have a disease, it starts to being studied, and in some cases, it showed promising results. But I would say it's very unlikely this type of intervention will replace the conventional drugs we are using.

18:09So now for the general public and as a prevention, what is now acknowledged as probably the best diet is what we call the Mediterranean diet. And there is quite good data about that, both epidemiological data, mouth work, but also intervention in humans. I mean, as good as you can do this type of intervention. And so globally, what it means is that what is good is to enrich your diet with fibers, many different types of fibers and globally high quantities, so fruits, vegetables, and diversity of them. Decrease the amount of ultra-processed food as much as possible. Decrease the amount of red meat.

18:53And you can also enrich your diet with fermented food. For this aspect, the strength in terms of benefit is weaker and usually confounded with other factors because usually people eating fermented food have an healthy diet associated to it. So it's usually a little bit difficult to differentiate the specific effect of fermented food. So globally, that's what we can say. It's also important to recognize the limitation. We do not have, you know, perfect randomized control trial with diet because it's very hard, very hard to do this type of study because diet act on the long term and it's very difficult to control.

19:37So you would need to do intervention study with diet for years and years and control everything and that's not feasible. So I'm not really sure we are going to get much better proof regarding the benefit of this type of diet, but I think we have now a lot of this data. And when you put together epidemiological data, mouth work, and a few intervention studies that have been done, I think it's enough to recommend a Mediterranean diet.

20:11Prof. Harry Sokol: And I think, as you mentioned, this is important for people to know specific populations we're talking about that. If it's at a general population level from that view of prevention, we're looking at some of these overall dietary patterns that can likely be productive or preventative over time. With regards to some of the more clinical applications, there's obviously much less work done in that area and it's much more difficult to do. And again, like you know, expecting that dietary interventions are going to have much of an effect compared to some of the others is probably unlikely. There are some few niche areas that have been showing recent work.

20:49Prof. Harry Sokol: I know that Kevin Whelan's group in London, for example, did a nice study in IBD patients looking at potentially the role of emulsifiers. I think that was kind of the first one, really looking at that, where it does seem to be that there's a difference in that clinical population, whereas we don't see much signal in general healthy populations of it causing an issue. So it seems like maybe from the dietary perspective, there's going to be more specific niche context for a very clear clinical population, for a very specific aspect that we might start to see some signal, but again, probably with more research needed, I'm guessing.

21:24Yeah, absolutely. So emulsifiers are part of what we call globally ultra-processed food, and they have been suspected to play a role in inflammatory bowel disease since some time now. You have quite strong epidemiological data linking the consumption of this type of additive with the onset of IBD, particularly Crohn's disease, and also data showing that patients who have already Crohn's disease have a higher risk to go into a flare if they consume a lot of this type of additive. So there are a lot of data already, mouse data as well. And the study you mentioned is actually one of the first to give actively ultra-processed food and particularly emulsifier or to remove emulsifier from the diet in patients with Crohn's disease.

22:14The study is not yet completely published, but the data that have been communicated are very interesting. They show a lower inflammatory signal in the patient removing emulsifier from their diet. It's not going to replace the drug we are using in the patient, but it goes into this global care of the patient. Using the drugs, of course, but also other ways to act on the disease, and diet is a strong candidate. Right. Removing emulsifiers and other ultra-processed food is one of the components. There are other components related to the amount of fibers, for example.

22:53Prof. Harry Sokol: Super interesting. One area that I did want to get to that you mentioned a bit previously, and that your work has been particularly illuminating in, and that you've published some really nice stuff here, relates to this interaction potentially between the gut bacteria and medications. And again, this is an area maybe people don't have much familiarity or maybe are unaware of. From a broad level, first of all, what is this potential connection? Where did that emerge from that we started to see a potential interaction between gut bacteria and medications? Yes. As you know, there is a huge variability in the effect of the drugs we take in terms of efficacy and in terms of toxicity.

23:34Some patients will, I mean, respond perfectly to a drug and not experience any side effects. and another one with the same drug, same disease, will not see any efficacy and experience side effects. So with all the progresses in human genetics, we thought that this will solve this question and we'll understand from the host genetics this variability. But the truth is it did not work. There are a few examples where it worked, but this is really a very tiny minority. So obviously there are something else and probably different other actors in this complex system. And what emerged in the last few years is the role of the gut microbiome.

24:18There are many ways the microbiome may act on the drugs. The microbiome may basically eat the drug you are taking. There is a very nice paper that has been published actually a few weeks ago on a drug called metformin, which is used for type 2 diabetes. It's one of the most prescribed drugs in the world. Very cheap drug, very efficient for type 2 diabetes. And it has been demonstrated in this paper that some bacteria in the gut can actually metabolize this drug. And the drug is not there anymore. So there is no effect and no efficacy. So this paper is very strong. Of course, the full causality in humans are not being completely demonstrated, but the data are compelling.

25:07So that's one way. The other way is regarding what we call the pharmacokinetics. For example, in Parkinson's disease, the treatment is based on the administration of dopamine. Dopamine is what is missing in the brain of patients with Parkinson's disease. We cannot give directly dopamine to the patient because dopamine cannot cross the blood-brain barrier and cannot enter the brain and so cannot have effect. So we are giving to the patient levodopa, which is a slightly modified version of the dopamine. And this molecule can go into the brain and in the brain can be converted into dopamine and then act on the patient.

25:49And this drug, which is, again, the basis for the treatment of Parkinson's disease, has huge heterogeneity in terms of efficacy and huge heterogeneity in terms of side effects. And one team from Boston showed that some bacteria are actually able to convert the levodopa into the dopa and actually even in further metabolites. And by doing that, the drug cannot cross the blood-brain barrier and cannot act. And on top of that, some of the metabolites may be responsible for toxicity. And there is huge heterogeneity from one patient to the other regarding the presence of these bacteria able to convert the levodopa into dopa and further metabolite that may play a role in this heterogeneity.

26:38Again, this is relatively preliminary work, meaning that the causal relationship in humans is not fully demonstrated, but the data are compelling as well. Finally, there is another example which is interesting. It's with chemotherapy. And this chemotherapy, which is used notably for poccleic cancer, is injected to the patient, and the liver will convert this molecule into a non-toxic molecule. This non-toxic molecule is then excreted in the bile, And when it goes into the bile, it is then secreted in the gut lumen. And in the gut lumen, at one point, the molecule will meet bacteria, and the bacteria will retoxify the molecule.

27:24So the molecule gets toxic again, and this is responsible for very strong diarrhea, which is the main side effect of this chemotherapy. And basically, people are trying now to act on that to prevent this toxicity.

27:39Prof. Harry Sokol: within some of these applications and like you said they're still at maybe a preliminary stage where we need some more work but if we do see this indication that there is this potential for bacteria to metabolize the medication in some way or have some of these other effects then foreseeably one would imagine then the next step is that that's going to dictate that patient's response that medication and maybe at least one of the factors why we might might see that difference in response from different patients is via this mechanism of depending on those bacteria that are there. What are some of the next steps in terms of research questions we need answered in this area that would kind of give us more concrete evidence of what's going on?

28:27So first, we have to validate exactly the concept you described. There is a first study, I mean, the study on metformin I mentioned, the author of this paper did that. So they studied patients treated with metformin, and they were able to separate the patients according to the amount in the bacteria supposed to be responsible for the degradation of metformin. And they show that in patients with high abundance of these bacteria, the treatment was less efficient than in the others. So this is a first step toward stratification, and this was done in a relatively small number of patients. This has to be confirmed prospectively in a larger number of patients.

29:11But if it's true, it may lead to some kind of biomarker to guide the treatment of this patient with type 2 diabetes. Another possibility would be to target the bacteria itself. There are different ways you can think of to try to basically kill this bacteria degrading metformin. and if you do that in theory, you should regain the efficacy of the drug. And the following step is intervention, meaning that particularly if you can find a bacteria that is such as the one with metformin responsible for degradation or metabolization of an active drug, if you can target these bacteria with something, it can be with a phage, for example, a virus that will specifically kill the bacteria responsible for the degradation of the drug.

30:06If you can show by doing that, you reverse the phenotype, you gain the efficacy of the drug again, it will be a definitive proof that this is occurring in the patient. And of course, on top of that, it will be a potential therapeutic tool for the future.

30:23Prof. Harry Sokol: Earlier, you mentioned that your research has then led then to your involvement as a co-founder for some of this development of essentially intervention and essentially working as a treatment using some of this. Can you maybe talk through that work that led to that, some of the background context for it and what you're specifically working on just to make people aware of? Sure. The story started with inflammatory bowel disease and with description. The first step was describing the alteration of the microbiome of patients with Crohn's disease particularly, compared to healthy subjects. And what we observed is a decrease in a bacteria named Thaecalibacterium prosiniti.

31:06And this bacteria is very special, I would say. This is a very prevalent bacteria, meaning that it's virtually present in all healthy humans on Earth. And it's also very abundant. In healthy humans, it represents 5 % of the whole microbiome by itself and sometimes even more. So if with these just two characteristics, this is a unique bacteria. And so we showed that the bacteria is decreased in ABD. And the lower is the bacteria, the higher is the risk to get a flare for the disease. So this is only correlation at this stage. We thought, OK, this is interesting. The bacteria may have biological effect.

31:47So we put it in mice and showed that the bacteria exhibit protective effect in colitis model. We worked on the mechanism of action. We found many different things. But obviously, the next step was to give it to the patients. Again, to see whether really the bacteria can have therapeutic effect. And this was particularly difficult because this is a bacteria very difficult to grow, very susceptible to oxygen. and also when we started with this idea, it was really early days in the microbiome field. It was very new to think of using an intestinal bacteria as a drug. So many obstacles and that's why it was just basically not possible to do it in the academic world and that's why we had to start this company called Exelium to do it.

32:38So we pushed the development. We just published the first study in Crohn's disease. It's a small study, phase one, in eight patients with Crohn's disease. There is no issue with safety. And we show some signal in the small intestine where the disease is the most active in patients with Crohn's disease. And we are now conducting a phase two study, which is randomized and controlled. While we were working on this topic of fecal ibacterium presenity and Crohn's disease, the field actually exploded in the context of cancer and particularly immune checkpoint inhibitors. You know these drugs are really a revolution for the care of patients with cancer.

33:18And these drugs are based on the fact that you can basically release the immune system of the patient so he can fight himself or itself against the cancer. It's not like chemotherapy, which are toxic drugs acting on cancer cells, but unfortunately also on healthy cells. Here, the idea is to release the immune system of the patient so he can fight the cancer himself. And a French team led by Laurent Zidvogel thought that maybe the microbiome could play a role in this effect because the microbiome is really crucial for immune response. And actually, they demonstrated that this is the case, notably showing that if you give antibiotics to mice or to patients taking this type of drug, the efficacy of the drug decreased massively.

34:06And basically, this field moved very quickly, and many studies were published at the same time, around 2017-2018. They showed that some bacteria are particularly important for a good response to immune checkpoint inhibitors. And among these bacteria, we observed Fecalibacterium prosiniti as one of the top hits. So as we were developing these bacteria for treatment in Crohn's disease, we thought maybe we should see whether this bacteria is also helpful to boost the response to immune checkpoint inhibitors. So we confirmed first a signal at the epidemiological level in different cancers. And we did in vitro and in vivo work in mice.

34:50And this is what we showed. We observed that the bacteria boost the response to immune checkpoint inhibitors. and so we moved to clinic because the bacteria was ready to be given to patients and so currently we have four clinical trials ongoing three in france and one in the u.s there is one in gastric cancer one in liver cancer one in lung cancer and the one in the u.s

35:16Prof. Harry Sokol: is on kidney cancer fascinating so we have essentially with these two applications we're at the point where there's ongoing trials looking at this you mentioned for the the first application we're already at phase two we've had that kind of successful phase one trial or don't see any safety issues and so building on that promise that's there and then the hypothesized benefit that could potentially happen from this application from the point we're at now again similar to what we said earlier what is the the gap between there and where you need to get to to have the the confidence in this? What is the, that kind of, can you maybe chart out that kind of next stage once you go through phase two, et cetera, and then depending on the application as well?

35:59So, unfortunately, in the microbiome field, there have been very few examples of probiotics or next generation probiotics. What we are doing with Fecalibacterium Presidency is called LBP, Live Biotherapeutic Product. There have been very few examples of this type of product pushed as a drug. So we want to push it as a drug. And if we push it as a drug, we have to follow exactly the same rules as any other drug. So we have to do phase one studies. This is done. Phase two study to see whether there is a signal. This is true for Crohn's disease. This is also true for cancer. We have also a study in prostitutinitis difficile infection to try to replace FMT.

36:43And then if this phase two studies are positive, if there is some signal, we'll have to move to larger studies, phase two B and phase three, with several hundreds of patients each time. And if we have positive results, then the drug will be registered as any other drug. So this is where the microbiome field, I think, should go. We should manage and think about microbiome-based drug as any other drug. The endpoint should be the clinical endpoint and not, you know, the diversity of the myclobiome or the level of this or the other bacteria. And it should be developed as conventional drugs.

37:21Prof. Harry Sokol: It's such a great point because especially with the types of outcomes we're talking about and their clinical importance, like you say, one of the maybe, whilst understandably from a logistical standpoint, one of the problems with looking at the probiotic literature is, again, you're nowhere near the level or the thresholds required for evidence that you are looking at with the drug here. And so if we have something that does go through a phase one, two, and three of a clinical trial at that type of threshold that's needed, we have a lot of certainty about its clinical effect. Whereas a lot of times we have potential issues interpreting some of the probiotics that are there.

38:00Prof. Harry Sokol: And unsurprisingly, maybe we don't see so much clinical benefit for some of those reasons. So it's going to be really fascinating to see where this goes. So it's exciting work that you're doing. Professor Sokol, one last thing before we round up here that I did want to ask you about, because this is a common question that people have, relates to microbiome testing, both for those that are working in clinical practice, as well as now people have a lot of availability of direct-to-consumer tests as well. I know you were one of the co-authors on a big international consensus statement last year, looking at microbiome testing in clinical practice.

38:35Prof. Harry Sokol: And I will link to that for people listening. I encourage you to go and read the whole thing for all the nuance there. But maybe for an overview level, as we finish out here, when it comes to microbiome testing, at least as it's available right now, do you see much in the way of clinical utility that would go beyond what we would otherwise be recommending from, let's say, a dietary perspective or otherwise a clinical perspective? And for people thinking about microbiome testing, is it giving the type of value that maybe they're expecting it in terms of what they can do with said results? Thank you very much for this question.

39:15Again, very important. There are many studies suggesting that the microbiome may be a source of biomarker of clinical importance. This is true for diagnosis. This is true for prognosis, potentially guiding treatments, and so on. Unfortunately, most of these studies have not been confirmed in large prospective clinical trials. I'm convinced that there is room for this type of biomarkers, but unfortunately, everything that is available now is just useless. First, because there is issue with reproductibility. There have been many studies published and one even last year in GUT, in which the same stool was sent to five different companies selling microbiome tests, and you get five different results.

40:09And not small differences, like very large differences, and even different recommendations and different conclusions. So first, you have a major technical issue. If you do not have an harmonized way to analyze the microbiome, you just cannot rely on the result. And then the problem is how do you interpret the result? And this comes basically to what we discussed earlier about what is a normal microbiome, what is an abnormal microbiome. We do not know precisely. And finally, one of the biggest problems is also the fact that these tests are global description of the microbiome. And it's very unlikely that in the future we'll have one test for any question.

40:56It's like when your doctor sent you to do a blood test. The prescription is not do a blood test. There is a list of tests he wants because he wants specific questions. he wants specific response to specific questions and it's very unlikely that it will be different with microbiome tests so the future as i see it is that we'll have some tests based on the microbiome very likely this test will be combined with other tests more common that we are already doing and these tests will be performed to address a specific question in a specific clinical setting

41:36Prof. Harry Sokol: Thank you for that. And again, a reminder for people listening, I'll link to that paper that I mentioned that has a lot more detail on this that we can maybe get to here. So with that, Professor Sokol, before I get to the very final question that I always end the podcast on, for people who are interested in keeping up with your work from the stuff that's going on with your lab, your company, etc. Where are some places on the internet that they can find you and the work that you're doing? So I'm on LinkedIn. I'm also on Instagram and I'm posting both my work, but also important work from other scientists in the field.

42:13I also wrote a book, which is one in French, but also one in English. So you can get it relatively easily on Amazon. and really the idea of this book is to help the general public but also the health professional to make the difference between what is true science, true medicine compared to promises, so things that are not yet fully validated and also from just lies because there are also lies in this field because people are trying to sell these tests, for example, we were discussing. I mean there is no good reason to recommend doing this test for now.

42:52Prof. Harry Sokol: Fantastic they will all be linked in the description box where everyone is listening right now so you can go and click through and check all of that out. With that Professor Sokol we get to the final question that I always end the podcast on which can be to do with something completely outside of what we've discussed if you wish. It's quite a broad open question so apologies for putting you on the spot with this but it's simply if you could advise people to do one thing each day that might have a positive impact on any area of their life what might that one thing be so the easy answer would be diet but i'm not going to tell you that i already mentioned it i would say try to find some try to find something that makes you happy so in my case besides seeing my family i like listening music and when i listen music it helped me not only focused but also relaxed and this is contributing to my happiness so it's not always about you know diet sport and things like that it's finding something that makes you happy because we know that happy people are actually healthier and this is what is life for we need to be happy brilliant way to to finish this off and with that professor harry sokol thank you so much first of all for taking the time to do this for all the information you've given, but more so for your contributions to the field and the excellent work that you're doing.

44:19Prof. Harry Sokol: It's very much appreciated. So thank you for doing this. Thank you very much.

44:36Prof. Harry Sokol: Thanks so much for listening in to today's episode. Before you go, I just wanted to remind you about Sigma Nutrition Premium, our subscription for those of you podcast listeners who want to significantly deepen your understanding of nutrition science and become truly confident in your knowledge. At the core of the subscription is our detailed study notes that you get to each episode full of useful descriptions, background context, diagrams, charts, etc. to allow you to more deeply understand some of the concepts that were mentioned throughout that particular episode, as well as them linking them back to previous episodes.

45:12Prof. Harry Sokol: You have your own premium podcast feed that appears on whatever app you already use, and you get these extra premium-only episodes. Some of them might be Ask Me Anything sessions where we answer your questions that you submitted directly, or they could be a variety of other episodes that you may have seen previews to in the public feed. So for full details on this, then check out the link in the description box wherever you're currently listening right now, or just go to sigmanutrition.com and you can see all the details there. And of course, your support is what keeps Sigma Nutrition going. We don't run ads, we don't sell supplements, anything like that.

45:49Prof. Harry Sokol: So your support is what allows me to continue to do this. So thank you for that. I hope you do come back for the next episode regardless. And until then, have a great week, stay safe, and take care.