How the Gut Microbiome is Leading the Future of Disease Prevention and Longevity - An Interview With Dr. Emmanuel Hanon

What follows is a transcript for the podcast Gut-Brain Axis - Dr. Emmanuel Hanon - Cognition.

Topics within the interview include:

• The role of the gut brain axis and gene expression in disease prevention
• How the gut microbiome informs the immune systemThe fascinating relationship between the microbiome,
• neuromodulation, and mood

How the Gut Microbiome is Leading the Future of Disease Prevention and Longevity

Naveen Jain: My name is Naveen Jain. I'm founder and CEO of Viome, a healthcare company that is fundamentally focused on preventing and curing chronic diseases, including cancer and aging.

Today it's my honor to be introducing to you  Dr. Hanon. Dr. Hanon is one of the experts in the field of immunology, and I think I'm going to have a conversation with him about his thoughts on COVID, his thoughts on immunity, his thoughts on staying healthy. How can we increase our longevity? How is our gut really connected to our brain? Why do people have this idea that all diseases begin in the gut? Was Hippocrates actually right? With that, I'm going to have Dr. Hanon introduce himself briefly, and then we'll have a conversation right after that. Dr. Hanon?

Dr. Hanon: Yes. Thanks a lot, Naveen. Hi, everybody, my name is indeed Emmanuel Hanon, and I'm actually... I want to define myself as someone that is passionate, that really wants to understand and find new solutions against diseases.

I spent more than 20 years in the vaccine industry developing vaccines against acute illnesses. But at the same time, I was really frustrated by the fact that we were not doing enough against chronic disorder. Basically, not detecting them early enough to activate an efficient treatment. But even most of the treatment against chronic disorder are symptomatic. They are not really actually going after the cause.

And I think, actually, that there is a high likelihood that we might find very concrete solution against chronic disorder by better understanding the interaction of the microbiome and the human host.

So, that's actually what defines me, the intent. But otherwise, my background is I'm actually a doctor in veterinary medicine. I did a PhD and a postdoc for seven years, and I'm very excited to be here with you today.

Naveen Jain: So, first, first of all, Dr. Hanon, you are a global head of R&D for Viome, a company that you and I are working together on. So, let me start with simply asking you a question. You had a one cushy job working for a large pharmaceutical company. Why did you join Viome? What is it that you see that we are doing here that was so exciting for you to leave that job and join us here? And then I'm going to ask you other questions after.

Dr. Hanon: Yeah. As I told you, I define myself through the intent, even not actually the whole. But obviously, with the intent comes the whole. I basically joined Viome because for the first time I saw a place that had the capability to understand, analyze, and actually extract critical information out of the interaction of the microbiome and the host.

And as I said earlier, in the intent of understanding and finding a solution against chronic disorder, I actually deeply believe that, up to now, most of those that tried didn't do that the right way. Viome is potentially the first company that is doing it the right way.

It has a unique database of close to 300,000 people for which molecular data clinical phenotype have been collected. And that, together with the technology and the artificial intelligence architecture that has been created at Viome, it actually gives really the opportunity to potentially find these new solutions.

Naveen Jain: And Dr. Hanon, coming back to you, I would love for you to be able to explain to the people who may not be very familiar with... What is this microbiome that you mentioned a couple of times in your initial dialogue? What is this microbiome? How does microbiome interact with the immune system? Because that interaction is what causes humans to have diseases.

What Is the Microbiome and How Does It Interact With the Immune System?

Dr. Hanon: Yeah. So, the microbiome is often defined as the additional major organ of the human body. Very interestingly, it is not made of our own, actually, genetic code. It's made of sometimes more than 1,000 different bacteria that are living in your gut constantly. These bacteria are doing a lot of things, and I'm going to summarize them.

This bacteria has been also associated, when the equilibrium is not the right one, with several heart disease state. Speaking about, for example, mood disorder, so impacting your brain. Or, what we call irritable bowel syndrome, which is actually some kind of a bad feeling in your gut. Involving metabolic disorder, like type-two diabetes, obesity. Neurodegenerative disease like Alzheimer's. So, anything that seems to alter the equilibrium that exists at the level of the microbiome has been, at least in several hundred publication available, associated with disease.

Actually, the number of publication associating chronic disorders, the one that I just cited, with microbiome has grown exponentially over the last 10 years. And why is that? It is like that because the microbiome, these bacteria, and actually not only the bacteria, there is also the phage viruses of bacteria and other microorganism living in your microbiome, they do different things.

They can produce vitamins, short-chain fatty acids, which are actually important for all metabolism. They generate neural mediator, which are molecules that plays a really important role in your brain. They can even produce hormones. Your gut is connected. And there is some kind of connection between the microbiome and actually the nerves. And so, there is some kind of bilateral information exchange.

And then lastly, there is a super tight and constant interaction between this microbe and the immune system. So, this immune system that is supposed to protect you against the invasion biomicrobe of your body. But this is the dilemma that you have, actually, with the microbiome that is constantly with you, is that the immune system needs to be there, needs to be checking, but cannot be overactive. Otherwise, your gut would be constant inflamed due to the activation of the immune system.

But at the same time, this specific immune system needs to make sure that there is no dangerous bacteria, for example, that take the whole space in the gut, like clostridium difficile. That can kill you. And in that case, act in a very selective and very efficient way.

So, we are speaking here about an extremely complex interaction between the microbiome and the host, and this very complex interaction is actually involving all the different disease processes. And so, the microbiome is one of the big hope moving forward for the pharmaceutical industry to actually to try to go after some of these interaction, modify them, and potentially have an impact on some specific disease process.

The Role of Gene Expression in Disease Prevention

Naveen Jain: Well, I think, Dr. Hanon, that very uniquely, that what Viome does that no other company has done, which is what really makes the whole thing very interesting, is we don't just look at the human DNA or human genes, we look at how the human genes are expressed. Similarly, we just not looking at what organisms are in your gut or in your mouth, we are looking at what exactly they are expressing or producing. Because at the end of the day, what they produce is what matters, not who they are.

And really, this idea of looking at the gene expression, both from microbes and human gene expression, how they interact with each other, is the key. How do you look at this gene expression? Because no one else has done it, and what are the kind of things you are learning as you're starting to see these unique interactions?

Dr. Hanon: So, first of all, I look at it like going on mass, to be really clear. And this is one of the most exciting part of this new job, actually, is to be in front of a long list, of a huge list, of information coming from these individuals or from this population, and trying to understand, trying to find if there is some kind of a meaning in all these moves.

But as you say, then I want to insist on, that what's unique at Viome is that it makes actually the platform highly differentiated and competitive versus others, is this ability not only to get the identity of the bacteria and the microbes present in your microbiome, but the information about what they are doing as we speak, which is critical. A tree without apples is not the same as a tree with apples. The difference is the apples, which is something that humans can eat.

So, it's not only important to know what bacteria present, what they do, but even more importantly, what's the reaction, the molecular reaction of the host. And again, this is what's unique with the technique that Viome has developed, is that actually with that very simple sampling of liquid biopsies, we are able to get the information from these gene expressions.

And I promise you, it's a dictionary for each individual patient. It's a huge amount of information. So, you actually, to be able to make sense of that huge amount of information, you need to combine the platform with an artificial intelligence capability, so that you can begin to digest that huge amount of information, identify molecular signature that are specific of disease process, or actually healthy process, and potentially begin to design therapeutic intervention or wellness intervention.

Dr. Hanon: And you can do different things. But let me, first of all, go back to the classical concept. Disease are defined with a set of symptoms that you develop, and these symptoms are well defined. Sometimes we use, in addition classical, what we call biomarker, like a blood test or a measuring. So, like a hygroscopy, to confirm the diagnosis of a given disease.

What Viome offers, and actually has been already able to, in a way, demonstrate for at least one disease, is that instead of waiting for the symptoms, or waiting for the appearance of the classical biomarker, we are going with a set of molecular marker that likely appears before the symptoms, and before the classical biomarker.

So, it gives you the ability to detect a disease process before it's going to be visible, before its detection using the conventional methodologies. For example, the oral and throat cancer. Cancer detect methodology that has been developed by Viome is not only able to detect at a higher level of sensitivity-specificity than the classical methodology, close to 90%, or actually above 90%, of specificity and sensitivity. But it also can detect earlier stage of the disease.

This is, I can tell you, transformative. This will save lives because treatment will be started much earlier than it was before. And, for example, for oral cancer, the probability of living five years after the diagnosis, only 50%. So, it matters a lot, and it'll save lives.

So, this approach of using molecules rather than symptoms to characterize, to detect, the possibility of a presence of a disease can be expanded to many other chronic disorder. And that create the possibility to obviously activate a treatment much earlier.

That's one of the possibilities that the Viome technology offers. Now, as you are able to identify the molecules that are involved in a pathogenic process, you are basically reading out the pathogenic process that is happening. And basically, that also means that the same methodology can be used as what we call a companion diagnostic. So, which is classically a methodology that you associate with a treatment to monitor whether the treatment is working or not, as the treatment usually goes after the pathogenic process.

But actually, there is an additional application in that field, which is what we call prognosis, trying to predict what will be the efficacy of the treatment. Viome is actually being able already to demonstrate and predict the effectiveness of Metformin in type-two diabetes, and there is no reason why we would not expand that beyond type-two diabetes. We simply need the time to demonstrate it.

So, these are the screening diagnostic prognosis application. There is a lot of therapeutic application. I can speak about it if you want.

Naveen Jain: Please do. Please go ahead, continue.

Dr. Hanon: So, as I told you, as we are really in the center of what we call the pathogenic process, the process that creates the disease, you basically have the list of actors, both from the human body as well as potentially the microbiome that are involved in the disease process.

And this is close to be the dream for a scientist that is trying to identify new targets, to inhibit or to favor, to manipulate the disease process, or to basically target specific microbes to prevent them to interact a certain way with the host and trigger specific mechanisms.

So, we use, actually, that information also as a way to identify what we call therapeutic targets. So, a list of targets that we are considering as a candidate for the development of a new generation of therapeutics.

And it goes back to your point around, yes, most of the treatment against chronic disorder. There are a few exception, obviously, but most of them are symptomatic. We have the ambition, at least for a few, maybe not all, but as long list as possible, to identify actually therapeutic target for which therapeutic might be actually curative, or at least stop the progression of the disease that would be confirmed in the field.

Can I say, because you spoke earlier about biological aging, and I wanted to refer about a recent publication that once more shows a connection between aging and the microbiome. So, first of all, Viome actually made the publication, showing that it was able, using microbiome data, or actually human gene data, they can use these two source of information, Viome is able to predict your biological age.

So, there is something in your microbiome that is synchronized with your aging, in a way. And the recent publication showed that it was possible, by transferring the microbiome of young mice into old mice to get the old mice reacting in terms of behavior, in terms of learning like young mice. So, in a way, microbiome, in that case, rejuvenates the health, the neuronal health, of the old mice.

This is really fascinating, but actually totally in alignment with the finding that Viome did a while ago, which was the fact that yes, there is indeed a big difference in terms of microbiome of aged individuals versus young individuals. Understanding the tight interaction between the microbiome and the host might actually pave the way to new kind of intervention that could potentially prevent aging, or least prevent disease associated with aging.

How the Gut Brain Axis Impacts Health and Mood

Naveen Jain: One thing, Dr. Hanon, everyone is worried about is our brain. How does gut and a brain, and how does microbiome affect your brain? Because to me, that is just so amazing to see these microbes sitting in our gut are like a puppet master pulling the strings and affecting our brain, our mood, and everything else.

Dr. Hanon: Yeah. So, that's a fascinating topic. But we know it. Actually, the first of all, let me give you a very concrete example where this, what we call gut-brain axis, has been made visible to you. I'm sure you remember the last time you had a gut problem. I mean, when you have a gut problem, you feel very bad. Your whole body, including, actually, your brain, your mood, is really impacted.

There is also an expression called "my gut feeling", while actually, it speaks about what you think in your brain. So, this gut-brain axis, at least it seems to be actually known empirically since many years. Now, we have actually collected many, many more pieces of information that materialize the connection. First of all, it is clearly a bilateral connection between your gut and your brain, going and sending information in two ways. And the information circulates through nerves, like the parasympathetic and sympathetic nerves, like the vagus nerve.

There is a clear demonstrated physical connection between your brain and your gut through these nerves, but there is also, obviously, the blood. And in the blood, a lot of metabolite out of the microbiome, like vitamins that are really important for the brain, but also short-chain fatty acids, which have been documented to have a direct impact throughout the body, including the brain.

These are released by the microbiome. And as I spoke a little bit earlier, there is in the blood also immune cells that spend a long time to be educated in the gut. And these immune cells, actually, that are recirculating constantly through of the body, are actually, in a way, reacting to what's happening in the gut. 

There are several hypotheses connecting what we call neuroinflammation, which is happening with Parkinson or Alzheimer's disease, with actually this chronic activation of the immune system that recirculate in the blood.
And finally, and not the last one, the gut microbiome is producing what we call neuromodulators. These are actually the molecules that the brain use to function. And believe it or not, 90% of serotonin, one of these major neuromodulators, are produced by the gut, not by your body. It's produced by the gut microbiome.

It's the same for dopamine, the reward neural mediator. It's the same for noradrenaline. It is the same for GABA, gamma-

Naveen Jain: GABA.

Dr. Hanon: ... aminobutyric acid. All these neuromodulators are extremely well known to play a critical role in mood, in anxiety, in depression. And it's actually your gut microbiome plays a major role in producing them, either too much or not enough. And understanding, really, the interaction will make a major step change in understanding this disease.

Naveen Jain: So, Dr. Hanon, as we wrap up here, I just wanted to ask you a few things. As you have been analyzing this data, and you have been looking at the things that most people would never see... I mean, this is an amount of information. As a scientist, it's like being a kid in a candy store. You're seeing this new information that is going to change the understanding of human biology. It is actually rewriting what we thought was going to happen in our body. And you are right at the forefront of actually discussing actually things that you see every day. What are the three or four or five things that you have seen in the last six months that just absolutely surprises you? So, like, "My God, I would've never thought that."

Dr. Hanon: So, without disclosing ongoing work that requires further, let's say, demonstration of the robustness of the finding, I'm in front of some kind of a paradox. On one end, we are definitely digesting, extracting from a huge mass of information, some kind of meaning and connection between different disease states, and comparing with healthy people.

And one of the thing that fascinates me is that it does not look like there is a lot of things that you need to put on the table to actually, not understand, but let's say associate with the disease state. So, it looks like there are only a few set of bacteria for which the presence or the absence seems to be close to be automatically associated with a disease state.

If that finding is confirmed, that's an extremely good news. Instead of discovering that you need a consortium of 200 different bacteria, let's say, to prevent a disease, that's much more complex to [inaudible 00:36:57] into a concrete application.

So, this short number of finding, I'm very impressed to actually be in a position where on one end we have huge amount of information, but at the end, it's always the same usual suspects that seems to be present in specific disease state.

Naveen Jain: Is it just a presence or absence or what they're actually doing-

Dr. Hanon: It's both.

Naveen Jain: ... when they are producing-

Dr. Hanon: What also, what is fascinating is that in some cases, it is the absence of specific bacteria that is associated with disease.

And the healthy states is actually associated with abundance of a given bacteria doing something specific, which is always has to be said.

In other cases, at least in one other cases, it's one of the presence of a consortium of bacteria that seems to be associated with a disease state. And, I mean, more work needs to be done, but it's, again, fascinating to see the same cluster that is actually present from irritable bowel syndrome, colon polyp, inflammatory bowel disease, up to colorectal cancer. This is fascinating, and I hope we will be able to further investigate that specific aspect.

And finally, as I told you earlier today, it really looks for me like landing on Mars and being able to be the first to observe once the land, and all of that. And so, being able in a single analysis to get this host microbial interaction is actually, it's amazing to be able do that.

And we are still actually trying to digest the amount of information to find the simplest, easiest, and most conclusive way to perform more analysis, because you can lose yourself in the quotient of that data that are generated.

Naveen Jain: I'm going to give you the last word here, on if you were to the audience with something they can do today, what is the thing that you give them the hope that the future for us as humanity is brighter than ever, and for them to not to feel that we have lost this, we are losing the battle, as opposed to we are actually in the forefront of that humanity is going to win this battle? How do you give people hope who are despaired because they hear nothing but bad news every day?

Dr. Hanon: Yeah. I think if you want to change the world, you need to start to change yourself. I think it's valuable also for your health. If you want to improve the health of the world, you need to improve first your health. And I'm now working at Viome since six months, but I've been interested in the field since many years. But over the last six months, more than ever, I got confirmation of the importance of the microbiome.

And in a way, the importance of the diet that we are having in our society, the diet we consume, is sometimes dramatically impacted by processing. It's really important to take care and pay attention to that. And in a way, I think that's really the chance that Viome offers to people that want to understand and find, let's say, a legitimate and reasonable solution moving forward.

Naveen Jain: Well, Dr. Hanon, this has been an absolute pleasure to have this discussion with you, and everyone who's listening to it, as you heard from Dr. Hanon, please go to Viome.com, sign up to get that test done. That is the only way you will actually know what is happening inside your body. Follow the guidance about what foods you should be eating, what food you should not be eating. And don't forget to order your supplement, because at the end of the day, just the food alone is not going to do the trick. You need both the supplements, the food, and they are called supplements, not replacement. So, you need the both together to actually make an impact on your health.

So, please go out and do things that you can actually take control of your own health. Empower yourself. You can't rely on someone else to take care of your own health. So, go out, sign up, and hopefully live healthy forever, and long time at least if not forever. With that, I'm going to conclude this discussion with Dr. Hanon, and thank you very much.

Dr. Hanon: Thanks a lot.