Episode 5: Trust your gut

Peter [0:00] 

You have it? All right, take a quick bite.

Dr. Neunlist [0:07] 

The food was clearly an apple. And the wine is red wine. I hope you gave me a French red wine.

Peter [0:17] There’s somewhat conflicting evidence on whether or not red wine is good or bad for Parkinson’s disease. We chose the apple for two reasons actually. First, because we saw that […] increasing fiber has been shown to help ameliorate Parkinson’s. But the other reason is that pesticides that are sometimes used in the growth of apples [are] actually a trigger environmental toxin that is associated with Parkinson’s. But I was wondering if you could use one word to describe how you were feeling when your eyes were closed. And when I was coming in with some food…

Dr. Neunlist [0:50]

I was anxious of what I would discover. But then I had the rewards of the sugar and the alcohol that’s contacted the anxiety

Peter [1:01] 

That’s good to hear.

Peter [1:13] 

Hi, my name is Peter, and I’ll be your host for The Gastronauts Podcast. Here at Gastronauts, we are committed to understanding communication in the body. And in particular, how our gut talks to our brain. We will be taking a deep dive into the mind and motivations of leading scientists and their work, and hope that by getting to know the individual behind the research, we can find out how scientists think and how we can build a better scientific community. So come join me as we explore our inner space on The Gastronauts Podcast.

Today, we are really fortunate to have Dr. Michel Neunlist speak with us. Dr. Neunlist did his PhD in cardiac electrophysiology, which is studies in the electrical activity on how the heart works, how it beats in Dr. Tung’s laboratory and Johns Hopkins and was awarded his PhD at the University of Louis Pasteur. He later went on to complete his postdoc in Dr. Sherman’s lab in Hanover, Germany, where he studied the entire nervous system, which is the system of nerves and supporting cells that controls our gut. Since completing his postdoc, he started his own lab and is currently the Director of Neurogastroenterology at the University of Nantes. So thank you for coming on the show. Dr. Neunlist, could you tell us a little bit more about the key functions of the enteric nervous system, and some of the efforts in your lab to study this?

Dr. Neunlist [3:03]

Thanks for your invitation to let me speak at this very interesting podcast session of Gastronauts. As you mentioned, the main focus of our laboratory is to study the enteric nervous system, what is commonly called as the second brain. And indeed, as you know, the gut is the second neurological organ, after the brain. And what we are studying is mainly how this nervous system that is integrated all along the gut wall, composed of about 200 million neurons, 1 billion glial cells in this nervous system is regulating major gut function, motility, barrier function. [We are interested in] how are so this nervous system is altered in various diseases, not only disease of the GI tract, but also diseases of the brain, neurological disorders, in particular, neurodegenerative disorders, such as Parkinson’s disease. And the last research axis that we’re developing is how to target this nervous system to restore organ function in disease condition.

Peter [4:25] 

That’s really interesting. It sounds like you have a lot of efforts that are going on in your lab. And I kind of want to break it down a little bit. The first thing […] that I want to ask about is, a lot of people may not be aware that the gut has- as many nerves you said 200 million neurons and then millions more glial cells; how does that compare to the number of neurons in the brain- is that more or less?

Dr. Neunlist [4:49] 

Of course, in terms of quantity, it’s much less. Quality is not always dependent on the number. But […] to give you an order of magnitude, it’s about 1000 times less nerve cells in the gut [compared to] the brain.

Peter [5:09] 

That’s really nice to have a visual representation of how many cells are part of this enteric nervous system. So it’s clear the enteric nervous system is essential for our day to day function for essentially life. You hinted a little bit earlier about some of the other efforts in neurodegenerative disorders that you are looking at. And I was wondering how the enteric nervous system plays a role in some of these neurodegenerative disorders like Parkinson’s or Alzheimer’s. And I was wondering what efforts you have done on that?

Dr. Neunlist [5:39] 

I think this is a very complicated question. And I think trying to prove the causal whole of the entire economic system in brain disorders is something that is still very speculative. But I think how we can integrate these two nervous system is that’s probably the affected by common mechanism. Because by definition, the two organs we consider the gut is a neurological organ.

Peter [6:06] 

So like the gut is a second brain?

Dr. Neunlist [6:08] 

Second brain in terms of quantity, but probably from an evolutionary point of view, it’s the first brain, the original brain […] because when you look at very primitive organs, like jellyfish, they have already neurons, they don’t have any brain on these animals, [and] they have already neurons within what is considered to gut. So to go back to the to the question, why is the nervous system affected in brain diseases in a large sense, not maybe only in genetic disease, but also maybe psychiatric diseases is probably because these disorders are in fact, associated with genetic defects, which all regulates neuronal function since they are co-expressed, both in the first brain and the second brain. They can induce GI comorbidity as well as a brain dysfunction. This is probably also the rationale why so often GI comorbidities observed in many neurological disorders, because they share common pathway, common origin.

Peter [7:19] 

Not many people are aware of the GI comorbidities or the GI issues that go along with the nervous issues. I think a lot of people when they think of Parkinson’s disease, they think of it as a movement disorder, kind of a little bit of the tremor, the unstable gait, but many patients with Parkinson’s often have constipation or diarrhea, is that correct?

Dr. Neunlist [7:40]  

Exactly […] What is also interesting to say is that these symptoms [or atleast] part of them can be considered as pre-symptomatic symptoms

Peter [7:49] 

That comes before the movement disorders.

Dr. Neunlist [7:51]

It comes before the movement disorders and there is this triad of pre-symptomatic symptoms, including sleep disorders, including anosmia or smell defects. […] and the third one is GI motility disorders such as constipation and dysphagia, which are the difficulties swallowing, and gastric emptying, slowing, which are considered as a frequent comorbidity that is pre-symptomatic.

Peter [8:30] 

These could be looked at kind of maybe warning signs of someone has two or three of the symptoms.

Dr. Neunlist [8:35] 

Exactly. So it’s not just one symptom, it’s not just because you’re constipated, that you are prone to develop Parkinson’s disease. But if you have sleep disorders, as well as constipation, then increased risk to develop Parkinson’s disease. So this has set the hypothesis that maybe if GI symptoms, presence prior developments of disease could originate within the gut. And probably, it’s still a very hot debate between pros and cons, because you could have GI symptoms and just because the systems is more sensitive to degenerative processes, and probably where the disease starts is very complex.

Peter [9:26] 

So you’re talking about kind of the GI or the gastrointestinal manifestations, whether they’re coming because the nervous system is more sensitive, or have these manifestations shown- is this chicken or egg, which one came first, right? The abnormalities within the GI nervous system versus the abnormalities in the central nervous system?

Dr. Neunlist [9:48] 

What is the driving hypothesis of not a pure brain origin, in Parkinson’s disease, but also more importantly, or degenerative diseases is that key molecules involved in the regulation of function for disease.

Peter [10:12] 

They all have misfolded proteins.

Dr. Neunlist [10:14]

Exactly. This mis-folding protein that can be used by probably a large spectrum of environmental factors. And effectively, this is one of the full diagnosis, the real diagnosis. And what is interesting is that access can only be done as a biopsy in post-mortem so the definitive diagnostic, Parkinson can only be done [after death].

Peter [10:37] 

And the reason it can only be done post mortem, is because we cannot grab that part of the brain and someone who is alive.

Dr. Neunlist [10:43] 

Exactly. So the idea is maybe you had to think about another organ, where we can do in a routine fashion. Biopsies result without being life threatening or with minimal risk.

Peter [10:57] 

You’re looking at a different organ where you can grab some tissue issues, where the person is still alive, is still alive and see if this is a diagnostic [tool].

Dr. Neunlist [11:06] 

Organs, which have neurons, we could use it as a [diagnostic tool] and what better than the gut that can fulfill this condition, meaning everybody […] has the opportunity or to undergo a biopsy, a colonoscopy. And the gut, as mentioned, has a nervous system. So this was a little bit the driving idea of looking at whether from a living patient, we could identify biopsies, identify the same normal v. pathological hallmark. So the idea supports that at least two organs are affected and whether treating the gut would improve treatment of brain function is something.

Peter [11:50] 

Is that something that you’re interested in? […] Is it known at this point? Or is it something that we need to continue to do research on?

Dr. Neunlist [11:57] 

Personally, I don’t really believe when patients have been diagnosed with Parkinson’s disease, you have a chance to free restore the disease, because you can slow the evolution of  […] disease progression, but there are some data suggesting that (and it’s an interesting, but still controversial study) showing that in patients that had appendectomy-

Peter [12:28] 

People who had their appendix taken out.

Dr. Neunlist [12:31] 

They have a significantly lower risk to develop [Parkinson’s] over the course of years. And what was even more interesting was that this observation lowered risk only was observed in patient living in the rural areas, but not impatient living in cities.

Peter [12:53] 

And there’s very different lifestyles and people who live in rural areas versus cities.

Dr. Neunlist [12:58] 

One of the hypothesis suggests that people (in cities) are more exposed to pesticides. For instance, farmers were exposed to pesticides develop higher risk of Parkinson disease. But again, this study is a controversial one… This is a study performed, of course, which could feed into good quality of medical studies, meaning you have […] 900,000 patients that were included over a long time, but you have other studies showing that there was no effects of appendectomy on the risk of Parkinson’s. And another one on showing that, in fact, it increases the risk.

Peter [13:44] 

The data is still a little muddy.

Dr. Neunlist [13:48] 

[…] And I’d probably point out to the fact that more research needed.

Peter [13:53] 

So it seems like Parkinson’s is kind of a combination of some genetic factors. And then certain environmental toxins or something that happens to affect the enteric nervous system.

Dr. Neunlist [14:03] 

And the brain and independently whether one is linked to the other is not known but affecting the two organs, of course, because of the function that will [be] responsible for, of course, for motor symptoms and GI dysfunction.

Peter [14:20] 

So understanding the interplay between the entire nervous system and the central nervous system, and how things can go wrong. And disease is somewhere where we have a lot of research to do.

Dr. Neunlist [14:31] 

And there is a lot of research to do especially to understand the mechanism of disease. And once we understand the mechanism of disease, we can propose an efficacious preventive treatment. This is mainly what is the goal is.

Peter [14:45] 

It’s challenging to do Parkinson’s research because we have to look at these environmental factors over time. And then there’s a certain time window where these environmental agents will have their most damaging effects. And getting the timing right now is just as important as understanding the entire progression. And I kind of wanted to take that to segway a little bit more so about your progression, as a scientist. I wanted to ask about your path. It’s being in the right place at the right time or having the right mentors at the right time. And I was wondering, could you tell us a little bit more about your training path. From the personal

Dr. Neunlist [15:20] 

From the personal point of view, I think you mentioned […] that encountering the right person at the right time is critical and crucial to develop your career. But overall, also you have to have and I think this is where a science of offers very much reward; you have to be passionate for science, and if you really want to do a career in science, you have to be curious. I mean, it’s like not easy, you have to keep your naivety, keep your motivation to discover to […] be really open minded. And you have also of course to be hard working. And I remember when I was doing my PhD in Hopkins, there was a flyer, where I saw a seagull, this is a builder that eats frogs. It had part of the frog in his mouth. And the frog was one of the arm was holding the neck of this bird in order to prevent it from swallowing it. And this is a little bit, the image of the scientist. As long as you don’t give up, you will always have hope and finding something. And if you give up, then you’ll be swallowed by the science. So it’s never give up. And this is the message of hope. I mean, this is a very critical because your hypotheses are not always [right] and your experiments don’t [always] work. But if you insist, insist there’s always a solution. I think it’s also message of optimism, you always have to be optimistic to go forward. And in science, there is one way is not the road is not the right one. And you have to go to another way in the end, the door will always open to success.

Peter [17:34] 

You mentioned briefly that maintaining an optimism maintaining a kind of a dedication to solving the science when something doesn’t go the right way, go another way. How do you know that this is not the right way to go? How do you know when to change directions?

Dr. Neunlist [17:49]  

This is the gut feeling, you know? That’s why we have nerves in the gut; that’s why we have the second brain.

Peter [17:57] 

As a graduate student, sometimes I’m thinking, I’ll do some experiments and they aren’t working out? Should I […] give up and move to a different project? Or should I continue to go on? Or and then how long should I continue on that process?

Dr. Neunlist [18:08] 

It depends […] I don’t like to give up. And you have to be confident in yourself that what you’re doing is the right thing. And if you don’t give up and you believe that what you’re doing is right. […] But often it’s your first ideas that are good ones. And again, the gut feeling. This is key: trust your gut and also trust, hear what your mentors are saying. I mean, that’s it.

Peter [18:36] 

You only have a few mentors in your life. And it’s important to develop those relationships with those mentors. You got your PhD from the University of the Louis Pasteur, but your scientific mentor at that time was Dr. Tung in Johns Hopkins. Is that correct? Could you tell me a little bit about that process about how you decided to go to Hopkins to do research?

Dr. Neunlist [18:56] 

This was not a gut feeling that drove me to Hopkins. But it was another type of feeling. meeting that I met someone. My girlfriend was American, so it was not a gut feeling. It was […] just life events. I mean, not everything is planned. So if you combine gut feeling with other type of heart feeling, then I chose Hopkins because of the reputation [of the] BME department in Hopkins, because I was a BME (biomedical engineer) […] and I tried. This is something you have to do, you have to try it. And then I wrote many letters. And then Dr. Tung [responded], and this is the huzzah; a good encounter at the right time. And when things are mature.

Peter [19:49]

How did you get interested in electrophysiology or in how electrical circuits regulate our body. I see that your passion, to my interpretation, is understanding how these circuits function.

Dr. Neunlist [20:02]

No, it’s understanding how biology works, how life is working, how organs are functioning, because this is basically also an engineering question. And what better and more complex machine for an engineer than understanding how the human body’s working, which is much more complex. So I think this is a little bit what drove me as an engineer to the world of biology. And as mentioned, then the opportunity was that I had to do this in the heart […] what’s kept me all along my career is looking at how electricity […] is involved in the […] biology of organs, the heart first and then the second, the gut because my definition as an neurological organ, bioelectricity places and recording functioning of the gut. And so this is a little bit [about my] path.

Peter [21:02] 

With your engineering background, and understanding the electricity and how circuits play a role in fundamental biology, was it kind of a natural segway from moving to the heart to studying the gut? Did you have any reservations? Were you thinking, Oh, you know, maybe the gut isn’t so similar to the heart?

Dr. Neunlist [21:19] 

No, because the link between the two was the methods. To measure electrical activity at that time, it was by microelectrodes. Then, of course, if you want to understand the activity of a neural circuit, it’s not just one neuron on at the time […], but it’s the global response of many neurons, that regulate. The advantage of optical sensing is that with optical measurements is that you can have a global measurement of electrical activity in the whole network. So it’s much closer to answer your question is how the network is altered in diseases […]So this is a little bit how the technology was used as a common path to ask a question to heart which was distinct from the question in the enteric nervous system and physiology.

Peter [22:12] 

So understanding the methods to understand the network is […] what you’ve used [to answer your questions]. You used it in the heart, and you saw there was applicability to the gut as well.

Dr. Neunlist [22:21]

Exactly. And then we’ll try to go further by integrating what was observed in terms of knowing the activity in terms of function, because the ultimate goal is to understand the function of the organ, whether motility or more a barrier function, which is more of interests to me.

Peter [22:43] 

What made it you have a seamless transition from studying cardiac tissue in the heart to gastro intestinal tissue in the gut, was the fact that you had this method, you had this technique that you could easily apply from one field to another. Being able to apply techniques to different fields is very powerful. But I also think it’s important to apply certain guidelines that you think are important for conducting science. Are there any of these principles that you instill in your mentees or people that you train? Are there any fundamental principles to approaching science that you like to share?

Dr. Neunlist [23:20] 

I mean, the most important aspect is to have a rigorous scientific approach in what you are doing. And [important for] science is also repeatability. I mean, you have to validate all the concepts; this is something that is crucial to study that I consider as a fundamental in any research in particular. It’s very basic principles I know. But this is the core structure of science, which is fundamental, especially in a world where science is declining very rapidly. It’s question very frequently [asked], and I think this is our only way to survive when we do our science. We also have to know it doesn’t mean that it’s right, because science is [going] to change, it [will] evolve. By the time you do science, it has to be running [appropriately].

Peter [24:28] 

So it’s essential to have good rigor or good dedication to your research. The reproducibility is something that you think is essential, something that you want to instill in others that you train; we want our science to be reproducible. I think there can be findings that are contrary to what we discover, but our experiments need to be reproduced. I think that’s really powerful. Because we live in a climate where news on certain scientific discoveries can be challenged very quickly. There has to be an understanding of the amount of effort, the amount of time that we put in each one of these discoveries, and to continue to instill that dedication in future scientists is something that we think is powerful.

Dr. Neunlist [25:10] 

I think this is fundamental, especially I think, where this credibility because science everywhere is also more and more driven by money. Especially in times of crisis where money is short, especially in this world. I think driven by money, it’s very important to keep your integrity.

Peter [25:29] 

Well, thank you so much Dr. Neunlist for being on our podcast.

Dr. Neunlist [25:31] 

Thank you very much was a pleasure for me to talk with you. Thanks.

Peter [25:45] 

Wow, I feel that’s a really important message to take home. At the beginning of your scientific journey, passion helps kickstart your research. But it is the integrity it is the rigor that helps your findings stay afloat and stand the test of time. I think it’s a lesson we’ve all heard before, but something definitely worth revisiting. How do we want our work and the work of our collaborators to be viewed years from now? Just think about it. Thank you so much for listening. And we’ll see you all on the next episode. For more of our content, you can follow us on Twitter @gutbrains, or visit our website at thinkgastronauts.com. The Gastronauts Podcast would be impossible without the incredible team that we have here. Meredith Schmehl is our producer and the music composer. Dr. Laura Rupprecht is our social media manager. And special thanks to the founders of Gastronauts: Dr. Diego Bohórquez and the Bohórquez laboratory.

Sep 2019 – Gary Wu

Dr. Wu is the Ferdinand G. Weisbrod Professor in Gastroenterology at the Perelman School of Medicine at the University of Pennsylvania where he is the Associate Chief for Research in the Division of Gastroenterology and is also the Associate Director of the Center for Molecular Studies in Digestive and Liver Disease. He is currently Director and Chair of the Scientific Advisory Board for the American Gastroenterological Association Center for Gut Microbiome Research and Education and is an elected member of both the American Society for Clinical Investigation and the American Association of Physicians. The research programs in the Wu laboratory focus on the mutualistic interactions between the gut microbiota and the host with a particular focus on metabolism. Growing evidence suggests that diet impacts upon both the structure and function of the gut microbiota that, in turn, influences the host in fundamental ways. Current areas of investigation include the effect of diet on the composition of the gut microbiota and its subsequence effect on host metabolism related to nitrogen balance as well as its impact on metabolic pathways in the intestinal epithelium, principally fatty acid oxidation. Through a UH3 roadmap initiate grant, he is helping to direct a project investigating the impact of diet on the composition of the gut microbiome and its relationship to therapeutic responses associated with the treatment of patients with Crohn’s disease using an elemental diet. Finally, Dr. Wu is leading a multidisciplinary group of investigators using phosphorescent nanoprobe technology to examine the dynamic oxygen equilibrium between the host and the gut microbiota at the intestinal mucosal interface. 

During his Gastronauts seminar, he shared some of his most recent findings on the role of the microbiota in interacting with three key components: Molecular oxygen, Urea, and bile acids.

See some of his work here.