Is chronic fatigue a gut-brain reflex?

Faculty Scholar Julia Kaltschmidt takes us inside a new Big Ideas in Neuroscience project aimed at understanding how the gut tells the brain we're sick – and what that might reveal about chronic fatigue and Long COVID.
Nicholas Weiler
From Our Neurons to Yours Wu Tsai Neuro Podcast

Why does being sick make you so exhausted – and why does that exhaustion sometimes outlast the illness itself? 

Today, neuroscientist Julia Kaltschmidt returns to the podcast to talk about the body's hidden "sickness reflex," the gut-brain circuitry behind it, and what those things might reveal about chronic fatigue.

Kaltschmidt, a Wu Tsai Neurosciences Institute faculty scholar and professor of neurosurgery at Stanford Medicine, is an expert on the enteric nervous system — the gut's own semi-independent network of 200 to 600 million neurons. She's leading a new Big Ideas in Neuroscience project mapping out exactly how the body tells the brain it's sick, alongside Luis de Lecea, an expert in the brain circuitry of sleep, and Christoph Thaiss, who studies communication between the gut, the immune system, and the brain.

The team believes that understanding the "reflex" of sickness fatigue could eventually lead to something patients with chronic fatigue and long COVID don't currently have: a real biomarker, and a path to treatment, for a condition that's too often been dismissed as "all in your head."

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Episode credits

This episode was produced by Michael Osborne at 14th Street Studios, with sound design by Mark Bell. Social media strategy is by Julia Diaz, and additional editing by Nathan Collins. Our logo is by Aimee Garza. The show is hosted by Nicholas Weiler at Stanford's Wu Tsai Neurosciences Institute and supported in part by the Knight Initiative for Brain Resilience. 

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Transcript

Nicholas Weiler (00:10):

This is From Our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University, bringing you to the frontiers of brain science. I'm your host, Nicholas Weiler.

(00:26):

You know that feeling when you're pinned to the bed with the flu, no energy to get up, get dressed, or even really think a thought? It turns out that experience, as miserable as it is, may actually be your brain doing something purposeful. What we're learning is that this kind of fatigue looks a lot like a reflex, a coordinated response that your body has evolved to help you recover.

(00:53):

But exactly how that reflex works, what triggers it in the body when we're sick, and where it lives in the brain, is largely unknown. This response to sickness and how it produces fatigue is particularly important, as we've come to realize the prevalence of chronic fatigue disorders, things like long COVID. It's become increasingly clear these can emerge following many kinds of viral infections. If we want to know how to treat them, we need to know where they come from.

(01:25):

A new Big Ideas in Neuroscience project aims to answer these questions, by mapping out how our bodies and brains communicate when we're sick. In addition to the basic science knowledge, the researchers hope that eventually this understanding will help us detect and treat chronic fatigue syndromes.

(01:44):

Today's guest, Julia Kaltschmidt, is a faculty scholar here at the Wu Tsai Neurosciences Institute at Stanford, and a professor of neurosurgery at Stanford Medicine. She's leading this project alongside Luis de Lecea, who studies the brain circuitry of sleep, and Christoph Thaiss, an expert on communications between the body and the brain.

(02:04):

Julia comes to this project as an expert on the enteric nervous system, basically the nervous system of the gut. So I started by asking her about one of our favorite topics, why people have called the enteric nervous system our second brain, and whether that name actually does it justice?

(02:29):

I want to start by talking about a big picture question. We've talked before a little bit about the gut as the second brain. This is the title of our last conversation. But I wanted to come back to it. Why do people say that? Is it just the sheer number of neurons in our guts? Or are they doing something more sophisticated that feels brain-y?

Julia Kaltschmidt (02:49):

Okay. So clearly there are a lot of neurons. There are 200 to 600 million neurons, just to sort of get a number on the amount of neurons, which, if you compare it to something like the spinal cord, it's more than those that reside within the spinal cord. And it's really a, call it a semi-independent neural network.

(03:11):

I think if you think about the brain as having particular components, like you have the neurons, you have a circuit, you have lots of circuits, in fact. You have signal molecules, and then a communication perspective. And so, if you think about these three different maybe perspectives, the enteric nervous system also has them.

(03:32):

So, there are sensor neurons, motor neurons, interneurons in the enteric nervous system. They form contacts, and they build circuits. Then there are more than 30 neurotransmitters in the enteric nervous system, that are being used by the neurons in the enteric nervous system, including those that we are familiar with, such as serotonin, or dopamine, or glutamate. In fact, these are exactly the same signaling molecules as used in the central nervous system.

Nicholas Weiler (04:03):

In the brain and in the spinal cord.

Julia Kaltschmidt (04:04):

So in the brain and the spinal cord, yes. Which makes actually studying the enteric nervous system itself sometimes difficult, because we have such an overlapping signal.

Nicholas Weiler (04:13):

And they might be doing different things, right?

Julia Kaltschmidt (04:15):

They might be doing different things. Yes, yes, yes, yes. Exactly. Which is the exciting part. And then, from a communication perspective, the enteric nervous system signals and receives information from the brain via something that we call the vagus nerve, and we'll talk a lot about the vagus nerve today.

(04:31):

Maybe what's important and interesting in this communication perspective is that when you think about the signaling and the receiving, it's really, I'd say, 90% of signaling to the brain, and only 10% of receiving.

Nicholas Weiler (04:46):

So the gut is actually telling our brain stuff, more than the brain is telling the gut what to do?

Julia Kaltschmidt (04:46):

Yes. Yes.

Nicholas Weiler (04:51):

This is interesting, because you made a comment earlier that it's sort of a semi-independent network in the gut, right?

Julia Kaltschmidt (04:52):

Yes.

Nicholas Weiler (04:58):

It's not depending on the brain to tell it what to do.

Julia Kaltschmidt (05:01):

That is correct. The brain can influence what it does, especially in diseases that is relevant. But it has a very strong independent signaling role, yes.

Nicholas Weiler (05:15):

So I don't want to spend... There's a lot that I want to talk about, but just listening to this, I feel like I need a picture in my brain of some of these things we're talking about. You were talking about how many neurons there are, and it's very complex. It's got similar structure, architecture, chemical makeup, cellular makeup, to the brain.

(05:35):

Give us a picture of what the enteric nervous system looks like. And also, I'd love to get a picture of what that vagus nerve looks like. Because the gut is a big, long, complicated place, and it's hard for me to imagine a nerve from the gut to the brain. How is that set up?

Julia Kaltschmidt (05:51):

Yes. Yes. This is my favorite subject. I love looking at how neurons are organized within the gut, right? Because you already mentioned, I think, one of the big challenges, which is that the gut is extremely long. We consider the enteric nervous system from the esophagus to the anus. And so, it's a very, very, very long region.

(06:12):

And so, my lab has looked a lot at the organization of the enteric neurons. And what turns out, is that they are organized into rings that basically embrace the gut tube. So, they're still localized within the wall of the gut. So you can imagine that if you take out the gut, the neurons are within the wall of the gut. But when you would slice open the gut tube and put it into a sheet, they would look like stripes. So you have the neurons, lots of neurons aligned into a stripe-y structure, so to say.

(06:50):

The stripes or this organization differs within different regions. For example, regions in the small intestines look very different than regions in the colon, which makes total sense, because in the small intestine we have very different functions of these neurons than in the colon. There are functions such as nutrient absorption, or water retention, or fecal matter production.

Nicholas Weiler (07:13):

Yeah. It's a whole assembly line in there, right?

Julia Kaltschmidt (07:14):

Yes, exactly.

Nicholas Weiler (07:16):

From gathering the nutrients, to pulling out the water, and all those things.

Julia Kaltschmidt (07:20):

Exactly.

Nicholas Weiler (07:21):

But it's rings all the way through, but the way that those rings are organized around the gut varies as you go through.

Julia Kaltschmidt (07:28):

Is different. Varies, yes. There's a substructure within these rings, in that the neurons that are organized into what we call ganglia. And it is these ganglia-

Nicholas Weiler (07:28):

Just sort of like a cluster, essentially.

Julia Kaltschmidt (07:40):

A cluster. Exactly, clusters. And these clusters, they form these rings. And somebody, Lori [inaudible 00:07:47] Dershowitz, when she was a graduate student in my lab, coined these clusters, mini-brains. So now I always think about my gut tube as lots of little mini-brains, because they have these interneurons and sensor neurons and motor neurons, arranged in these clusters that are arranged in these rings, along the length of the gastrointestinal tract.

(08:05):

And they, as we discussed, are slightly organized differently, depending on where you are, depending on the function that they have to do. But overall, they are working together to make sure that our process of digestion happens in a normal way. Then you asked about the vagus input.

Nicholas Weiler (08:27):

Right. Are those all coming out of those? I'm imagining those coming out of those ganglia, and making a nerve that goes to the brain. Is that wrong?

Julia Kaltschmidt (08:34):

This is a current research topic.

Nicholas Weiler (08:38):

That we don't know yet. Okay.

Julia Kaltschmidt (08:39):

We don't know yet exactly. It's actually a super interesting question of how the vagus influences the enteric nervous system, or vice versa. Are there particular cell types that might be targeted? For example, could it be that the vagus is interacting with, for example, sensory neurons in particular, for the enteric nervous system? Or is it just random?

Nicholas Weiler (09:06):

That's so interesting. This makes the project that we're going to be talking more about later in the conversation all the more important, to understand that while we know that the gut is doing really important things for our digestion, and digestion is critical, not only for our survival, but we've heard over and over, I hear conversations all the time about the field of neuroscience realizing how important the gut is to things we used to think of as exclusively the territory of the brain.

(09:37):

We've heard things on the show about constipation and Parkinson's disease. We hear all kinds of things about gut processing and mental health, depression, and anxiety, and so on. Anyone who's ever had a gut problem knows the connection with anxiety very well. I mean, there's a very obvious connection, I think, that most people can imagine.

(09:58):

So, it's interesting, because having come up in neuroscience, this was never a topic of conversation when I was in graduate school, or undergraduate, or anything. It's a little surprising, because we are so used to thinking about our behavior and our emotions and our cognition in a very brain-centric way.

(10:17):

Until you think that like, well, we all evolved from worms, and basically we're a tube for taking in nutrients and extracting energy from our environments to do interesting things with. So, it made me think that, I don't know, we talk about the gut as the second brain, but maybe we should talk about it as the first brain, right?

Julia Kaltschmidt (10:40):

Yeah. So, it's true. A lot of the conferences I go to, there's oftentimes this sort of... We talk a lot about this. Why not call the gut the first brain? And actually what you pointed out is interesting. If you think about this from an evolutionary perspective, multi-cellular animals like ancient sponges, or sea anemones, or jellyfish, they developed a gut long before anything that resembles a brain. So the gut was there before.

(11:13):

And also when you think about the embryonic development, gastrulation occurs very, very, very early. I think once the animals evolved and moved away from just drifting to actually moving forward, I think then they developed sort of a front end and a back end. The front end has all of the sensory elements, like eyes and receptors that sense chemical changes.

(11:42):

So I think evolutionary, one could make the argument that the gut was there before the brain, and that the brain was built around the gut, or to sort of move the gut towards the food.

Nicholas Weiler (11:54):

So, in a way, you could imagine it makes more sense to think about ways in which the gut might be in charge.

Julia Kaltschmidt (12:00):

Yes.

Nicholas Weiler (12:01):

The brain is there to serve the gut, not the other way around, at least not entirely.

Julia Kaltschmidt (12:05):

Yes. Yes, yes. And actually, you know I'm a big fan of Giulia Enders.

Nicholas Weiler (12:10):

I've got the book right behind me.

Julia Kaltschmidt (12:12):

Oh, okay. Good, good. Yes, that book.

Nicholas Weiler (12:14):

This is this great book called, The Gut, which you give to basically everyone in our office has had that.

Julia Kaltschmidt (12:18):

I give it to everybody. Yes, yes, that's right.

Nicholas Weiler (12:20):

It's one of these books that you read, and then you're like, "I need to read that again."

Julia Kaltschmidt (12:23):

Exactly, yes. So, she comes back to this idea that, as I said before, most of the information, or a lot of the information, actually comes from the gut to the brain, and that travels along this nerve, the vagus nerve. She really puts forward this thought that the gut really works as a massive sensory organ. While we are not having conscious gut thoughts, there is a direct feeding of the information that's happening in the gut to the brain, and really influences our emotions and thought processes.

Nicholas Weiler (13:01):

Yeah. It feels like it's part of this bigger conversation about taking what we think of as our, I don't know, our consciousness, our cognition, our minds, whatever you want to call it... I've been reading Michael Pollan, so forgive me if I'm waxing philosophical here.

Julia Kaltschmidt (13:15):

Yes.

Nicholas Weiler (13:16):

Out of the skull, and thinking of it as something that occurs throughout our bodies. The brain is specialized for certain aspects of this, but there is a lot going on in our bodies that we really think with, or feel with, or are aware of our bodies. And maybe for most people, this is pretty intuitive, but in neuroscience, it's a bit of a new thing to say, "Oh, let's look outside the brain."

(13:50):

So, let's talk about this project that you have that tries to get at some of these big questions about whether we want to call it communication between the body and the brain, how the body influences our behavior, or thinking about behavior outside of just the brain.

(14:06):

This is a project that you're doing with several other faculty members that focuses on that most special of feelings, which is being stuck in bed with a stomach bug. Before we get into the details of that project and how it came about, why study sickness? Why study how sickness influences our behavior? How does this help us think about some of these questions about the brain and the body, and how they communicate?

Julia Kaltschmidt (14:30):

Yeah. So, when we get sick, that clearly has effects on our brain. There is oftentimes a inflammatory process that is associated with sickness, and there are inflammatory mediators or proteins or signaling components that are called cytokines, that travel to the brain and really change our behavioral priorities, maybe, in sickness.

Nicholas Weiler (15:02):

Right. So we know there's some kind of communication going on there. And when you think about it, when you get really sick, it does change your behavior. Your project focuses in particular on this idea of fatigue. Why is it that we just cannot get out of bed, even if we're usually a go-get-it, "I'm going to go to work no matter what." Sometimes you get sick and you're just in bed all day, and there's not much you can do about it.

Julia Kaltschmidt (15:24):

Yes. I think actually I should have emphasized that. We used to think about this as, okay, so now we get sick. We have fatigue. We can't go to work, or we can't do our normal activities. We want to really try to change that. Oftentimes we take some medicine and treat the symptoms, but the fatigue aspect of this, it's a little bit more of a nuisance at the moment, because we can't just do what we usually do.

(15:51):

What we are really trying to do is to emphasize the fact that fatigue is, in fact, and I know that the field has changed a lot in looking at fatigue as something actually positive. As something what we call an adaptive response, meaning a change that helps us, for example, conserve energy. It allows us to, for example, redirect our power or resources towards the immune system to fight off the infection.

(16:22):

In lots of ways also by us just staying at home and lying in bed, it limits the spread of the infections to the community, and really accelerates healing.

Nicholas Weiler (16:35):

I love that idea. I absolutely never thought about that before. But the idea that being confined to bed is a sort of quarantine that your own brain is doing, as a pro-social response to prevent... You could imagine this evolving in a social species like us, as a way of preventing the spread of disease, plus, it helps you redirect energy.

(16:58):

But you had this phrase in the project proposal for this research of fatigue as a behavioral reflex to getting sick. And so, it seems like such an interesting way of asking about communication between the body and the brain, to say, okay, we study reflexes in the spinal cord, things where you burn your finger and you jerk your hand away. Hit your knee and your leg moves back like they do at the doctor's office.

(17:28):

But this is the idea of a behavioral reflex coming probably through other circuits in the body, where somehow, and this is the subject of your research, somehow there's a detection that there is an infection, there's a virus, there's something going on. And the brain responds with this pretty significant behavioral change that does not permit you to get up and walk around, beyond just being a side effect of your body's using a lot of energy to fight off the disease.

Julia Kaltschmidt (17:56):

Yes. I mean, what's really interesting in this comparison is that the reflex circuit in the spinal cord is so well-studied, that it serves as the toolbox to look at what are the molecular mediators that are important in this reflex in the spinal cord.

(18:12):

And so, that's really what we want to get to in our system as well, except that we are so far behind in knowing what the reflex itself is. And so, what we need to do is do a very sort of defining this, I mean, you could call it [inaudible 00:18:30]. It's a big word, but really mapping this reflex for the gut-brain axis, in the context of fatigue.

Nicholas Weiler (18:40):

Yeah. So, I was trying to understand this reflex. And as you say, these spinal reflexes have been studied for ages and ages. Now let's figure out, what is this reflex that's going on when we're sick? And so, you've got a fantastic team. You as the expert in the enteric nervous system and spinal reflexes, understanding these circuits.

(19:00):

Luis de Lecea, who's an expert in the brain circuitry of sleep, to help us understand, well, what are the circuits in the brain that switch on when we're sick to confine us to bed, essentially, to get this terrible feeling of fatigue? And Christoph Thaiss, who is really interested in these questions of the back and forth communication between the body and the brain across the vagus nerve, and so on.

(19:24):

So, sort of a dream team, came together partly at the Neuroscience Institute retreat a few years ago, where we basically asked researchers from different parts of the university to come together and say, "How could we move this field forward?" I wish I could have been a fly on the wall at that table, where you and Luis were talking about this.

(19:45):

Was there a particular moment? I mean, do you remember any particular moment from that conversation, where it occurred to the two of you that, "If we studied fatigue, we could really move this field forward. It would answer a lot of questions maybe beyond the specific questions we're going to study."

Julia Kaltschmidt (19:59):

So as you said, so the initial idea of just even working together, came at the Wu Tsai retreat. At the time, the call for the Big Ideas wasn't out there yet. But Luis and I, we found ourselves at the same table, and both immediately thought about connecting his expertise, as you said, on brain sleep with my expertise on gut function.

(20:22):

And then I had known Christoph Thaiss from actually a conference on the Galapagos Islands. I knew, of course, of his expertise in gut-brain axis, on how external influences might mediate gut-brain axis, and challenge that, and especially on the immune system. I think it was just through Christoph joining the team that we thought about not just sleep, but also about the moment when it all goes awry, basically, in fatigue.

Nicholas Weiler (21:22):

So, this project, I want to think through how you all are going to tackle this question of how this behavioral reflex happens? It seems like there are three main components there, and maybe we can talk a little bit about what we know about these things and what the real questions are that still need to be addressed.

(21:44):

We need to know, how does the body know we're sick, and how does it communicate that to the brain? What we think is going on in the brain that takes in that signal, and says, "Okay, we need to stay in bed."

(21:58):

And then there's another aspect of the project which seems really interesting, which is, how does that actually help? Does it actually help us get better? Or maybe it is more of a quarantine thing like we were talking about before, where it's not really about you, it's about you not getting everyone else sick. So maybe we can tackle a few of those.

(22:19):

First, let's start with the brain. I did come up in neuroscience. I'm going to start with the brain. There was a fascinating study that you mentioned in laying out this project that I think is really instructive, that suggests that there's a memory of illness in the brain. Can you tell us a little bit about that study, and how it influenced the way you're thinking about what you're looking for in this project? What are you looking for in the brain?

Julia Kaltschmidt (22:46):

Yes. Okay. Awesome. Yeah. Yeah. So, very beautiful study. It was done by Asya Rolls' lab, was actually a postdoc with Luis. They found that the brain basically can memorize or trigger an immune memory in the context of inflammation.

Nicholas Weiler (23:10):

What does that mean, an immune memory?

Julia Kaltschmidt (23:12):

Meaning that there is a particular region in the brain called the insula. Basically what they are suggesting or showing, is that there's literally a circuit or a physical blueprint of past inflammatory events. And very specifically, actually, because they've shown that different inflammatory cues can trigger a distinct circuit activation.

Nicholas Weiler (23:40):

That's so fascinating. So they made, I think this was in mice, if I remember correctly.

Julia Kaltschmidt (23:43):

That's correct. Yes, yes. Very important. It's done in mice.

Nicholas Weiler (23:46):

They made mice feel sick in a couple of different ways, and they saw representations of those in the brain. This is the part that kills me. They could re-trigger the body's response to those two different kinds of nausea, or whatever it was, by stimulating the brain, which suggests that the brain still has some sort of behavioral trigger that's stored in the brain, and not in the body.

Julia Kaltschmidt (24:09):

Yes. Super cool. Yes, I agree. I think thinking about the brain memorizing the inflammatory response, to me, is always fascinating.

Nicholas Weiler (24:20):

Fascinating. And then seeing how that connects with the normal kinds of tiredness that we experience in our regular lives. Is it triggering the same circuits, or different circuits? It sounds like there are a lot of open questions there about what are the cells that are responsible for keeping us in bed when we're sick.

Julia Kaltschmidt (24:39):

Yes.

Nicholas Weiler (24:41):

Okay. And so, then I guess the other question is, and you guys had some very interesting preliminary data on this. What are some of the signals we think that are coming from the body to the brain? Is this a vagus nerve signaling approach? What do we know about that?

Julia Kaltschmidt (24:58):

So, it's interesting. We generally think about two potential ways. One of them being the vagus, as I mentioned, this is the highway that connects the periphery with the brain. There are studies where you, for example, cut the vagus, right? Because if you have a highway, if you interrupt it, that will dampen that response.

(25:17):

And then there are also circulatory factors which are not confined to the vagus, they are in the bloodstream. They also have the ability to signal to the brain. So there are these cytokines, these molecules, traveling towards the brain to tell it, "Here we have an inflammation state."

(25:35):

I think this comes to this question of, I think, fatigue, and I don't know whether we have really vocalized that. In lots of ways, if you think about the elements of the periphery, the gut, you think about the vagus or the circulatory system in the brain. They're all elements. We talked earlier about the fact that there is this reflex circuit that we want to map out, and its actions, in fact, and what are the molecules that really trigger the responses?

(26:05):

In fatigue, it is one of these elements is non-functional, is stuck. We'd love to know which cells in the vagus are the ones that mediate the information transfer. Could it be that there's something wrong with those? Or if we could identify the molecules that signal from the periphery to the brain, maybe there is something wrong with those. So, trying to take apart the circuit will help us understand more about how fatigue is generated.

Nicholas Weiler (26:42):

Right. You bring up a really such an important point about, this fatigue might be an adaptive response, as you guys have been arguing, but it can go overboard. I want to talk a little bit at the end about there are these chronic fatigue syndromes, where what might start as an adaptive response gets stuck on, and never goes away even after the sickness resolves.

Julia Kaltschmidt (27:07):

Yes.

Nicholas Weiler (27:07):

I want to come back to that in just a moment. I just wanted to ask about this last idea that you brought up in talking about these studies that you and Christoph and Luis are doing, which is to really understand that adaptive side of things. This is something that I hadn't ever heard or thought about before. You mentioned that fatigue maybe helps keep the gut moving, even when we're sick. Can you tell us just a little bit about that? What is the hypothesis there?

Julia Kaltschmidt (27:35):

So we think about, as we talked about, peripheral inflammation induces sickness sleep. We are thinking about that strengthening the immune system, and reserving or restoring energy levels. But the question is, whether sickness sleep also, and if it does, how does sickness sleep resolve infection in the periphery? Because what we do know, is that if we have infection in the periphery, we're going to have an effect on gut function, gut motility is changed.

Nicholas Weiler (28:09):

Interesting. So, how do these signals that there's an infection, we've got a virus, something like that, not only how are those changing behavior through interacting with brain circuits, but how are those changing the workings of the gut itself, in a way that maybe the fatigue helps, or maybe it's just a separate signaling pathway, other nervous system reflexes that are triggered by being sick?

Julia Kaltschmidt (28:33):

Yes. And so, for example, let's say you are fatigued, and you want to catch up with sleep. If you now interrupt that catching up of the sleep, if you now interrupt that process, what's the effect on the gut, on the periphery?

Nicholas Weiler (28:50):

You brought up a moment ago that one of the objectives here is to understand not only how the system works when we're healthy, but also how it goes wrong in disease. These chronic fatigue syndromes, I mean, my understanding is, they used to be and maybe in some cases still are, often kind of dismissed by our medical system, in part because standard medical tests couldn't really explain what was happening.

(29:17):

It looks like someone's just tired. Are they malingering? Are they, just don't want to go to work? Is it all in their head? Which is my least favorite thing. People always say that, as if that means it's not real. All of us is in our head and in our bodies, and that's what we're trying to figure out. It seems like after the pandemic with long COVID, that there's been a real shift in taking these kinds of disorders much more seriously.

Julia Kaltschmidt (29:43):

Yes.

Nicholas Weiler (29:43):

Where are you going to be looking to try to understand what is going wrong in these chronic fatigue disorders, as opposed to just the regular fatigue that we experience when we have a flu, or something?

Julia Kaltschmidt (29:57):

Yeah. So I think what you said is absolutely correct. I think the non-resolving fatigue, we don't have diagnostic tools. There is no blood test, and these diseases are defined symptomatically. And so, having a biomarker would be really fantastic. But to get to a biomarker, we need to do basically the research that we are proposing.

(30:23):

We need to understand again, how the factors that we, for example, propose come from the periphery, where they originate, and how they get to the brain, which encompass all of these questions of the origin, the pathway, and where in the brain they might play a role.

Nicholas Weiler (30:44):

To the extent people have looked at this, is this idea of, well, maybe we need to look in the body, maybe we need to look at the gut and the immune system and so on, as for those biomarkers, is that a new approach to this?

Julia Kaltschmidt (30:55):

Yes. I would argue it's a new approach. I think it is going away from the brain-centric approach, really taking into account the entire body. I think the benefit, or the difficulty from just looking at the brain, I think it's complicated, and potentially less accessible for eventual medicine. You could potentially administer medicine much easier via the gut. That might help us to find biomarkers, treat chronic fatigue in a novel way.

Nicholas Weiler (31:31):

Before we end, I just wanted to return to this idea about how a holistic thinking about the body and the brain can help us... I don't know. In regular speech, we say, "Get out of our own heads." In neuroscience, we've been very much in the head, and trying to understand the circuits of the brain, which are nice and complicated and very important.

(31:52):

But that the brain is there to do much more than that. So, I'm just curious if you see there being a shift in perspective from just being in the brain, to thinking about brain-body circuits that the field could use, or that might come out of this type of project?

Julia Kaltschmidt (32:10):

Yes. So as we alluded to at the beginning, as you said, I mean, I think generally the field has moved away from the brain-centric view, to a more body-brain, gut-brain interactive state. I think in this case for fatigue, as I said, we hope that our proposal and our research will bring opportunities to further understanding fatigue, and it emphasizes the importance of moving just out of the center of the brain, into the periphery.

(32:47):

We do think that new biomarkers or new medical intervention might be found from expanding to the body-brain circuit, and understanding how it regulates sickness sleep, and really understanding the physiological benefits from modifying and understanding the periphery.

Nicholas Weiler (33:10):

It just emphasizes again so much how you need people from different disciplines to answer questions like this. This is not something that any one lab could do, right?

Julia Kaltschmidt (33:18):

Yes. Yes. And I would like to emphasize that. I think it's actually super important that science is moving towards a transdisciplinary approach. I mean, it's already there. I think this proposal is a nice illustration of how that would be without it. Without me working with Christoph and Luis, this project wouldn't be possible.

(33:40):

It's through our combined expertise, which combines the brain and the gut, and actually somebody who works exactly on the element that connects us. I think that that's going to be very powerful, as you said, a dream team.

Nicholas Weiler (33:55):

Well, I so look forward to seeing the results of these studies, and learning more about why I feel so terrible when I catch a stomach bug, and how maybe it's really good for me.

(34:05):

And also for all these people who have long COVID and these chronic fatigue syndromes, like finally getting a biomarker for that, finally having an idea of where to release that emergency brake will just be so transformative. So, thank you so much, Julia, for coming on From Our Neurons to Yours. It's been a pleasure.

Julia Kaltschmidt (34:22):

Yes. Always a pleasure talking to you, Nick.

Nicholas Weiler (34:25):

Thanks so much again to our guest, Julia Kaltschmidt. She's a professor of neurosurgery at Stanford Medicine, and a faculty scholar here at the Wu Tsai Neurosciences Institute. To read more about her work and our Big Ideas in Neuroscience Initiative, check out the links in the show notes. If you enjoyed this episode, be sure to subscribe for more conversations from the frontiers of brain science.

(34:47):

We also love hearing from listeners. If you have thoughts about the show or questions about the brain you'd like to hear us discuss in a future episode, send us an email. We're at neuronspodcast@stanford.edu, or leave us a comment on your favorite podcast platform.

(35:02):

While you're at it, please give us a rating and share the show with your friends. It may seem like a small thing, and I know everyone asks this, but it is tremendously valuable for us to be able to bring more listeners to the frontiers of neuroscience.

(35:19):

From Our Neurons to Yours is produced by Michael Osborne at 14th Street Studios, with sound design by Mark Bell. Our social media strategy is by Julia Diaz. Additional editing by Nathan Collins. Our logo was designed by Amy Garza. I'm Nicholas Weiler, until next time.

 

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