Understanding the Gut-Brain Connection

Q&A with Diego V. Bohórquez, Ph.D.
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Author:
Kayt Sukel
Published:
September 16, 2019
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Assistant Professor of Medicine and Neurobiology
Duke Institute for Brain Sciences, Duke University

Dana Foundation Grantee: 2016-19

How do you feel when you take a bite of your favorite food?

If you are like most people, even the smallest morsel of that tasty dish not only offers you a wonderful flavor but also feelings of pleasure and, sometimes, may even evoke past memories. Just how does the gut, the largest organ inside the body, transmit information about food, your favorite or otherwise, to the brain to result in such strong emotions and experiences? And how might those signals be disrupted, leading to eating, anxiety, or neurodevelopmental disorders? Diego Bohórquez, Ph.D., an assistant professor in medicine and pathology at Duke University’s Institute for Brain Sciences, has spent his career trying to understand how cells along the gut walls communicate with the brain and what happens when that signaling goes awry.

Using multi-disciplinary approaches, he and his team have identified a special type of sensory epithelial cell that forms a synapse with vagal neurons, making a direct connection from the gut lumen to the brain stem. Moreover, the signaling that occurs through that synapse, powered by glutamate, a powerful excitatory neurotransmitter, happens very rapidly, making sure the brain is able to quickly and easily make sense of what you just ate.

We talk with Bohórquez about the challenges involved with studying gut-brain interactions, the richness of the information the gut’s neuroepithelial cells can transmit to the brain, and how his work may offer new insights into the gastrointestinal symptoms that accompany many neuropsychiatric disorders.

What first interested you in studying gut-brain interactions?

I’m originally from Ecuador and came to the United States to study for a doctorate in nutrition. In 2003, I heard a story from a patient who underwent a gastric bypass surgery to lose weight. She told me, after the surgery, not only did she lose 40 percent of her body weight and resolve her diabetes, but her tastes changed. She said before the surgery she couldn’t even look at sunny side up eggs without feeling ill.  The yolk would make her feel queasy. But then, somehow, someway, after the surgery, she said, “I actually was craving the yolk.”

To me, the fact that this change to your gut could change your preferences for food and flavor was fascinating. So, once I received my Ph.D., I found myself drawn to the gastrointestinal tract, nutrition, and behavior—and I started a fellowship in gastroenterology. There, I was studying the biology of hormones that are produced in the gut in response to nutrients and all of these different pieces fell into place, leading me to investigate how the gut communicates information to the brain about food in particular.

There has been a lot of work recently looking at how the microbiome, or the diverse population of bacteria and microbes that live within the human gut, affects human behavior. What are some of the big questions your lab is trying to answer?

The microbiome has raised a lot of awareness regarding just how much the gut and brain communicate with each other. It has raised a lot of questions about how these microbes affect the brain. But what we still know very little about is just how food affects the brain. So, we are interested in looking at the direct connections between the gut and brain in response to food. How is it that the gut is able to sense, to feel, and to not only detect nutrients but the quality of the nutrients you are eating? How does the gut sort through information like a food’s color, taste, and other information before passing it up to the brain so the brain can have a feeling of what it is we just consumed? These are important questions but we don’t know much about it yet.

What are some of the biggest challenges involved in trying to study gut-brain interactions?

The biggest challenge, I believe, is technology. Historically, we have lacked the technologies to answer the questions we have, but in the past few years there have been vast improvements in technologies available to study the brain’s circuitry. Many of those techniques can now be applied to the gut, but there is still a long way to go.

The gut is a very different type of environment than the brain. There is a lot of liquid and a lot of bacteria in there.  And the gut, as an organ, is also very pliable. It moves—quite a bit—and these neuropod cells, or gut epithelial cells that synapse with a nerve, are distributed across the gut.  You won’t find them plastered in one single area. So, in order to report activity from the cells as a proxy of activation or deactivation, we need new technologies to be developed so we can better understand how the gut sends information to the brain but also how the brain controls sensations in the gut when it comes to food.

This is very important because, in many diseases like irritable bowel syndrome and anorexia, there is a very strong connection between the sensory function of the gut and behavioral disorders in the brain.  It is clear that the brain is talking directly to the sensory aspect of the gut, but there is a lot left to learn. If we could develop new technologies to work better in the gut environment, it would make a big difference.

Your work involves imaging, genetic, and molecular neurobiology techniques. Why is taking such a multi-disciplinary look so important to a better understanding of the gut-brain connection?

It is extremely important to use many different methods because the gut is not only made of neurons. For that matter, neither is the brain. There are neurons, of course, but there are also absorptive cells, secretory cells, immune cells, muscle cells, and bacteria, and, of course, the food. To really understand such a complex system, you need to understand all of its features. You need to be able to look at nutrition, gastrointestinal physiology, and neurobiology—and then put those pieces together.

Those needs have pushed us to envision new ways in which different types of technology can come in to help us answer particular questions. For example, when we were looking at how is it that we can feel sugars in the gut, we had to use many different techniques to track the circuitry and see how sugars affect the gut epithelium.

Using so many different techniques, of course, would not be possible with a single investigator or group of people. Multi-disciplinary approaches require multi-disciplinary collaborations. So we’ve been lucky enough to work with a lot of talented neuroscientists, as well as engineers who are working on developing new technologies that we can use in the study of these systems.

Your research led to the discovery that the gut has special neuroepithelial cells (neuropods), much like the tongue does. What are the implications of having such cells in the gut? How do they help mediate communications between the gut and the brain?

These neuropods are, essentially, the predecessors of all other sensory cells in the body. If we go back millions of years, animals had very few different cell types. But you’d still find these special neuroendocrine cells. So, as we fast forward in evolution, the entire body has been wired to find food. It makes sense:  we need food in order to survive. These cells inside the gut can sort through the different information about different foods. They have the ability to sense a range of macronutrients, micronutrients, and bacteria alike. In our work, we’ve discovered that, by connecting with a nerve, they can rapidly pass this information to the brain.  In fact, they can pass that information within a few milliseconds using a specific neurotransmitter called glutamate. So this work discovered that these cells use glutamate to tell the brain very quickly what we just ate.

cartoon of gut-brain interaction in a mouse
(Top left) Neuropod cells synapse with sensory neurons in the small intestine, as shown in a confocal microscopy image. Blue indicates all cells in villus; green indicates green fluorescent protein (GFP) in neuropod cell and sensory neurons. (Bottom left) This neural circuit is recapitulated in a coculture system between organoids and vagal neurons. Green indicates GFP in vagal neuron; red indicates tdTomato red fluorescence in neuropod cell. (Right) Neuropod cells transduce fast sensory signals from gut to brain. Scale bars, 10 µm. Image courtesy of Diego Bohórquez

Given that the gut and brain are in such close communication, why aren’t these two organs helping us choose healthy foods?  Why are we so interested in sugary junk foods?

Ultimately, it feels good to eat these junk foods. It’s fascinating to me that the gut, literally, has a sweet tooth. There is a portion of the gut, right after the stomach near the proximal lower intestine, that reacts to sugars. When sugars are delivered to that portion of the intestine, they send a signal to the brain that results in a very rapid release of dopamine. It makes the person eating those foods feel really good. And that fits back into what may be changing after gastric bypass surgery: when that portion is bypassed after the procedure, what felt really good before may not feel as good anymore. What didn’t feel good may start feeling good.

Does that translate into sugar “addiction,” per se?

We don’t know enough to say one way or another.  That being said, we know that animals who have undergone gastric bypass, where a portion of these neuroepithelial cells are located, don’t develop as strong desires or cravings for sugars. Now that we better understand this circuitry, it’s easier to approach and understand how these signals in the gut can help us control our cravings for sugar.  In fact, one could imagine that if we overstimulate this system, the brain could start feeling too good about eating sugars and therefore continued to seek out more.

Your Cell paper (Han et al.,) shows that there is a strong connection between the gut and the brain’s reward system. What are the implications of this for our understanding of mental health disorders like eating disorders, anxiety disorders, and even neurodevelopmental disorders such as autism?

Understanding these pathways, essentially, gives us a target. The gut is a very large organ. And when we talk about the gut and the brain, we are talking about a specific cell, connected to another specific type of cell, that joins up with a specific area of the brain that is involved with reward processing. Now that we have identified that entry point in the gut, we have an opportunity to act on it and try to control the output, to somehow influence the neuropod in order to steer behavior. I believe being able to do that will be very important in the future—because it is possible that different parts of this circuit are contributing to specific behavioral disorders. There may be more secretion of glutamate in some disorders that leads to hyper-excitability in the system which can result, ultimately, in anxiety. So you can imagine, if you can use this circuit as a target, you could find a way to reverse that and eliminate the anxious feelings.  Similarly, there may be different aspects that are involved with autism, where we see many gastrointestinal symptoms, or eating disorders.

What would you say is the most surprising thing you’ve discovered over the course of your research in this area?

The most surprising thing is that, from the surface of the gut to the brain, there is only a single connection between two cells. It is very surprising, as well as exciting to me, to see how hard-wired the surface of the gut is to the brain and how these two organs work in synchrony.  In general, there are two main functions essential to survival:  moving and feeding. And one could argue that we move in order to find food. It is amazing to me how the machinery of the body is a conglomerate of cells that have formed this connection to help us find food, get food, eat food, and remember food. And it starts with the gut processing all this information to tell us whether a particular food source was actually valuable or not.

How do you think your work fits in with the microbiome research?

Most of the microbiome work has been focused on secreted molecules or the different ways microbes might affect inflammation in the brain. But, in our lab, we are talking about the cell that is exposed to the surface of the gut that can steer our cravings and emotions. One can imagine that even the microbe is able to communicate directly with these cells. That microbe may be using these cells in order to help steer our desires or a need to feed.  By understanding these cells and how they communication with the brain, as well as how the microbes may be directly talking to these cells, we may find that connection between microbes and specific behaviors.

What comes next?  What are your plans for future research?

We are very interested in investigating how the brain picks up signals from the gut that tells it a particular food felt very good or sweet but not fully satisfying. Like our other work, we plan to use a multi-disciplinary and systematic approach to understand, primarily, how one cell type can sort these different nutrients and also, perhaps, different bacteria, to tell pathogenic versus commensal signals to the brain.

Publications

Han, Wenfei, Luis A. Tellez, Matthew H. Perkins, Isaac O. Perez, Taoran Qu, Jozelia Ferreira, Tatiana L. Ferreira, et al. “A Neural Circuit for Gut-Induced Reward..” Cell 175, no. 3 (October 18, 2018): 887–88. https://doi.org/10.1016/j.cell.2018.10.018.

Han, Wenfei, Luis A. Tellez, Matthew H. Perkins, Isaac O. Perez, Taoran Qu, Jozelia Ferreira, Tatiana L. Ferreira, et al. “A Neural Circuit for Gut-Induced Reward..” Cell 175, no. 3 (October 18, 2018): 665-678.e23. https://doi.org/10.1016/j.cell.2018.08.049.

Kaelberer, Melanie Maya, Kelly L. Buchanan, Marguerita E. Klein, Bradley B. Barth, Marcia M. Montoya, Xiling Shen, and Diego V. Bohórquez. “A gut-brain neural circuit for nutrient sensory transduction..” Science 361, no. 6408 (September 21, 2018). https://doi.org/10.1126/science.aat5236.

Bohórquez, Diego V., Leigh A. Samsa, Andrew Roholt, Satish Medicetty, Rashmi Chandra, and Rodger A. Liddle. “An enteroendocrine cell-enteric glia connection revealed by 3D electron microscopy..” Plos One 9, no. 2 (2014). https://doi.org/10.1371/journal.pone.0089881.[/vc_column_text][/vc_column][/vc_row]