Dr. Elaine Hsiao: Trust Your Gut

Illuminating (gut-brain) interactions.

Dr. Hsiao wears a lab coat and leans on a lab bench surrounded by experimental equipment.
Dr. Elaine Hsiao. Photo by Shelby Duncan.

Our guts are home to trillions of microbes, collectively known as the gut microbiome. These microbes range from bacteria, to fungi, to worms! This might sound scary, but this diverse microbial community is essential to our health. Our microbes help us digest food, fight off infection, and stay in a good mood. But how? The short answer is we’re not totally sure yet! This is an exciting field of research and scientists are actively working to understand how gut microbes impact our entire bodies. Among them, Dr. Elaine Hsiao is especially interested in figuring out how our gut microbiomes communicate with our nervous systems. Her lab is exploring and probing the gut-brain connection with the hope that one day, we might be able to treat complex brain disorders not by treating the brain, but by treating our human gut bacteria!

To understand how Dr. Hsiao is examining the connection between the gut and the nervous system, we need to understand each of these systems on their own, and how they talk to each other.


Table of Contents:

A Bacterial Helping Hand

Enzymes: The Workhorses of Our Cells

We're All a Little Nervous

Bridging the Gap

Living Germ-Free

Happy Bacteria, Happy Nervous System

The Microbiome and You

 

A Bacterial Helping Hand


Animated cartoon of a brain and intestine communicating using a tin-can-phone.

People tell us to trust our guts all the time. But what is the gut? When we talk about our “gut,” we’re really referring to our gastrointestinal (GI) tract. When we eat a snack, the GI tract is the canal that the snack journeys through. It starts at our mouth and ends in our rectum. On its way through the GI tract, the snack gets broken down by digestive enzymes in our stomach. The nutrients that make up the snack are absorbed in the intestines – so if we choose to eat potato chips, we’ll absorb mostly carbohydrates, but if we choose to eat a handful of almonds, we’ll absorb proteins. But our own enzymes are sometimes not very good at breaking down all the nutrients we eat. That’s where our gut microbes come in! The bacteria in our GI tracts also break down the food passing through, and with our microbes’ help, we get way more nutrients out of our food.

The GI tract is a hollow tube made up of human cells, with the food traveling through the center of this tube. The inner surface of this tube is made up of large sheets of cells, called epithelial tissue. Epithelial tissue is present on all surfaces of our body that come into contact with the outside world, like our skin and our airways. The epithelial tissue in our intestines absorbs water and digested food, and protects our inner organs from outside stuff (like undigested food and our microbes). The epithelial tissue also secretes hormones, mucus, and enzymes that help maintain healthy cooperation between our body and our microbes.

 

Enzymes: The workhorses of our cells


At any given time, your body is simultaneously performing thousands of chemical reactions. Somewhere in your body, a cell is dividing and needs to replicate its DNA. Another cell is trying to make energy. And another cell has encountered a toxin and needs to clear it to protect itself. Each of these cellular functions requires enzymes! An enzyme is a biological catalyst. A catalyst is any substance that increases the rate of chemical reactions without reacting itself. The enzymes in your body help your body run all the essential biochemical reactions it needs to survive by making all these reactions faster and easier.


Enzymes are highly reaction-specific – one enzyme has one job and it must do that job well. For example, there are enzymes called proteases that break down the proteins that we eat, and other enzymes called amylases that break down the starch. Enzymes function by recognizing and binding to specific surfaces or molecules, like proteins. When protease breaks down proteins, for example, it first binds to the protein before it chops it into pieces. This reaction can happen over and over until the materials are broken down enough to be absorbed by our body. If not for the protease, this reaction to breakdown proteins would take too long and we wouldn’t be able to get the nutrients we need in time. So enzymes are crucial for all the biochemical reactions in our bodies!

 

We're All a Little Nervous


Cartoon of the brain connected to the spinal cord with several offshooting bundles of nerves.
A simplified map of the nervous system.

Now that we’ve got a handle on guts, let’s talk about brains! Your central nervous system is made up of your brain and spinal cord. It is “central” because it receives information from all parts of the body and runs the whole shebang. Information travels through the nervous system in the form of signals through nerve cells called neurons. Neurons communicate with each other through special connections called synapses. They send chemicals through these connections, chemicals called neurotransmitters (neuro means related to the brain and transmitter is something that carries a signal). Depending on the exact type of neurotransmitter, the signal can tell neighboring neurons to either stop the signal or pass it on. There are lots of different types of neurotransmitters, and they have different roles in the brain, including happiness (dopamine), mood regulation (serotonin), and learning (GABA).

But the brain and spinal cord aren’t the only parts of your nervous system. There’s actually a whole other system of connections, called the peripheral nervous system, made of nerves that branch off of the spinal cord. All these nerves are like the players on a sports team, with the central nervous system acting like the coach that tells the peripheral nervous system what to do. Although the coach is in charge, the team is at the front line of the action, with different players responsible for different tasks. For example, the nerves that relay information to and from the gut are called the enteric nervous system. Since the GI tract has to respond to all the food we eat, it needs carefully coordinated movement to ensure that the food is mixed and transported correctly down our GI tract. The nerves in the enteric system keep our gut moving, with close communication with the central nervous system! And because of these close connections between the gut and the brain, diseases that affect the central nervous system often have gastrointestinal symptoms.

 

Bridging the Gap

The chemical structure of serotonin, an important neurotransmitter.

You may have noticed that when you feel stressed or anxious, your stomach hurts. Or when you eat a lot of greasy food, you may feel sleepy, and your mood may shift.

And in more extreme cases, some brain diseases, like Alzheimer’s or Parkinson’s, also affect the gut’s microbiome. Why does this happen? How do our guts and brains talk to each other? This is what Dr. Elaine Hsiao is interested in figuring out.


To figure out exactly how our gut microbes and nervous systems communicate, she’s studying one of the neurotransmitters we talked about earlier: serotonin, which affects mood, thinking, learning, and memory. Although it plays important roles in the brain, more than 90% of our serotonin is made in the gut!

 

Living Germ-Free


To understand how serotonin interacts with a body’s microbiome, Dr. Hsiao needs a model system that’s easy to understand. More importantly, she needs a way to compare a healthy organism with a microbiome to an organism with no microbiome at all. To do this, Dr. Hsiao studies what’s called a germ-free mouse.

Cartoon of a normal mouse with a robust and diverse microbiome, versus a "germ-free" mouse with a very simple microbiome.
"Germ-free" mice don't have the complex microbiome that normal mice do. This allows researchers to study the effect of changes in a mouse's microbiome.

Germ-free animals don’t have ANY microorganisms and live in a microbe-free (‘sterile’) environment that is tightly regulated and continuously monitored to avoid contamination. Though “germ-free” might sound like a positive thing, scientists who study these animals have noticed that all sorts of things go wrong with their development, including issues with their organs and immune systems! This goes to show just how important our microbiomes are.


Germ-free animals are used in microbiome research because they allow for controlled changes to be made to the microbiome. For example, if we wanted to study the effect of a specific bacteria on a mouse, we can use a germ-free mouse and introduce only the bacteria we’re interested in. Now we have an experimental system where we can directly see the impact of that bacteria on the mouse’s health. This is a super important tool to study all the ways in which our microbes impact us.

 

Happy Bacteria, Happy Nervous System


Using her germ-free mice, Elaine Hsiao has been able to make some incredible discoveries about how certain groups of gut bacteria control how much serotonin the body makes. And when there was no bacteria at all in the mice, Dr. Hsiao found that there was much less serotonin made. This serotonin does more than just affect our moods. Dr. Hsiao found that it also activates neurons in the intestine, which improves digestion and the mobility of the GI tract. Without the bacteria that trigger serotonin production, the GI tract does a much worse job of digesting food.


But why would bacteria fiddle with our serotonin at all? To answer this question, Dr. Hsiao fed normal mice with complex microbiomes extra serotonin and looked at what happened to all the bacteria in their guts. It turns out that the bacteria that trigger serotonin production grew faster when extra serotonin was provided. So these bacteria weren’t just increasing serotonin levels for our benefit – the serotonin was somehow helping them colonize our gut better!

Hsiao’s team found a specific gut bacterial species, Turicibacter sanguinis, that has a serotonin transporter which carries the serotonin from our guts into the bacterial cell. Interestingly, when given a common antidepressant, this bacteria’s growth in the gut reduces! This interplay between psychological medication and the microbiome emphasizes just how interconnected these systems are, which is important to remember for how we treat depression, anxiety, and other psychological conditions.

Diagram of a bacterial colony and a zoomed in diagram of some individual bacteria.
A species of gut bacteria called Turicibacter sanguinis fiddles with the serotonin in our gut.

 

The Microbiome and You


In the past few years, Hsiao and her team have made essential discoveries to understand how gut bacteria influence our nervous systems. Now, she’s working on understanding how serotonin made in the gut affects how organisms behave and brains develop. Dr. Hsiao is also interested in eavesdropping on the chatter between our gut microbes and our nervous systems to try to understand the rules of this two-way conversation. She hopes that overhearing these conversations will allow us to tune the microbiome to help treat neurological disease.


When you think of the things that make you “you,” you might think about your personality, your love of a particular type of music, or some special talent or ability you have. But “you” are also made up of billions and billions of other organisms, working together to help you digest food and be in a good mood. Thanks to the amazing work of Elaine Hsiao and other biologists, we’re just starting to understand the role that all of these microbes inside us play. But there’s still so much to learn about the diverse and complex ecosystem living in each and every one of us!


Credits:

Written by Manasvi Verma

Edited by Caroline Martin

Illustrations by Lindsey Oberhelman


Primary sources:

Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis by J. M. Yano et al. in Cell

Intestinal serotonin and fluoxetine exposure modulate bacterial colonization in the gut by T. C. Fung et al. in Nature Microbiology

Mouse Microbiota Models: Comparing Germ-Free Mice and Antibiotics Treatment as Tools for Modifying Gut Bacteria by E. A. Kennedy et al. in Frontiers in physiology

The gut microbiota–brain axis in behaviour and brain disorders by L. H. Morais et al. in Nature Reviews Microbiology

 

Learn about the nervous system and microbiome!


Interact (10 minutes): The gut-brain interactions that Dr. Hsiao studies depend on neurons to fire signals across their synapses. To learn more about how these signals are transported, interact with this simulation of a neuron.


Expand (5 minutes): To learn more about the hidden world of microbiomes (just in our gut), check out this video.


Deepen (5 minutes): Watch Dr. Hsiao's TED talk about her research and how tiny bugs can alter our brains.


Experiment (15-20 minutes): Biologists like Dr. Hsiao often have to grow bacteria in controlled environments like petri dishes. Experiment with growing your own virtual bacterial colonies, and figure out what conditions are just right .