Light Lab: Understanding the gut microbiome to treat disease

Editor’s Note: This is part of a series called Inside the Lab, which gives audiences a first-hand look at the research laboratories at the University of Chicago and the scholars who are tackling some of the world’s most complex problems.

Over the last decade, researchers have begun to untangle the network of billions of bacteria, fungi, and microbes that live within our guts. 

It’s a monumental task that requires both new ways of thinking and specialized equipment. In his UChicago lab, Asst. Prof. Sam Light and his team study these microbes by getting rid of the very gas that gives us life: oxygen. In a specialized chamber, they create an oxygen-free environment necessary to test microbes that live in our large intestines.

Light and his team’s work has implications not only in understanding biology but in treating disease and enhancing health — from inflammatory bowel disease to Type II diabetes to liver disease.

To learn more, we spoke with Light, the Neubauer Family Assistant Professor of Microbiology, and Ph.D. student Joyce Ghali, who works in the Light lab. 

First, what is the human gut microbiome?

Light: The human gut microbiome comprises hundreds of species of different microorganisms, primarily bacteria, that colonize our gastrointestinal tract. It really co-evolved with us to perform this important digestive function. It wouldn't be possible for our digestive systems to digest everything in food. And so evolution came up with this clever strategy where we outsource that job to the microbes.

We digest simple sugars, fat, and protein in the small intestines. What remains — dietary fiber — goes down to the large intestines. The large intestines are this perfect environment for microbes to digest different components of the food. Different species of microbes have unique capacities to break down different elements in the food. These microbes are able to extract and pass along an additional 5 to 10% of energy from our diet. 

Why is it important to understand how the gut microbiome works?

Asst. Prof. Sam Light

Light: Through the digestive process, these microbes make small molecules known as metabolites, which are analogous to drugs. They can enter our bloodstream and can have a variety of different implications for human health. Given the fact that there's so many microbes intimately interacting with us and that each one makes numerous metabolites, it's not really surprising that the microbiome can influence health in a variety of different ways.

Ghali: Over the past couple of decades, the microbiome has been implicated in so many different diseases. If we understand how the microbiome functions and its composition, that can help guide treatments. 

What do we know so far about the relationship between the microbiome and health?

Light: The field is still at a very early stage, in my opinion, of understanding the microbiome — what all of these different microbes are doing and how they interact with us. If you have a healthy group and a disease group, you can sequence the DNA of the microbiome and see that there are differences in what microbes are there, but we don't really know what that means for the most part. 

The questions that we're tackling are really trying to understand what role the microbes play, and how that relates to the different ways in which they can impact human health, particularly through metabolites. How do they produce these different metabolites that influence our health in different ways? Can we identify the principles that will allow us to understand why the microbiome is dysfunctional in some disease states? And can we come up with ways to intervene to correct that?

Joyce Ghali, a Ph.D. student in the lab of Asst. Prof. Sam Light

What diseases are potentially affected by the microbiome?

Light: The microbiome has been linked to a lot of different diseases, including preventing infectious disease. Some people argue that the microbiome is essential because one of the main things microbes do is provide colonization resistance through various mechanisms to make it harder for pathogens to cause disease.

Ghali: Some projects in the lab are focused on studying the relationship between the gut microbiome and diseases such as type 2 diabetes and liver disease. We know a lot about how the microbiome can correlate with disease but determining the causative nature of how specific bacteria contribute to specific diseases is a goal we are working toward in the lab.

Which questions does your lab investigate?

Light: We have specific disease-driven projects. There's this specific microbiome dysfunction that has been shown to occur in a subset of patients with Type 2 diabetes. And it's been shown very convincingly that this exacerbates their disease. But exactly which microbes are responsible for that, and why, haven't been known. So we're trying to identify those microbes and dissect the process and how it relates to the diet.

In our lab, we also ended up discovering that there are these different microbes that modify certain hormones. That includes sex hormones, like testosterone, and stress hormones, like cortisol. Microbes inactivate these hormones, and we think that there's relevance to inflammatory bowel disorders. The microbes that do it tend to appear more often in the guts of people with inflammatory bowel disease, so we think that they are actively working to produce a more pro-inflammatory environment that benefits them.

Ghali: My project is focused on understanding the ecological factors that underlie the microbiome. I’m interested in resource competition — how different bacteria interact with each other and compete for resources. The gut is a cutthroat environment, and I want to understand how bacteria are able to colonize and stably co-exist in the gut. My ultimate goal is to leverage resource competition to manipulate the composition of the microbiome.

How does your lab study how the microbiome works?

Light: The large intestine is this anaerobic environment, which means that there's no oxygen present there.

That means that when we want to grow these anaerobic microorganisms in the lab, we need to make environments that are free of oxygen. So we have these big chambers where we vacuum out all the air and replace it with nitrogen; within the chamber, we have a catalyst that will react with any oxygen that’s left and remove it. It's kind of clunky, but that's what you have to do to grow them and to test them. In other studies, we'll put different microbes into the mice and study what effect that has on their health.

We can also take a fecal sample and then extract all the DNA from it and then sequence that to identify exactly the microbes that are present. We also have mass spectrometers that can determine what metabolites are in the sample, and then we can measure the concentrations.

How will this work ultimately affect patients?

Light: Doctors use antibiotics to treat disease, but an unintended side effect is that it wipes out the gut microbes. Currently, we don't really do anything to fix that upon the cessation of antibiotic treatment.

My lab is part of the Duchossois Family Institute, which specializes in studying the microbiome. Dr. Eric Pamer, the director, has overseen the construction of a facility where they can prepare gut microbes. They are about to start this clinical trial where they're going to administer gut microbes to people who have had their microbiomes wiped out by antibiotic treatment. Now we're starting to get involved to try and figure out the best way to do that — what are the best microbes to give patients. 

Hopefully this will be a proof-of-principle and establish some of the critical data that's needed to lead to a more widespread adoption of this type of approach.

Ghali: My research project is focused on developing tools that will improve microbiome therapeutics, like giving patients food termed “prebiotics” that can selectively shift the composition of the gut microbiome into a desired state, or giving them next-generation probiotics (beneficial bacteria) that are better able to colonize the gut and perform their desired functions. Our goal is to increase the abundance of specific bacteria that are known to make compounds that are beneficial to human health and that can alleviate disease symptoms.