The Fascinating Symphony at Play Between the Gut’s Neurons, Immune Cells and Microbes

The phrase ‘immune system’ might evoke images of a variety of cells, such as the B cells that produce antibodies or the T cells that target and kill bacteria or viruses. But that’s just part of the story. The mucosal surfaces of our bodies, such as the tissues that line our gut, are a critical part of our immune system as well, because they are in direct contact with the external environment. The gut’s nervous system, which is known as the enteric nervous system and often called ‘the second brain,’ is the largest and most complex division of the nervous system outside the brain itself. Problems with the enteric nervous system might be related to diseases ranging from irritable bowel syndrome to neurodegenerative diseases like Parkinson’s and Alzheimer’s. Recent advances have shown that neurons in the gut act in harmony with the resident immune cells and neighboring gut microbes. And their maintenance throughout adult life is affected by the fine balance among them. Begüm Aydin, a Junior Fellow with the Simons Society of Fellows, studies the mechanisms mediating this fine balance.

Aydin is a postdoctoral researcher in the Laboratory of Mucosal Immunology at Rockefeller University, working with Daniel Mucida. She received her doctorate from New York University and her B.S. from Boğaziçi University in Istanbul. We recently discussed Aydin’s work and its implications. Our conversation has been edited for clarity.

The gut is known as a mucosal surface. What does that mean?

Essentially, a mucosal surface is a barrier between the environment and the inside of the body. It differs, however, from barriers like our skin, as it is composed of a single layer of epithelium covered in mucus. We see mucosal surfaces lining the intestines, our noses and the genital tract, for example. Mucosal immune cells must distinguish between the useful molecules that we get from food or healthy microbes, which are admitted into our bodies, and dangerous bacteria like Salmonella that must be kept out. Mucosal immunology is the study of how such immune responses work at barrier surfaces like the gut. In addition to the vast collection of immune cells, the gut harbors a large number of neurons with remarkable diversity.

My research is not focused on the gut’s immune cells per se, but rather their effect on the development and function of the enteric neurons. I want to understand how the healthy microbes in the gut directly, or indirectly via the immune cells, contribute to the development and maintenance of enteric neurons.

That sounds fascinating! Before we dive into your current work at Rockefeller, tell me more about your doctoral research at NYU.

In graduate school, I studied what I think of as the nervous system’s intrinsic signals; basically, what makes a neuron a neuron. There’s a concept in development called the specification of cell fate, which refers to the developmental trajectories that different cells take as they assume different identities. There has to be some kind of spark or trigger that causes a developing cell to become a specific type of cell — for example, a neuron. At NYU, I studied the intrinsic factors — things that need to happen inside the cell — that would then direct the cell into becoming a neuron. I used mouse embryonic stem cells as a model.

There are myriad neuronal types in the nervous system. After cells’ initial commitment to become a neuron, the next step is to diversify into different types of neurons, for example a motor neuron, which controls muscle movement, or a serotonergic neuron, which regulates mood, appetite and sleep. I addressed both steps of this process: the initial neuronal specification step, and the diversification into neuronal subtypes based on their gene expression profiles.

Did you have a particularly striking finding during your doctoral work?

Yes! I studied the activity of two factors that commit a given cell to becoming a neuron by binding to that cell’s DNA and changing the structure of their chromatin and gene expression profile. These so-called proneural factors are extensively used in cell reprogramming strategies to program clinically relevant neuronal types for stem cell-based therapies.

While I was at NYU I engineered a new type of proneural factor — called a chimera — by swapping the DNA-binding domain of one proneural factor with another. To our surprise, the DNA-binding domain itself was sufficient to turn one proneural factor into another. We published this work in 2019 in Nature Neuroscience.

How has your research focus changed since you began your postdoctoral work at Rockefeller?

Having studied the intrinsic factors that contribute to specification of neuronal fate, now I’m studying the things that happen outside the cell, namely, the environmental cues that affect this process. Interestingly, the neurons in the gut are an excellent model system for studying this, as they are exposed to the external stimuli from the environment via the microbes that live in the gut or the molecules (or pathogens) that enter the gut from the things we eat.

We found that intestinal infections or antibiotic treatments result in neuronal loss in the mouse gut. What is striking is that when we reintroduce the ‘healthy microbes,’ the neurons recover. I’m now studying how these neurons come back.

How do you do that?

We have several strategies to model the interaction between gut microbes and neurons in mice. One is to use an antibiotic treatment that depletes the microbes of the gut. When this happens, some neurons in the gut die. Next, we introduce the feces of healthy mice into the microbe-depleted mice. The ‘healthy’ microbes in these feces cause the animals’ neurons to recover. In tandem with these approaches, I’m using specific mouse models to pinpoint the source of these newly generated neurons. I’m addressing the role of resident immune cells in this process as well.

We also work with germ-free mice models. These mice are raised in a sterile environment devoid of microbes, which means they are also shielded from typical immune stressors. Once again, introducing feces from healthy mice into these germ-free models yields new neurons in the gut. At this stage, we’re quite confident of a connection between microbes and neurons.

Do you have any hypotheses about why this might be happening? 

One possibility is that our guts have evolved to maintain inactive neural progenitors. These undifferentiated cells linger in the background throughout adult life, leaping into action to generate new neurons after the gut has experienced an infection or needs to heal itself.

Alternatively, cellular plasticity may play a role, in the sense that one cell type can turn into another under the right conditions. Given that gut neurons are in contact with the external cues, unlike the brain, we think these could be evolutionary mechanisms to maintain tissue integrity. That said, proving or disproving this idea would take more research.

Were there any challenges to doing this work during the pandemic?

My postdoc began in February 2020, and by the time I had completed all the paperwork everything had shut down, and I couldn’t go into the lab until June. Even then we had to go in shifts, and so it was hard to collaborate with my new colleagues at Rockefeller. Plus, we had to decrease our mouse colony because of the pandemic shutdown, and this caused some delays in mice breeding. This all means that I couldn’t fully start my research until this year. Everyone had a terrible time during the pandemic, of course. These are just some challenges that particularly impacted me and my work.

It’s great to hear that your research is now in full swing! How has the Simons Foundation helped?

The generous financial support is truly wonderful as it allows me to pursue my ideas. I am very grateful for that. And I’m so happy that the weekly Fellows dinners are being held in person again, as of September. I feel very fortunate to be a part of this multidisciplinary scientific community.