by Aleks Prochera
figures by Corena Loeb

Imagine working in a factory as part of a logistic team whose job is to coordinate and oversee the flow of incoming materials. It’s a 24/7 job – you don’t know what will be delivered or when, but regardless of the nature of the shipment, you have to deal with it. Additionally, you must be in constant contact with many other departments – the transportation team, the upper management, the security division. Sounds intense, right? Yet this is the job that must be dutifully performed by enteric neurons, specialized cells that innervate practically every inch of your gut. Every day these cells face the heroic task of managing the flow of diverse materials that enter your stomach (Figure 1). From digestion, through the extraction of fluids and nutrients to the elimination of waste, all these processes are overseen by enteric neurons. And although this sounds like a full-time job, a new study in the journal Cell shows these cells have another gig on the side: enteric neurons get their hands dirty in the protection of the gut against microbial invaders. The research published in January sheds new light on how these gut neurons contribute to our general health.

Figure 1: The intestine – a bustling, busy factory. Enteric neurons (in purple, seen here directing food trucks through the digestive system) are the logistic team that ensures the smooth operation of the gut. They coordinate transport as well as digestion and processing of ingested food. Goblet cells (in green) are among many cell types that protect the intestine against pathogenic invaders. They generate the mucosal layer, which prevents microbial entry into the gut.   

The gut: the Wild West of the body 

The intestine is a wild, occasionally dangerous, site in your body. It is colonized by an ecosystem of microorganisms that are beneficial for your health and is also exposed to a whole swathe of potentially harmful pathogens, such as Salmonella, that can hijack the food we eat. In order to ensure a peaceful existence with the beneficial microbes while preventing an attack from pathogenic invaders, the gut is armed with various tools that maintain a healthy environment.

The first obstacle a would-be invader encounters in the intestine is an actual physical barrier. Produced by a specialized cell type known as Goblet cells, this protective layer made of mucus separates the wall of the intestine from the contents of the gut (Figure 1). What allows this mucus barrier to ward off any potential intruders is its composition – large, bulky proteins physically prevent microorganisms from invading the gut while other factors called antimicrobial peptides kill microorganisms that come too close to the gut wall. Even though scientists have long studied this first line of defense, it turned out that formation of the mucus layer still holds many surprises. One such surprise – the involvement of enteric neurons – has recently been discovered by a group of scientists from Yale. 

Wearing two hats: logistic coordinators by day, security guards by night 

The story begins with the protein IL-18, one of the many chemical messengers, or cytokines, used for communication between various cells. IL-18 was initially described as a protein secreted by a specific flavor of immune cell to induce an inflammatory response, but recent studies have demonstrated it is also produced by other cell types, including intestinal barrier cells called epithelial cells. 

Since its discovery, scientists have learned a great deal about the role IL-18 plays in various circumstances. For example, scientific papers published in the last few years have suggested that the cytokine is crucial for protection against intestinal invaders. Compared to normal mice, laboratory mice that cannot produce IL-18 suffered more severe infection when exposed to Salmonella bacteria (Figure 2). This fascinating discovery raised many new questions: what cell types release IL-18 to protect mice against Salmonella, and what specific information are these cells communicating?

Figure 2: IL-18 is necessary for protection against intestinal infection. Mice genetically modified to lack IL-18 in all cells (right) experience more severe Salmonella infection as compared to the normal laboratory mice (left). 

These were the questions that Dr. Richard Flavell’s group decided to tackle.  First, the research team needed to figure out the exact source of IL-18. Given the protein has been shown to be produced by specific immune and intestinal epithelial cells, the authors zeroed in on those two cell types as the possible makers of the cytokine. Surprisingly, when they blocked IL-18 production in these cells, they discovered that neither played a role in how the mice responded to Salmonella infection (Figure 3). 

Figure 3: Enteric neurons are the source of IL-18 necessary for protection against the intestinal infection.  Blocking IL-18 production in immune cells or intestinal epithelial cells has no effect on the severity of Salmonella infection. In contrast, lack of IL-18 production in the cells of the enteric nervous system leads to more severe disease in response to Salmonella exposure. 

To find the mystery source of IL-18, the authors used microscopy to visualize what other cell types in the gut produced the protein. When they inspected the intestinal tissue, they observed that it was none other than enteric neurons that churn out the cytokine. 

This observation suggested that enteric neurons could supply IL-18 that conferred protection against microbial invaders. To test that hypothesis, the researchers developed a mouse in which production of IL-18 was blocked in cells of the enteric nervous system but was unchanged in immune or epithelial cells. When researchers exposed these mice to Salmonella, the animals experienced severe symptoms of infection (Figure 3). Just like the animals in which no cell could produce IL-18, they failed to control the bacteria and succumbed to the infection faster than the regular mice. 

But how does the lack of neuronal IL-18 lead to a worse intestinal infection? When the scientists drilled down to answer this question, they discovered that Goblet cells were the culprit. In the animals with enteric neurons unable to produce the cytokine, the makers of the mucus layer (Goblet cells) were sluggish with their production of specific antimicrobial peptides. In turn, the mucosal layer of these mice was less effective at protecting them against intestinal invaders, making the animals highly susceptible to infection by the pathogen. What’s more, the everyday microbes that are normally found at a sizable distance from the tissue, gained access to the gut wall, thus posing a danger to the health of the animal.

By describing a novel role for enteric neurons in the regulation of the mucus layer, this recent study adds to the expanding list of immune-like functions fulfilled by members of the nervous system. However, many questions remain. What are the processes by which enteric neurons produce and secrete IL-18? Do they release this cytokine at all times or in response to specific stimuli? One thing is clear though – enteric neurons are highly multifaceted cells: from skilled logistics coordinators to security team members, these cells do wear many hats.


Aleksandra Prochera is a Ph.D. student in the Harvard Immunology Program. You can find her on Twitter as @Aleks Prochera.

Corena Loeb is a first-year Ph.D. student in the Harvard-MIT program in Speech, Hearing, Bioscience and Technology.

For More Information:

  • Interested in diving deeper into the topic of the enteric nervous system? Check out this YouTube explainer and these articles, which provide an overview of how the neuronal logistic team in the gut works. 
  • Want to learn more about how the intestinal security team operates? This scientific review covers the current state of the gut immunity field.
  • To learn more about the recent discoveries at the interface of immunology and neuroscience and how they inform what is being done in the clinic, check out this series of open access articles on the topic of neuroimmunology. 

One thought on “The Secret Life of Gut Neurons

  1. The pictures are really great—they clearly communicate the messages in a way nonscientists can understand while at the same time retaining the detail necessary to communicate the significance of the research

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