Its symptoms aren’t unusual: heartburn, chest pain, and difficulty swallowing. But the etiology of eosinophilic esophagitis (EoE) isn’t completely understood. Potential causes point to allergies, genetics, and environmental factors.

Some researchers, including Amiko Uchida, MD, suspect that the microbiome plays a role in this chronic inflammatory condition, which affects 1 in 700 individuals in the US.

“I think that we’ve come a long way in the last 10 years in understanding key players and what drives EoE disease,” said Uchida, assistant professor with the Division of Gastroenterology, Hepatology, and Nutrition, University of Utah Health, Salt Lake City. Still, new therapies and dietary modifications haven’t helped all patients, which points to a need for more research into EoE’s origins, new treatments, and the reasons for its increasing incidence.

Uchida is a recipient of the National Institute of Diabetes and Digestive and Kidney Diseases K23 career development award for her proposal, Dietary Impacts to Microbial Composition and Function in Eosinophilic Esophagitis. The study will investigate how diet and the microbiome may influence inflammation and disease progression in EoE.

“My proposal focuses on beneficial microbes and how they could be anti-inflammatory, but it also has the potential to identify pathogenic ones,” she said.

In an interview, Uchida offered more details about her research, current understanding of EoE, and possible reasons for its rise.

How does EoE present, and how do you inform patients about this condition?

I make sure they understand it’s a chronic disease. It’s generally something that doesn’t go away on its own and needs some sort of long-term maintenance therapy plan.

They should also understand it’s a type of allergic disease or allergy. Oftentimes patients have other allergic diseases, like seasonal allergies or asthma, that help bring into context what they might expect for the esophagus in EoE. We see this chronic inflammation affecting the esophagus and leading to swelling and scarring of the esophagus over time.

Adult patients will present with trouble swallowing, which is one of the main functions of the esophagus. They’ll notice that food goes down more slowly or it’s more difficult to get food down. Pediatric patients often present differently. They may avoid eating or have poor weight gain, abdominal pain, nausea, and vomiting. Sometimes patients have heartburn. Symptoms can vary for different patients, and you need to have a high index of suspicion, especially in those patients who have a strong history of allergies of other types.

What other factors might lead to EoE?

There are a couple of other hypotheses that might be contributing to EoE.

There’s exposure to specific irritants that lead to destruction to the esophagus barrier. If you have acid reflux — contents coming up and destroying the bottom of your esophagus — raw mucosa will open and be introduced to microbes, which might be beneficial or pathogenic. There was a study from Benjamin L. Wright, MD, and Alfred D. Doyle, PhD, that looked at exposing the esophagus to soaps, essentially detergents. This causes a breakdown in the cells that should be tightly closed together. Detergents found in things like toothpaste can open that barrier so that it’s no longer as tight.

How might the microbiome play a role in EoE?

The microbiome is full of 30-plus trillion different microbes. There are a lot of different potential interactions that can take place, some of which might be pathogenic or drive disease and some that might actually be beneficial.

Published research has focused predominantly on the esophageal microbiome — microbes that are found in the esophagus, which is a very different environment than the skin or the colon. These studies have been largely descriptive, if you will. It’s a very natural first step where we’re taking a snapshot in time, sampling this area and looking at the microbes that are there. When we look at people with EoE and without it, we see different organisms present. What we don’t know is when we see more of a presence of one microbe, is it driving disease, or is it a sequela of the underlying disease, and what are the consequences?

Those are big questions that we don’t know answers to yet. My current research is focusing on possible ways that the microbiota could be relevant and beneficial. I’m also interested in microbes beyond the esophagus, including the distal gut or the colon.

Why is EoE increasing in incidence?

This is not unique to EoE, meaning that the increase in diagnoses and prevalence is increasing in other allergic diseases as well. There are a lot of different hypotheses around why we are seeing more patients being diagnosed with EoE. The increase in incidence or new diagnoses of EoE is outpacing the advent of endoscopy. At least one study accounts for the increased utilization or use of upper endoscopy, which is the gold standard way of diagnosing the disease. And when you account for or control for that, the EoE diagnosis is outpacing that utilization.

There’s a lot that’s changed in western societies about our microbiome, the foods that we eat, and things like parasitic infections. But with that comes this hygiene hypothesis, which is also known as the “lost friends” or “old friends” hypothesis. This relates to parasitic infections, where parasites are in the environment and humans are colonized. That interaction provides an educational opportunity for the immune system to learn what a parasite is and to react against that parasite and hopefully clear it.

There’s this hypothesis or idea that with an absence of that early education we get misfiring or misidentification of things like food or pollens that are not actually pathogenic but are resulting in an allergenic response. There’s a lot we still must uncover about the microbiome and EoE.

What about certain drugs designed for EoE, like Dupixent (dupilumab)? With this option available, why is there a need for more research into treatment?

There are several aspects of EoE that are not well understood, things like how the environment interacts with either developing or propagating EoE. Just a few years ago, we got our first FDA-approved therapy that targets one of the driving mechanisms of EoE. Dupilumab is a monoclonal antibody injection medicine that targets the key drivers of inflammation: interleukin-4 and interleukin-13.

But some patients don’t respond to this therapy. In the phase 3 trial that led to FDA approval, 40% of patients did not reach their endpoint.

So what’s driving those patients? EoE is starting to mirror other chronic inflammatory diseases of the gut, notably something like inflammatory bowel disease, where we now have nearly a dozen targeted or advanced therapies. But one patient may respond to one treatment and not the other, and we don’t know why. And so there are certainly big gaps in our understanding.

Also, dupilumab costs around $100,000 a year. This is one of the most expensive EoE medications, and it remains poorly covered. Insurance companies continue to deny care, which we know over the last 10 years has exponentially increased where they're unwilling to pay for approved therapies, even if they have FDA approval. So, we need more therapies and affordable therapies for patients as well.

Some patients respond to dietary changes such as eliminating dairy and wheat. How successful has this approach been?

We find that some patients respond to the sequential removal and/or reintroduction of specific food types. Indirectly, we’ve concluded that this disease is a food-antigen or food-allergy driven disease because of what we remove and stepwise reintroduce.

What’s interesting is you can remove all foods and put somebody on an elemental diet, or a very broad elimination diet where we remove six to eight food groups, yet we are increasingly seeing that patients are not responding as they once used to or as we might have expected. Somewhere between 10% and 30% of patients still do not improve on elemental diet, depending on the study, and for six-food elimination diet, we saw around a 40% response rate.

To me, this presents a big gap in our understanding of what is really driving EoE. Is it food or could there be something more? This is where I enter the microbiome because if you think about something that largely shapes our intestinal microbiota, that is the diet. When we make these dietary changes in EoE, I think we’re also affecting the microbiota. It may be that people have a certain microbiota that lends themselves to having a more robust (or not) response to an elimination diet. For example, you might have certain communities present in your microbiome that when you do a food elimination diet, this allows these microbes to have a more beneficial response. Microbes may now be better able to secrete anti-inflammatory factors, for example, and those can help drive remission.

What has research uncovered so far about EoE? You’ve published a number of studies and papers. Anything you’d like to highlight?

One of the studies I co-authored looked at infection and later risk for EoE in life using a Swedish population cohort. We examined patients diagnosed with EoE and looked back to see if they had a previous infection that was significant enough where they sought hospital-related healthcare. What we found is having a previous infection did increase the risk for later development of EoE.

Additionally, in a subgroup analysis, we looked at the risk of antibiotic use and found that antibiotics themselves also carried a risk for development of later EoE. We aren’t alone in those sorts of endeavors. There’s been work by Elizabeth T. Jensen, PhD, and Evan S. Dellon, MD, MPH, among others that have found similar associations in early life exposures, such as antibiotic use and mode of birth delivery, that increase the risk for later EoE. To me, this data suggest that perturbations to the microbiota may be important for later development of EoE.

What’s the next logical step in EoE research?

There are many important steps for the field that range from direct patient care research to studying basic science at the bench in seemingly unrelated ways. However, my laboratory’s next step is to understand the microbial environment in this disease under a standard-of-care treatment of diet.

We’re setting out to understand what happens before to EoE patients throughout their journey of treatment with diet, and how does the microbiome shift. Can we reference that and learn from how biology is already happening a care that we’re enacting that we don’t understand? How can we learn from the microbes that are there, and can we capitalize on any of that? Can we look for microbes that are enriched in somebody who achieves remission? What changed in their microbiome? What changed in their biology? Can we track that and magnify that to help apply what’s different between that patient population and the ones who went on diet and didn’t respond? Are there certain things that the microbes are making — microbial metabolites that can be beneficial generally? Can we harness those sorts of things to administer to other patients to help?

I don’t think that there’s one direction. The direction is to support novel ideas and things that are patient facing but also not diminish the value of the fundamental understandings of basic science.

Uchida reported serving as an advisor/consultant for Sanofi-Regeneron, AstraZeneca, Takeda, Areteia, and Uniquity.

Jennifer Lubell is a freelance medical writer in the Washington, DC, Metropolitan Area.