Study to examine the esophageal microbiome as an influence on patients’ response to topical steroids.

Since many children with eosinophilic esophagitis (EoE) do not respond adequately to treatment, researchers are turning to the esophageal microbiome to look for clues that might explain the sub-optimal therapeutic response.

“We’re using genomic information to learn about microbiome differences between children who respond to the topical steroids that are often used to treat EoE and children who don’t,” said Seesandra Rajagopala, Ph.D., a research assistant professor of medicine at Vanderbilt University Medical Center. “We hope to understand the esophageal microbiome’s role in influencing the response to topical steroid therapy in EoE.”

Together with Giresh Hiremath, M.D., M.P.H., a pediatric gastroenterologist at Monroe Carell Jr. Children’s Hospital at Vanderbilt, Rajagopala is working with esophageal biopsy samples that yield surface microbiome.

“We have developed a novel method that is highly sensitive in capturing the microbiome’s signature,” Rajagopala said. “With this method, we can separate the signatures coming from the host, from bacteria, from fungi or from viruses and use that information to tease out the differences between responders and non-responders to topical steroids.”

Dangerous Inflammation

EoE is a chronic, inflammatory disease of the esophagus wherein the immune system can trigger extreme inflammation in response to an allergen. It affects about 1 in 1,000 people living in the United States and is one of most common causes of upper-gastrointestinal morbidity in children. Its incidence has been rising in many industrialized countries, Hiremath said.

The disease occurs when an excess of eosinophils accumulate in the esophageal lining as a reaction to allergens, acid reflux and even foods. This build-up leads to inflammation and can sometimes cause severe damage.

Emergencies Can Occur

Children’s symptoms may include aversion to bottle or breast feeding, trouble eating, vomiting, belly pain, and difficulties in swallowing, Hiremath explained, potentially precipitating malnourishment and failure to thrive.

“If the inflammation is not adequately controlled, then the esophagus can remodel over time and become quite narrow, leading to food impaction,” Hiremath said. “Patients may need an emergent intervention to relive that impaction.”

The disease has only been recognized as a distinct illness for about 30 years, he added. Prior  to that time, eosinophilic esophagitis was often misdiagnosed as reflux.

Treatments Inadequate

Swallowed topical steroids, the mainstay of treatment, can sometimes provide relief from symptoms and lead to remission. Other longstanding interventions include the use of acid-blocking medications and the elimination of dietary allergens.

However, around half of the children affected by EoE do not respond to the topical steroids, Hiremath said. Non-responders continue to suffer symptoms that can erode their own quality of life and put enormous stress on their caregivers.

The FDA approved the first monoclonal antibody treatment, dupilumab, for the condition in May 2022.

“The monoclonal antibody is not widely used yet, and it’s only approved for use in patients age 12 and older, ” Hiremath said.

Characterizing The Microbiome

The new research will determine the structure and function of the esophageal microbiome that is most closely associated with a positive response to treatment.

Hiremath and Rajagopala hypothesize that changes in esophageal bacterial diversity and enrichment of select microbial species drives the response to steroid therapy in children with EoE.

The biopsies they will examine contain samples of the esophageal surface microbiome, Rajagopala explained.

“Our method captures the entire transcriptome landscape. So, we can clarify distinct throat microbiome communities among children who benefit from topical steroids and those who do not.”

Underexplored Area

Little is known about what leads to positive or negative treatment response for this condition.

“Very little research to date has focused on determining the factors that are associated with a good response to treatment or a poor one,” Hiremath said.

The current study is believed to be the first to use metatranscriptomics to explore the functional activity of the microbial consortium living in the esophagus and how it affects treatment outcomes in children with EoE.

“Who is there? Who is active? What’s the community structure?” are among questions they seek to answer, Rajagopala explained.

In a preliminary study of nine patients, a specific bacterial species, Acinetobacter, was predominate in nonresponders. The full study will include more than 75 children.

New treatments may result from this work.

“The microbiome is modifiable. Maybe we can identify certain bacteria whose presence or absence influence the therapeutic response,” Hiremath said. “That could offer us something we can alter via probiotics.”

Bios

Girish Hiremath, M.D.

Girish Hiremath, M.D., is assistant professor of gastroenterology at Vanderbilt University Medical Center, and a pediatric gastroenterologist at Monroe Carell Jr. Children’s Hospital at Vanderbilt.

Seesandra Rajagopala, Ph.D.

Seesandra V. Rajagopala, Ph.D., is a research assistant professor of medicine in the Division of Infectious Diseases at Vanderbilt University Medical Center. His research focuses on the interface between infectious diseases and systems biology. His metagenomics and transcriptome studies use deep-sequencing methods to explore the complex host-microbial interactions in various diseases.