Research also reveals a potential new test for predicting which children will develop celiac disease
By Amy Ratner, director of scientific affairs
At-risk children may have an increased chance of developing celiac disease if they have had multiple prescriptions for antibiotics, according to a new study. Antibiotics are tied to increasing levels of a protein that loosens the connections between cells that line the intestine, according to the study published in the journal Pediatrics.
This new evidence regarding the role of the protein zonulin in the development of celiac disease in at-risk children leads to two conclusions, note study authors from the Center for Celiac Research and Treatment at Mass General Hospital for Children and colleagues from several Italian institutions.
The study found that at-risk children had a significant increase in zonulin and intestinal permeability as early as 18 months before developing celiac disease autoimmunity. The increase in zonulin was tied to three or more courses of antibiotics.
Researchers counted all antibiotic prescription courses taken by children and did not tie development of celiac disease specifically to unnecessary antibiotic prescription. But they concluded that since a reduction in the number of antibiotics taken is beneficial to at-risk children, it is important to eliminate those that are not really needed.
The study did not recommend avoiding antibiotics prescribed for bacterial infections, as these are necessary treatments.
Antibiotics are routinely and correctly prescribed for a number of common early childhood bacterial conditions, but can also sometimes be prescribed unnecessarily. Unnecessary antibiotics include those prescribed for conditions that are viral and not bacterial, for example bronchitis, colds and the flu.
Children who did not develop celiac disease autoimmunity did not have comparable zonulin increases despite similar rates of antibiotic usage, leading researchers to suspect more than antibiotics are at play when children do develop celiac disease.
“Other unknown factors must be part of the progression in [children] who develop celiac disease autoimmunity,” the study says, noting that all study participants were at-risk for the condition.
Children were considered to have celiac disease autoimmunity if they were diagnosed with celiac disease or had two blood tests taken over time showing they had elevated celiac disease antibodies.
The cells that line the intestine let beneficial substances, such as nutrients, pass into the bloodstream while blocking harmful substances from getting through much like a fine mesh kitchen strainer catches bits of turkey when straining the drippings to make gravy.
Previous studies have shown that zonulin weakens the barrier, making the intestine more permeable or leaky. Increased intestinal permeability has previously been implicated in celiac disease.
In celiac disease, when the cells in the intestinal lining encounter gliadin, the harmful protein in gluten, zonulin is released.
The new study set out to determine whether intestinal permeability was altered before celiac disease autoimmunity developed and whether environmental factors such as antibiotic use affected the role of zonulin.
The study included 51 children who had developed celiac disease autoimmunity and are part of a larger on-going study of 500 children with a first-degree relative with celiac disease. Another 51 children from the larger study who did not develop celiac disease autoimmunity were also included as controls. The children ranged in age from 1 to 7 years old.
The Celiac Disease Genomic Environmental Microbiome and Metabolomic (GEMM) study began in 2014 and follows children from birth through age 10. Blood and stool samples and information from parents about when gluten was introduced in the diet and how much gluten the children consume are collected. Parents also fill out questionnaires about illnesses, symptoms and antibiotic use. A number of insights into the development of celiac disease have come out of the study and the work is continuing.
In this analysis, researchers tested for zonulin in blood samples taken from the time children in the study were one year old until the celiac disease autoimmunity was diagnosed. For controls, levels were measured following a corresponding timeline.
The study is the first to demonstrate an increased rate in the rise of intestinal permeability before children develop celiac disease autoimmunity, the authors wrote. The research provides new insights into the possible mechanisms in celiac disease that cause the immune system in the gastrointestinal tract to treat the gluten protein like an invader and go on the attack.
The number of antibiotic courses was the only environmental factor investigated in the study that had an effect on increases in zonulin levels.
Understanding of the changes in the normal function of the body of at-risk children before celiac disease develops is crucial to early intervention and preventing celiac disease, the study says. It notes that while zonulin levels during active celiac disease have been explored, few studies have looked at how they change before the disease begins. Also, earlier research into intestinal permeability has focused on adults.
Previous studies of the role antibiotics play in the development of celiac disease autoimmunity have had conflicting results.
A 2017 study concluded antibiotics commonly prescribed for children do not increase the chance of celiac disease or type 1 diabetes developing in kids who are already at risk for either of the conditions.
Researchers found that antibiotics, including penicillin, amoxicillin and cephalosporin, prescribed during a child’s first four years were not associated with the development of autoimmunity for celiac disease or type 1 diabetes.
Meanwhile, a 2013 study of antibiotic exposure and celiac disease found a positive association, concluding that antibiotics, possibly through changes in the gut microbiota, could play a role in early celiac disease development. But the study also noted that a possible explanation was that antibiotics were often prescribed to patients who had symptoms of undiagnosed celiac disease. In that study, which included children and adults, penicillin was the most commonly prescribed antibiotic.
Authors of the new study suggest that changes in the gut microbiome occur in children before they develop celiac disease autoimmunity, particularly if they are exposed to multiple cycles of antibiotics. Microbiome changes then cause an increase in zonulin-driven intestinal permeability, powering its role in health and disease. Some are helpful and some are harmful. An imbalance between the two is called dysbiosis.
Antibiotic prescription is tied to bacterial infections, but study authors said it is not clear whether increased zonulin is tied to the number of infections or an imbalance of harmful and beneficial bacteria in the gut caused by use of antibiotics.
“We hypothesize that in genetically pre-disposed individuals, antibiotic exposure, as a proxy of infections, or as a direct effect on the gut ecosystem, leads to intestinal dysbiosis and a resulting rise in zonulin-dependent intestinal permeability,” the study authors wrote. This leads to gluten improperly crossing the barrier of connective tissue that should stop it, which is followed by a break in the immune system being able to tolerate it and the subsequent start of celiac disease, according to the study.
“If greater antibiotic use increases the risk of intestinal permeability and [the] risk of celiac disease, this serves as important guidance to families and physicians on the risk of unnecessary antibiotic use,” the study says.
A 2022 study by Washington University and the Pew Charitable trust found that inappropriate prescriptions for antibiotics for children by outpatient healthcare providers resulted in higher healthcare costs and health complications. In addition to bronchitis, colds and the flu, antibiotics are improperly prescribed for some ear infections, according to the study.
Study limitations include the fact that it did not focus on celiac disease alone but grouped together children with celiac disease and celiac disease autoimmunity, which may not lead to celiac disease in all children.
Additionally, the study did not include details on the particular time periods when children were given antibiotics, which the authors say might be equally important. But they noted that all the children with celiac disease autoimmunity were exposed to antibiotics in the first few years of life, which they say is the most vulnerable window when the microbiome programs the immune system threshold for generating inflammation.
Future studies would be needed to determine how the timing of antibiotic use affects zonulin.
As rates of celiac disease and other autoimmune diseases have been rising for unknown reasons, the authors wrote, the current study could help identify ways to reverse that trend by examining what’s happening before celiac disease develops.
You can read more about the study here.