Delayed maturation of gut microbiota associated with pediatric allergic disease

Key takeaways:

• Immature microbiota at age 1 year were associated with atopic dermatitis, asthma, food allergy and allergic rhinitis at age 5 years.
• Functional and metabolic imbalance were significant mediators.

Infants with immature gut microbiota faced greater risks for developing atopic dermatitis, asthma, food allergy and allergic rhinitis by age 5 years, according to a study published in Nature Communications.

Shifts in the infant microbiome also may indicate potential onset of allergic disease,

Courtney Hoskinson, BSc, PhD candidate in the department of pediatrics at BC Children’s Hospital, University of British Columbia, and colleagues wrote.

Study background

“Children in our society are increasingly at risk of developing allergic disorders, which is a sign that their immune system is confused and reacting to otherwise benign signals,” Hoskinson told Healio.

Courtney Hoskinson

Most of these disorders, including hay fever, asthma, food allergy and eczema, have their own set of symptoms, Hoskinson continued, and yet incidences of all of them have increased across the board.

“Previous work in our labs and others suggested that changes in our environment which have affected the community of bacteria living on our bodies — we call it our microbiota — may be the common link between this rise,” she said.

Instead of studying each allergy diagnosis individually, Hoskinson said that she and her colleagues took the relatively unique approach of simultaneously looking at all these diagnoses to test this hypothesis.

“We were particularly interested in studying the bacteria in infants because this is such a critical time for healthy immune development,” she said.

Bacteria begin colonizing human beings at birth, primarily in the gut or in the digestive tract, Hoskinson explained. Their abundance fluctuates with exposure to more bacteria in the environment.

“It seems a little bit chaotic for the first 1 to 2 years of life until the bacteria are able to form a stable community that will remain relatively the same for most of our lives,” Hoskinson said. “Importantly, though, this is occurring right at the same time that our immune system is figuring out which signals are dangerous, and which should be tolerated.”

Study design, results

The CHILD birth cohort included 523 children (45.1% boys) who did not have any evidence of allergic sensitization and 592 children (60.6% boys) with a diagnosis of at least one allergic disorder at their 5-year visit.

The researchers evaluated the microbiomes in the stool of 589 of these patients collected during their 3 month and 1 year visits. The patients with an allergic diagnosis at age 5 years had a significant decrease in Shannon diversity at age 1 year.

“One of the most significant findings came from studying that initial formation of the microbiota in infants,” Hoskinson said.

“Even though it seems chaotic, when we took a step back and looked at all those fluctuations over time, we observed a common pattern to how the infant microbiota develops. We call this microbiota maturation, and we believe that this pattern is likely optimal for supporting healthy development,” she continued.

Noting that infant microbiota can accurately predict an infant’s chronological age, the researchers found the patients with no allergic history through age 5 years had an average microbiota-predicted age of 11.53 months (standard deviation, 1.32) at the 1-year visit.

The researchers also found statistically lower predicted microbiota ages for patients with atopic dermatitis (n = 367; P = .000014), asthma (n = 165; P = .0073), food allergy (n = 136; P = .00083) and allergic rhinitis (n = 187; P = .0021) despite having the same chronological age.

These reductions in microbiota-predicted age at age 1 year were detected in children who had an allergy diagnosis at age 5 years regardless of their skin prick test history and their specific allergic condition, the researchers said.

“Importantly, no matter which allergy we were looking at, microbiota maturation was delayed in 1 year old infants who would later develop allergies by 5 years,” Hoskinson said.

Although there were children in the cohort with multiple allergy diagnoses at age 5 years, the researchers continued, children with a single allergy had significantly lower predicted age as well.

“Even more helpful, we were able to find out which bacteria were most important for this process and then ask what they were doing in the infant gut to support healthy immune responses,” Hoskinson said.

“This turns out to be maintaining a healthy intestinal barrier and also reducing inflammatory signals that would call infant immune cells into action. We noticed a breakdown in these mechanisms prior to the development of all four major allergies,” she said.

Patients who developed an allergic disease by age 5 years had decreased abundances of Anaerostipes hadrus, Fusicatenibacter saccharivorans, Eubacterium hallii and Blautia wexlerae and increased abundances of Eggerthella lenta, Escherichia coli, Enterococcus faecalis, Clostridium innocuum and Tyzzerella nexilis at 1 year.

These changes in abundance of these nine overlapping species indicate reduced infant gut microbiota maturation and the development of multiple clinically distinct allergic disorders, the researchers wrote.

The researchers additionally found that 193 pathways were significantly associated with at least one of the composite or individual diagnoses of allergic disease at age 5 years, and 281 pathways were associated with predicted age. Also, predicted age was associated with 171 of the 193 significantly altered pathways in the allergic groups.

There were similar patterns across all four allergic diseases as well, the researchers continued, but 11 pathways were significantly different in at least two of the allergic disease groups and in one of the composite groups, with significant associations with predicted age as well.

There were negative associations between nine of these pathways and microbiota-predicted age, and these pathways were subsequently elevated in the infants who later developed allergies, the researchers continued.

The other two pathways had positive associations with predicted age and allergy protection, along with significant connections with B. wexlerae, F. saccharivorans, A. hadrus and E. hallii. E. coli primarily was correlated with elevated pathways in the allergy group.

Based on these findings, the researchers found a link between reduced infant gut microbiota maturation and broad functional dysregulation that overlapped with allergic disorder development.

Using stool samples from 509 of the patients, the researchers additionally assessed 245 relevant metabolites, with microbiota-predicted age significantly explaining the 2.2% variance in the 1-year metabolome (P = .0009).

Seven modules and 27 unclustered metabolites, representing 120 of the 245 total, had significant associations with predicted age, indicating a strong relation between microbiota maturation and the infant gut metabolome too, the researchers said.

The researchers then identified 10 individual metabolites and four metabolic clusters that had significant relationships with important pathways in the infant gut microbiota, in addition to 11 individual metabolites and seven metabolic clusters with significant associations with important species abundance.

Sulfur oxidation correlated with the most metabolic features, including six metabolites and two metabolic clusters. Among the microbiota, E. coli correlated with the most metabolic features, including five metabolites and two clusters.

There also were significant correlations between 17 of 20 (85%) important features and trace amines derived from aromatic amino acids, tryptamine, tyramine and phenylethylamine, the researchers foumd, in addition to correlations between the short-chain fatty acid butyrate, which the researchers called key to immune tolerance, and F. saccharivorans, A. hadrus and sulfur oxidation.

In addition to each 5 year allergy diagnosis, delayed predicted age was significantly associated with dysregulation within microbiome functional capacity and the metabolic landscape of the gut at age 1 year, the researchers continued.

Each dysregulated feature, such as altered mucous degradation, increased oxidative respiration, oxidized monosaccharide utilization, diminished sulfur oxidation and secondary fermentation capacity, contributes to a significant indirect effect (P = .002; beta = –2.28) for the 1-year stool latent variable.

Conclusions, next steps

The multi-omic signals that mediate this association between impaired microbiota maturation and allergies at age 5 years are at the forefront of mechanistic targets that could collectively predict and/or prevent the development of allergic disease, the researchers wrote.

Additional studies including independent cohorts would strengthen these findings, the researchers added.

“Our study highlights that seemingly different allergy diagnoses likely have a common origin related to the bacteria that colonize us as infants,” Hoskinson said. “These bacteria are essential for supporting healthy development in childhood, especially for our immune system.”

Studying these specific bacteria not only can tell physicians when that development needs help, Hoskinson explained, it also can tell physicians how to help as well.

“In other words, this sets the stage to use this common bacterial signature to identify infants who are at risk of developing allergies and potentially prevent all allergies from ever developing,” she said.

The study also demonstrates that exposure to the microbial world is changing, with measurable effects on healthy development, Hoskinson said.

“We hear constantly about our changing environment and how that has affected the biodiversity of animals, plants and insects,” she said. “But the reality is that our microbial world is being affected too, including the bacteria that colonize us.”

Hoskinson noted that people tend to think of bacteria in a negative context, as germs or pathogens that need to be eliminated. Yet the vast majority of them are beneficial, and human beings have co-evolved with them, she continued.

“Our exposure to these beneficial bacteria during infancy is important for lifelong health, so we need to be thoughtful about how to support and maintain our interactions with them in order to slow or stop this rise in allergies,” she said.

These findings may inform future treatment in allergy prevention, Hoskinson said.

“Our dream would be that infants at risk for developing allergies could be identified in the future using just their poop, and then we could replace important missing bacteria to prevent allergies,” she said.

In the meantime, she continued, there are many strategies that parents and clinicians can employ to prevent food allergies.

For example, Hoskinson recommends increasing exposure to beneficial bacteria, such as by letting infants play outside where they can be exposed to a diverse microbial community.

Also, she recommends supporting the nutrient needs of gut bacteria.

“In a young infant, this means breastmilk, so we should all be supporting nursing moms however we can,” she said. “After weaning, this means eating nutrient-dense foods that feed both us and the bacteria inside of us.”

Hoskinson additionally recommends reducing unnecessary antibiotic exposure. Although antibiotics may target harmful pathogens, she said, they also wipe out beneficial bacteria.

“So, we really only want to use them when they are absolutely needed,” she said.

Further research is warranted, Hoskinson said.

“Ideally, we would want to see these findings replicated independently,” she said. “We would also love if other researchers were to study this at a more mechanistic level and develop a preventative therapy.”

Reference:

• Researchers discover common origin behind major childhood allergies. https://www.eurekalert.org/news-releases/999837. Published Aug. 29, 2023. Accessed Aug. 29, 2023.