Mature microbiomes in infancy associated with less wheeze in early childhood

Key takeaways:

• A more mature microbiome at age 1 year decreased odds for atopic wheeze at age 1 year and 4 years.
• There was no association based on gut microbiota maturation at ages 1 month or 6 months.

Infants with more mature microbiota had less allergy-related wheeze or asthma in early childhood, according to an abstract presented at the European Respiratory Society International Congress.

This study builds on earlier work finding associations between more mature gut microbiota and reduced risk for food allergy, allergic rhinitis and atopic dermatitis, according to Yuan Gao, PhD, an associate research fellow at Deakin University in Geelong, Australia, and colleagues.

Gao noted that atopic wheeze is a case condition that requires children to have wheezing in the preceding 12 months and atopic sensitization.

Yuan Gao

“Atopic wheeze at 4 years of age is strongly predictive for asthma in later childhood and indeed through to adulthood,” Gao told Healio. “However, the underlying basis of developing atopic wheeze in childhood remains unclear.”

Previous research based on the European COPSAC and PASTURE birth cohorts has indicated an association between a higher risk for asthma in childhood and less mature gut microbiota at age 1 year, she continued.

Additional research based on the Canadian CHILD birth cohort extended these findings by showing that delayed gut microbiota maturation at age 1 year may be universal to pediatric allergies including atopic dermatitis, allergic rhinitis, food allergy and asthma, she said, adding that these findings in regard to food allergy are consistent with her own team’s previous work.

“We found that a more mature infant gut microbiota at 1 year of age is associated with reduced food allergy,” Gao said. “So, our hypothesis is that a more mature infant gut microbiota in infancy is protective for atopic wheeze in childhood.”

Study design, results

The Barwon Infant Study collected fecal samples from 1,074 infants at ages 1 month, 6 months and 1 year. Also, the researchers assessed atopic wheeze in the previous 12 months at ages 1 year and 4 years based on parent reports.

The researchers additionally conducted skin prick testing for 10 common allergenic foods and for airborne substances such as rye grass or dust during the reviews at ages 1 year and 4 years.

Further, the researchers derived fecal amplicon sequence variants (ASVs) via 16S rRNA gene amplicon sequencing for 323 of these infants and used them to determine microbiota-by-age z scores (MAZ) at each time point during the first year of life.

Results indicated an association between each standard deviation increase in MAZ at age 1 year and decreased odds for atopic wheeze at age 1 year (OR = 0.51; 95% CI, 0.36-0.71) and at age 4 years (OR = 0.52; 95% CI, 0.31-0.87). However, the researchers did not find any evidence of an association using MAZ at ages 1 month or 6 months.

Previously, Gao and her colleagues found an association between each standard deviation increase in MAZ at age 1 year and a decreased odds ratio for food allergy (OR = 0.45).

Also, Gao continued, PASTURE found an association between higher MAZ value and reduced risk for asthma (OR = 0.72), and COPSAC found an association between risk for developing persistent asthma and low maturity below the median in MAZ at age 1 year (OR = 1.77).

“The association between gut microbiota maturity and allergies has been replicated across four high-qualified birth cohorts. It is unusual to see this degree of replication in the microbiome field,” Gao said.

Whereas preclinical studies have shown that gut microbiota play a key role in driving immune development in early infancy, Gao said, the mechanisms behind how advanced maturation of the gut microbiota in late infancy protects against allergic disease are understudied, and little is known.

“One possibility is that a more mature gut microbiome promotes the induction of regulatory T cells to food and other environmental antigens via increased production of short chain fatty acids,” Gao said.

Elevated concentrations of butyrate in stool samples partly mediated the protective effect of a more mature MAZ in late infancy on subsequent asthma in PASTURE, Gao added.

Earlier work in the PASTURE cohort found that participants with levels of butyrate and propionate above the 95th percentile were less likely to develop allergic sensitization and asthma, she said.

“We found that a higher concentration of propionate, but not butyrate, in 1-year stool was associated with decreased food allergy at 1 year and atopic wheeze at 1 year, but not 4 years, but the protective effects of propionate and MAZ appeared to be independent of one another,” Gao said. “The therapeutic potential of promoting propionate production during late infancy warrants further evaluation.”

Conclusions, next steps

Gao said that the specialty is at a very early stage of understanding the basis of how a more mature MAZ impacts the risk for allergic disease and asthma.

“However, in our previous study on food allergy, we found that both older siblings and dog in the home promote the maturation of the infant gut microbiota at 1 year of age,” she said.

Also, a more mature gut microbiota at age 1 year mediated the protective effect of older siblings and dog in the home on food allergy at age 1 year by 63% and 27%, respectively, she continued.

“Though we found that a more mature gut microbiota at 1 year of age mediated the protective effect of dog on atopic wheeze at 1 year of age by 29%, we found no evidence for atopic wheeze at 4 years of age,” she said. “More studies are still needed before evidence regarding the MAZ can be translated into clinical practice.”

Despite these uncertainties, the researchers said, these results may still inform new strategies for preventing allergy-related disease, such as advancing the maturation of gut microbiota early in life.

“The benefit of a mature gut microbiome in late infancy may relate to the immune effects of rich microbial environment,” Gao said.

Next, the researchers intend to recruit 2,000 children from Australia and New Zealand for the ARROW study.

“ARROW is a multicenter placebo-controlled clinical trial in Australia and New Zealand designed to test the hypothesis that oral administration of the bacterial lysate OM-85 (Broncho-Vaxom, Minapharm Pharmaceuticals) reduces the risk of hospital readmission among children with preschool wheeze,” Gao said.

References:

• Depner M, et al. Nat Med. 2020;doi:10.1038/s41591-020-1095-x.
• Gao Y, et al. J Allergy Clin Immunol. 2023;doi:10.1016/j.jaci.2023.02.034.
• Healthy guts containing diverse and mature bacteria are linked to less allergy-related wheezing and asthma in early childhood. https://www.ersnet.org/news-releases/healthy-guts-containing-diverse-and-mature-bacteria-are-linked-to-less-allergy-related-wheezing-and-asthma-in-early-childhood/. Published Sept. 10, 2023. Accessed Sept. 10, 2023.
• Hoskinson C, et al. Nat Commun. 2023;doi:10.1038/s41467-023-40336-4.
• Stokholm J, et al. Nat Commun. 2018;doi:10.1038/s41467-017-02573.2.

For more information:

Yuan Gao, PhD, can be reached at yuan.gao@deakin.edu.au.