Does Childhood Asthma Begin Before Birth?

The risk for childhood wheeze is greatly reduced when babies collect the right bugs in their microbiome early in life, new research from two studies shows.

"We've gone from the hygiene hypothesis to the microbial dysbiosis hypothesis," said Christine Cole Johnson, PhD, from the Henry Ford Health System in Detroit.

"The microbes established in a baby's first months of life from the mother are important," she explained. The type of community that develops in a baby's gut and skin "affects not only asthma, but the whole immune system."

"The answers aren't all in," she acknowledged, but evidence is mounting that we need more exposure to microbial diversity early in life. "We've seen that when a mother has a dog in the house, the cord blood lgE of the baby is lower, indicating that early exposure is a factor."

Johnson presented new data on the interplay between maternal factors and infant gut microbiota and the effect that has on the risk for allergic asthma at the American Thoracic Society (ATS) 2019 International Conference in Dallas.

She and her colleagues looked at fecal samples from infants — members of the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) — taken at 1 and 6 months. They used 16S V4 sequencing to see whether the bacterial taxa in the gut microbiota of those infants would predict who would have allergic asthma 10 years later.

Gut bacterial diversification during infancy was slower in the now 10-year-old children with allergic asthma, and immature gut communities at 6 months increased the odds that a child would have allergic asthma at 10 years.

Predicting Asthma

Previous studies have shown that the risk for asthma is lower in children raised on farms and when a parent licks a pacifier to clean it, as reported by Medscape Medical News.

"We're the first group to show that very early microbial gut communities actually impact asthma outcome at the ages of 10 and 11," Johnson reported. In fact, the odds that a 10-year-old child will have allergic asthma are elevated if he or she was born by emergency cesarean, does not have a dog, is black, and has an immature gut bacterial community.

In general, boys are more likely than girls to have asthma at a young age; however, boys often grow out of it but girls are less likely to.

In the WHEALS cohort, a more mature bacterial community at 1 month and a more immature bacterial community at 6 months were associated with allergic asthma in both boys and girls.

However, the increase in allergic asthma at 10 years related to this downward trajectory in diversity was more likely to affect girls than boys. "We don't understand why," Johnson said.

Various hypotheses include the difference in lung size in boys and girls at birth and the difference in the placenta makeup. "Boys and girls may be different much earlier on than we think," she explained. Or perhaps as babies, boys have higher hand-to-mouth exposure than girls. "Maybe boys ingest more microbes as infants," she suggested.

One day, a baby's microbiome might be predictive of asthma risk, but adequate evidence has yet to be gathered to provide definite answers. "There's a lot we need to find out," said Johnson.

Infant Microbiome

The risk for wheeze is also decreased in children exposed to microbes through vaginal delivery and exclusive breast-feeding, according to results from another study presented at the meeting.

The first major exposure to microbes occurs when babies pass through the birth canal and acquire maternal bacteria. That could be important, said Christian Rosas-Salazar, MD, from Monroe Carell Jr. Children's Hospital at Vanderbilt in Nashville, Tennessee.

He and his colleagues looked at a population-based birth cohort of 1456 children and determined that breast-feeding (particularly exclusive breast-feeding) was associated with a decreased risk for recurrent wheeze later in life, especially in children delivered vaginally.

"The mechanisms through which vaginal delivery decrease the risk of recurrent wheeze are still unknown," Rosas-Salazar told Medscape Medical News, but the study shows that these children have "an establishment of healthy upper airway and gut microbiomes."

The researchers assessed 416 nasal filters taken shortly after birth and 116 stool samples using 16S ribosomal RNA sequencing to characterize respiratory and gut microbiomes. Then, when the children were 3 years of age, they looked at parent-reported recurrent wheeze, defined as at least three episodes in the previous year.

The researchers will be going back to look at asthma in this cohort soon, as participants turn 5 and 6 years, Rosas-Salazar reported.

Investigators identified recurrent wheeze in 132 of the children (9%) on multivariable logistic regression adjusted for infant's age, sex, maternal asthma, early-life exposure to antibiotics, and secondhand smoking.

The risk for recurrent wheeze decreased by about 40% in children who had been delivered vaginally and were breast-fed (adjusted odds ratio [aOR], 0.63; 95% confidence interval [CI], 0.41 - 0.98; P = .04). However, in children delivered by cesarean section, breast-feeding did not affect the risk for recurrent wheeze (aOR, 1.51; 95% CI, 0.76 - 2.98; P = .2).

This study — which took into account the duration and exclusivity of breast-feeding and examined potential underlying mechanisms of its association with wheeze — "addresses the limitations of previous studies and supports a protective effect of breast-feeding on recurrent wheeze," Rosas-Salazar explained.

The upper airway and gut microbiomes in early life might change the way the immune response develops in infants and "protect against the development of certain childhood respiratory diseases," he added.

Breast milk might be responsible for feeding the gut bacteria that babies collect in the birth canal, which could be the reason that the combination of breast-feeding and vaginal delivery has a protective effect, said Johnson.

"Microbes might actually be transferred to the baby through the breast milk to feed those bacteria. It's complex," she explained. "We know that breast milk changes almost every day to match the needs of the baby," but more research is needed to understand the association better.

The research by Johnson's team is funded by the National Institutes of Health and the Agency for Healthcare Policy and Research. The research by Rosas-Salazar's team was supported by the National Institute of Allergy and Infectious Diseases, the Vanderbilt Institute for Clinical and Translational Research, the National Center for Advancing Translational Sciences, the K12 mentored research program at Vanderbilt University, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Parker B. Francis Fellowship Program. Johnson and Rosas-Salazar authors have disclosed no relevant financial relationships.

American Thoracic Society (ATS) 2019 International Conference. Johnson study presented May 21, 2019; Rosas-Salazar study presented May 22, 2019.

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