Gut Bacteria Disparities Offer Clues to Asthma Etiology

Tara Haelle

September 30, 2015

Young infants may be more likely to develop allergic asthma if they lack four beneficial bacteria in their gut, according to a study published in the September 30 issue of Science Translational Medicine.

Children with lower levels of Lachnospira, Veillonella, Faecalibacterium, and Rothia bacteria in their gut in their first 3 months were at higher risk for asthma and tended to receive more antibiotics than healthier children before they turned 1 year old, report Marie-Claire Arrieta, PhD, from the University of British Columbia in Vancouver, Canada, and colleagues. In a follow-up experiment in the study, adult germ-free mice who received an infusion of these four bacteria had offspring with less airway inflammation and less asthma.

The authors note that asthma risk has previously been linked with various environmental factors, such as antibiotic exposures, cesarean birth, formula feeding, and not living on a farm.

"The microflora hypothesis suggests the intestinal microbiota as the link between these environmental changes and our immune system, and many recent studies have identified the intestinal microbiota as a potential therapeutic target in the prevention of asthma and atopic disease," write Dr Arrieta and coauthors.

"Our findings indicate that in humans, the first 100 days of life represent an early-life critical window in which gut microbial dysbiosis is linked to the risk of asthma and allergic disease," Dr Arrieta and colleagues write. "Further, our data also show that these gut microbial changes are much less apparent by 1 year of age, suggesting that therapeutic interventions to address microbial dysbiosis would need to occur very early in life." They add that "the fact that [Lachnospira, Veillonella, Faecalibacterium, and Rothia] supplementation was protective and induced a marked reduction in lung inflammation in mice emphasizes that these taxa are immunomodulatory and involved in asthma."

Dr Arrieta's team tracked 319 children enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study until age 3 years. The researchers divided the children into four different groups based on assessment at age 1 year: those who tested positive for an allergen skin prick test (atopy; n = 87), those who had a wheeze (n = 136), those who had a wheeze and atopy (n = 22), and control participants (n = 74). The children also underwent assessment with the Asthma Predictive Index (API) at age 3 years. Prior studies show that a positive API at age 3 years confers a 77% risk of asthma by ages 6 to 13 years, whereas a negative API at age 3 years confers only a 3% risk.

Compared with control children, the 22 children with wheeze and a positive allergen test were 13.5 times more likely to have a positive API at age 3 years (95% confidence interval [CI], 3.2 - 57.4; P = .0003) and 21.5 times more likely to have diagnosed asthma by age 3 years (95% CI, 2.4 - 196.0; P = .002). The risk for a positive API in children with atopy and wheeze was 5.6 times greater than in the children with atopy alone (95% CI, 1.8 - 17.5; P = .0037) and 4.9 times greater than the wheeze-only children (95% CI, 1.8 - 14; P = .0036).

Similarly, risk for an asthma diagnosis was 5.4 times greater in the wheeze-with-atopy group than among the wheeze-only children (95% CI, 1.5 - 19.0; P = .0137), and 3.9 times greater than among atopy-only children (95% CI, 1.09 - 14.5; P = .0429).

In addition, early-life exposure to antibiotics increased the odds 5.6 times that a child would end up one of those with atopy and wheeze compared with control children (P = .009). No significant links existed between the group with atopy and wheeze and having a cesarean birth or exclusive formula feeding.

Gut Microbiome Differ Among Groups

When the researchers turned their attention to microbiome data from stool samples collected at 3 months, they found that the 22 children with atopy and wheeze had less abundant Lachnospira, Veillonella, Faecalibacterium, and Rothia bacteria compared with children in the other groups. However, stool samples collected at 1 year showed no significant microbiome differences across the groups.

In contrast, the authors saw no significant differences in bacteria between the groups with atopy or with wheezing and other groups.

The researchers did find that children with atopy and wheeze had a significantly lower concentration of acetate in 3-month fecal samples, and previous research has indicated acetate as a protective factor against airway inflammation in animals with asthma.

To test causation, the researchers injected into four adult germ-free mice a fecal sample from one of the children with atopy and wheeze who also had a particularly lower population of the four bacteria at 3 months and who had a positive API and asthma diagnosis at age 3 years. The mice received either an unmodified sample of this feces or a fecal sample supplemented with live Lachnospira, Veillonella, Faecalibacterium, and Rothia bacteria. Offspring of the mice injected with the supplemented sample showed a greater abundance of the four bacteria than the other mice's offspring. Further, the offspring born to the mice without the supplemented bacteria had a severe lung inflammatory response when exposed to ovalbumin to induce asthma.

These findings illustrate "the importance of the early, maternally transmitted microbiome in health," write Maria Gloria Dominguez-Bello, PhD, and Martin J. Blaser, MD, from the New York University Langone Medical Center in New York City, in an accompanying editorial. They point out that a coevolution of microbiota and their hosts continues through the birthing process, when a baby is exposed to a mother's microbiome via vaginal birth, breast-milk, and mouth contact with the mother's skin.

"It is becoming clear that early life is indeed the crucible for healthy development and that the vertically transmitted and now progressively disappearing microbiota have been of critical importance for optimizing later health," they write.

Many questions remain unanswered, however. For example, it is unclear how long the protective effect of giving bacteria to mice will last, said Dr Arrieta during a press conference. This study also focused specifically on allergic asthma, not other phenotypes, added coauthor and pediatrician Stuart E. Turvey, MBBS, DPhil, from British Columbia Children's Hospital in Vancouver.

The clinical implications of these findings for providers points potentially to earlier treatment of at-risk children who develop asthma, said senior author Brett Finlay, PhD, from the University of British Columbia, during the press conference.

"We see sort of two applications. The first would be identifying children at high-risk of asthma by analyzing their stool microbial composition in that first 100-day window," Dr Finlay said. "Our longer-term vision would be that potentially children in early life could be supplemented with [Lachnospira, Veillonella, Faecalibacterium, and Rothia] or some look to prevent the ultimate development of asthma," although he emphasized that possibility is far off presently.

Another implication includes continued awareness of the importance of antibiotic stewardship, Dr Turvey added. "This study starts to emphasize that we need to revisit our relationship with bacteria," he said. "This study and others like it emphasize that we've evolved with bacteria and they are really important for our health."

The research was funded by the Canadian Institutes of Health Research. CHILD funding came from the Allergy, Genes and Environment Network of the Centres of Excellence, Health Canada, Environment Canada, Canada Mortgage and Housing Corporation, and the Childhood Asthma Foundation. Dr Arrieta, Dr Turvey, Dr Finlay, and two other authors filed a provisional patent on the composition of the four bacteria and a method for detecting and preventing asthma. The other authors have disclosed no relevant financial relationships.

Sci Transl Med. 2015;7:307FS39. Abstract


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