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Longitudinal Child Study Uncovers Early Gut Microbes With Apparent Asthma Protective Effect

NEW YORK (GenomeWeb) – The relative levels of bacteria from four genera in the gut microbiome may provide clues to infants' risk of developing asthma, new research published online today in Science Translational Medicine suggests.

Researchers from the University of British Columbia and elsewhere used 16S ribosomal RNA gene sequencing to profile gut microbial communities in 319 children enrolled through the Canadian Healthy Infant Longitudinal Development (CHILD) study.

In the almost two-dozen children who appeared to be at elevated asthma risk by their first birthday, the team saw significantly lower levels of Lachnospira, Veillonella, Faecalibacterium, and Rothia bacteria and other signs of dysbiosis during the first few months of life.

The results seem to fit with the so-called hygiene hypothesis, which suggests excessively clean environments can deprive infants of exposure to microbes involved in early immune system development, co-corresponding author Brett Finlay, a microbiology, immunology, biochemistry, and molecular biology researcher at UBC, told GenomeWeb.

Asthma rates have been ratcheting up over the past six or more decades, particularly in westernized countries, he and his colleagues explained. They noted that the chronic inflammatory disease now affects more than 300 million people globally.

"Asthma is really on the rise throughout the world in developed countries," Finlay noted during a telephone press briefing yesterday.

"Ironically, it has not increased in poorer countries or developing countries," he added, noting that past studies point to somewhat higher asthma rates among children born by cesarean section and lower asthma risk in children born vaginally, breastfed children, and children with pets.

To search for potential gut microbiome differences in asthma-prone children, he and his colleagues used Illumina HiSeq 2000 and MiSeq instruments to do 16S sequencing on fecal samples collected from 319 infants from the CHILD study after 100 days of life.

By the time infants reached their first birthday, 136 of those children had developed clinical wheeze, 87 tested positive for allergen skin prick test, and 22 children showed both wheeze and a positive allergen skin prick test — features believed to coincide with high risk of asthma later on. The remaining 74 children were classified as unaffected controls.

When the researchers compared gut microbial community members in the 22 infants at highest risk of asthma with those in other infants at the three month mark, they saw significantly lower levels of Lachnospira, Veillonella, Faecalibacterium, and Rothia bacteria.

In the asthma-prone infants, the team found few or no reads from these microbes, together dubbed FLVR, while three-month-old infants at lower asthma risk had relatively robust levels of the FLVT bugs in their guts.

In urine samples collected from the three month old infants, meanwhile, the team's metabolomics tests pointed to lower-than-usual levels of a short-chained fatty acid called fecal acetate in the 22 at-risk infants, coupled with unusual patterns for some liver-related metabolites and higher levels of some bacterial metabolites.

By the time children were a year old, the team saw less pronounced differences in Faecalibacterium bacteria levels between children predicted to be at higher or lower asthma risk.

Similarly, gene content differences turned up when the researchers bioinformatically inferred metagenomic patterns from 16S RNA reads generated for the three-month-old infants, but diminished in the samples taken from one-year-old children.

It remains to be seen how the lower-risk infants acquire FLVR and other potentially beneficial microbes during their first few months of life. But follow-up experiments suggested offspring of germ-free mice inoculated with FLVR are also protected against lung inflammation.

The researchers are continuing to follow members of the CHILD cohort, a group that includes more than 3,000 children and their families. So far, children born to pregnant women recruited since 2007 have been tested at three months, one year, three years, and five years.

Clinical data collected when the children were three years old indicated that eight of the 22 at-risk children have already developed asthma, though the team suspects that number may rise with time.

Generally speaking, past work suggests some 77 percent of children with wheezing and positive allergen skin prick tests will develop asthma by the time they reach school, compared with 3 percent of children who test negative on a predictive index for asthma.

To further validate the FLVR findings, the researchers plan to test fecal samples from hundreds more Canadian children from the CHILD study, including all of those who appear to be at high risk of asthma as well as children who developed asthma despite being classified at lower risk.

The team also plans to scrutinize gut microbiome patterns in fecal samples from 93 three-month olds from Ecuador who are part of a longitudinal child cohort being clinically assessed over time to get a look at microbiome patterns in those at higher or lower risk of asthma in other populations.

If the findings hold, Finlay noted that it may eventually be possible to develop a gut microbiome-based test for asthma risk in infants and/or to come up with probiotics that contain microbes from the protective bacterial genera.

Still, the study's authors cautioned that the latter application may take time and will require additional work to investigate the role of each FLVR representative.

The University of British Columbia has applied for a patent related to findings from the study.