Baby Microbiomes

Antibiotics cut stability and diversity of gut microbes in the first three years of life

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A comprehensive analysis of changes in the intestinal microbial population during the first three years of life has revealed the impact of factors such as mode of birth—vaginal versus cesarean section—and antibiotic exposure, including the effects of multiple antibiotic treatments.

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In the June 15 issue of Science Translational Medicine, a team led by investigators from Massachusetts General Hospital, the Broad Institute of Harvard and MIT, and Harvard Medical School describes findings that may help explain how the gut microbiome is established and how the combination of microbes in individual children may contribute to the risk of these children developing conditions such as Type 1 diabetes and inflammatory bowel disease.

“One of the key motivations of microbiome research is that the microbial population of early childhood appears to be critical to human health.”—Ramnik Xavier

“One of the key motivations of microbiome research is that the microbial population of early childhood appears to be critical to human health, in that decreased diversity of the gut microbiome has been implicated in a number of allergic and autoimmune diseases,” said Ramnik Xavier, the Kurt J. Isselbacher Professor of Medicine in the Field of Gastroenterology at Harvard Medical School, chief of the Mass General Division of Gastroenterology and an institute member at the Broad.

“Not only did our study analyze the gut microbiome at a high resolution that allowed us to identify both microbial species and strains, but by following our study participants over time, we also were able to uncover findings that would not have been revealed by single samples from each patient,” said Xavier, who is a co-senior author of the paper.

In collaboration with Finnish researchers, the team enrolled 39 children from whom monthly stool samples were taken from birth until 36 months of age. Each sample was analyzed with a standard RNA-based sequencing procedure that is used to identify microbial populations.

More-detailed whole-genome sequencing was conducted on about 25 percent of the samples, which revealed the specific strains of identified microbial species. During the study period, 20 of the children received antibiotics to treat respiratory or ear infections, totaling 9 to 15 treatments.

Some clear differences

Many features of the developing gut microbiome were found to be consistent across all study participants, with the presence and abundance of particular species rising and falling at similar age points. The researchers also found several clear differences from previous research regarding the impact of breast-feeding.

Earlier studies comparing breast-fed with formula-fed children reported increased abundance of Bifidobacterium species in those who were breast-fed for longer periods of time. All of the children in the current study were breast-fed for some period of time, and while there was some correlation between the length of breast-feeding and levels of Bifidobacteria, some of the children in this group had low levels of those bacteria even while being breast-fed.

Previous studies also have reported finding a particular microbiome signature, with low abundance of the Bacteroides genus in cesarean-section-delivered children during the first six months of life. In the current study, the researchers found the same pattern in the four cesarean-delivered children but were surprised to find it also occurred in seven of the vaginally born children.

No identified factors, including maternal antibiotic treatment, differentiated between vaginally born children with or without the low-Bacteroides signature. Because this pattern has been associated with reduced overall diversity of the microbiome, Xavier noted, it warrants further investigation.

Impact of antibiotic treatment

Children who had been exposed to antibiotic treatment had reduced diversity in their microbial population, a difference that was even greater in those who also had the low-Bacteroides signature. Whole-gene sequencing also found that bacterial species tended to be fewer and dominated by a single strain in antibiotic-exposed children, instead of the several species and strains seen in those not treated with antibiotics.

The analysis of many samples taken over time revealed that the microbiomes of antibiotic-exposed children were less stable, particularly around the time of antibiotic treatment.

The presence of genes known to confer antibiotic resistance rose rapidly during antibiotic treatment. Levels of antibiotic resistance genes encoded on microbial chromosomes dropped quickly after treatment was discontinued. But antibiotic resistance genes encoded on small DNA molecules called mobile elements—one means by which resistance genes can be transmitted among bacteria—persisted much longer after antibiotic withdrawal.

Next steps

“Some of the things we’d like to investigate next are how the microbiome gets established during the first week of life—particularly what the primary mechanisms of transmission are —how the composition of the early-life gut microbiome affects children’s health and what factors underlie the resilience of the infant microbiome,” said Xavier.

“The kind of high-resolution sequencing done in this study should lead to better understanding of the natural history of the infant gut microbiome and the impact of perturbations caused by antibiotics and environmental factors,” Xavier said.

Support for the study includes the National Institutes of Health (grants U54 DK102557, R01 DK092405, P30 DK043351 and 2U54 HG003067-10), the Klarman Family Foundation, the JDRF (formerly the Juvenile Diabetes Research Foundation), the Leona M. and Harry B. Helmsley Charitable Trust, and the Crohn’s and Colitis Foundation of America.

Adapted from a Mass General news release.