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Human Gut Microbiome Continues to Develop Through Early Childhood

NEW YORK – Researchers in Sweden and Denmark have mapped the developmental of the healthy human gut microbiome throughout the first five years of a child's life.

In a paper published on Wednesday in Cell Host & Microbe, the researchers noted that mode of birth, diet, antibiotic use, and host factors are major contributing factors to the initial seeding and development of the gut microbiome and have been associated with health outcomes later in life, but that it's unclear to what extent these factors contribute to the development of the adult gut. The order by which bacterial species appear in the gut could have long-lasting effects on community structure and gut function, they wrote, but it is still relatively unknown.

For their study, they analyzed the gut microbiomes of 471 Swedish children, 302 born vaginally and 169 through C-section, who were followed from birth to five years of age. The researchers collected fecal samples from the children at birth, after four and 12 months, and at three and five years of age, as well as from 357 mothers at birth, and also compared their microbiota to the general adult Swedish population.

They found that bacterial genera followed four different colonization patterns. Importantly, they said, Methanobrevibacter and Christensenellaceae, which both correlate with increased species diversity in children and adults, colonized late and didn't reach adult levels at five years. This demonstrated that although the gut microbiome largely reaches an adult-like composition by five years of age, several bacterial taxa that have been associated with human health are acquired later in childhood.

"Today, we know very little about how differences in the microbiota early in life may contribute to disease risk later in life," corresponding author Fredrik Bäckhed, a researcher at the University of Gothenburg, said in an email. "Animal experiments have shown that it may be important, but causally link[ing] the altered gut microbiota to disease later in life has not yet been demonstrated. In our study we demonstrate that the microbiome is developed in individual trajectories and that C-section-born children have a different microbiota early on, but it normalizes at three to five years of age."

After performing 16S rRNA gene profiling on their samples, the researchers identified an average 1,434 operational taxonomic units per sample. The alpha diversity — an estimate of the richness of the bacterial community using phylogenetic diversity — increased as the children grew older but was still lower at five years than in adults.

Interestingly, the researchers also found that mode of birth, sex, antibiotic use during the first year of life, or exclusive breastfeeding at four months did not significantly affect the increase in alpha diversity over time.

The researchers also performed a sub-analysis on 213 children from whom they had collected samples from four months to five years of age. This analysis revealed that alpha diversity increased significantly with age.

Further analyses demonstrated that the overall composition of the gut microbiota changed markedly at different ages, resembling a more adult microbiota as the children grew older. However, the children's microbiome composition at five years was still significantly different compared with the mothers and adults, the researchers said.

They also identified four major trajectories for individual genera in the developing gut microbiota: genera with highest relative abundance at four months, those with peak relative abundance at 12 months, genera with relative abundance increasing rapidly between four and 12 months and reaching stable levels by three years, and those increasing in relative abundance after 12 months and continuing to increase between three and five years.

Interestingly, both low community richness and high proportions of Ruminococcus gnavus, which showed up in the second trajectory, have been repeatedly linked to diseases such as metabolic syndrome, obesity, cardiovascular disease, and inflammatory bowel disease, the researchers said. In contrast, increased abundance of Methanobrevibacter and Christensenella, which showed up in the fourth trajectory, has been linked to metabolic health. Similarly, Archaea, as well as Christensenellaceae, Tenericutes, and Desulfovibrio have been negatively associated with BMI and blood triglycerides. These also showed up largely in the fourth trajectory.

"Future, larger studies are required to identify potential developmental windows when the gut microbiota may be particularly sensitive for development of diseases," the authors concluded. "Furthermore, re-analyses and meta-analyses of previously published datasets in combination with ours using amplicon sequence variants might facilitate the identification of important taxa independent of reference databases."