A pediatric study at the University of Alberta shows how birth events influence infant gut microbes, potentially leading to childhood obesity and allergies.
Anita Kozyrskyj, a department of pediatrics researcher, follows not only the stories of gut microbes, but also the stories of mothers and children. According to her research, the story, or “pathway,” to obesity and allergic sensitization can begin with either prolonged labour or a cesarean section, both of which change infant gut microbes.
After a cesarean section, certain microbes like Bacteroidetes that an infant would normally acquire from the mother during vaginal delivery are depleted. But according to Kozyrskyj, the Bacteroidetes do not act alone. There are “critical periods” in a child’s postnatal development where Bacteroidetes and another type of microbe, Enterobacteriaceae, act together in what Kozyrskyj calls, “the E/B ratio.”
If the ratio between Enterobacteriaceae and Bacteroidetes is higher at three months of age, a child is at an increased risk of being overweight, whereas if it is higher at twelve months, a child is at an increased risk of developing allergies.
“Normally, infants have higher amounts of the Enterobacteriaceae,” Kozyrskyj said. “[Enterobacteriaceae are] friendly, they’re not pathogenic.”
Kozyrskyj further explained as children grow, it’s natural for Enterobacteriaceae levels to decline while Bacteroidetes levels increase, thus creating a healthy, but lower, E/B ratio not found in children who later develop obesity and allergies.
Alternatively, the pathway to potential obesity and allergies may start with prolonged labour. This involves another group of microbes, separate from the E/B ratio, called Bifidobacteria. Specifically, prolonged labour depletes Bifidobacteria, which makes formate, a short-chain fatty acid that can lead to both overweight and allergic sensitization.
“This is a new finding,” Kozyrskyj said. “Not many have tested… if you delay labour, whether this affects microbes, and we found that yes, it does.”
“[Formate is] not commonly reported on.. I think it’s because researchers haven’t detected it, but we did. It’s present in very low concentrations.”
Sometimes, more than one microbe can affect a metabolite. For example, Kozyrskyj’s study also showed that children colonized with C. difficile showed an increased risk of allergic sensitization.
“C. difficile in infants is not the same as C. difficile in adults,” Kozyrskyj emphasized. “If you have C. difficile as an adult, then you’re quite ill. You have diarrhea, sometimes it’s severe that you’re hospitalized, but with babies, … they don’t have symptoms. However, in the long term, people have reported that there is an increased risk for allergies and that’s exactly what we found.”
This result occurs because C. difficile lowers Bifidobacteria levels by competing with it.
“You have microbes that are competing for nutrients and then they compete with their ability to produce metabolites,” Kozyrskyj explained. “If you have more Bifidobacteria, you have more formate, and if you have more C. difficile, you have lower Bifidobacteria, and that lowers your formate.”
While there are numerous past studies that have explored some of the individual associations discussed in Kozyrskyj’s report, she claims none of them have studied these associations so comprehensively.
“We studied the whole path,” Kozyrskyj said. “From the start of birth, at three to four months in terms of gut microbes, and then what happened to the infants in terms of their health. I would say that our study, for the first time, shows the extent to which all of these microbes interact with each other.”
“[Our study] shows that multiple bacteria interact at one single metabolite, [formate,] but they also produce their own metabolites,” Kozyrskyj explained. “We were able to show intersecting pathways — along with non-intersecting pathways — from cesarean section to [these] health outcomes and we said in our paper that there were over a hundred different pathways you could [take to] get from cesarean section to certain gut microbes and then [to] the metabolites they produce and then [to] allergies or overweight.”
This study created a massive data set, studying hundreds of microbes and 20 metabolites at two different time points of life. Khanh Vu, one of Kozyrskyj’s postdoctoral researchers and the first author of this study had to do intensive computing to analyze it all.
“[It] all needs to be teased out in terms of association,” Kozyrskyj said. “These associations were concurrent, so [one] association happened at the same time as [another] association. It took a long time to sequence the samples and compare them to databases before you would end up with an excel spreadsheet with the names of all the microbes. That’s pretty exciting, you know, after billions and billions of records of [DNA] sequences.”
But, they didn’t stop there. After all the biological data were collected, the team factored in other specialty areas of Kozyrskyj’s previous research: breastfeeding and infant antibiotic use.
At three months, breastfeeding was shown to reduce C. difficile, thereby increasing the Bifidobacteria. Since antibiotic exposure occurs in 40 per cent of infants through their mothers, Kozyrskyj believes their role is already factored in when studying cesarean section and labour.
Kozyrskyj maintains that cesarean section delivery and prolonged labour, along with the E/B ratio, had the “strongest influence.”
Completing the study on infant gut microbes has left Kozyrskyj enthused about the various ways microbes affect human development.
“There’s just so many interactions, competition for nutrients, productions of different metabolites. The goal of the analysis was really to show how complex our microbiome is.”