Can modifying the early microbiome reduce food sensitization after Cesarean birth?

Q. Could you give a brief overview of the link between the early life microbiome and allergy development?

The early-life microbiome is of interest because the microbes we are exposed to early in life are thought to play an important role in immune development. In turn, exposure to microbes modulates the risks of developing allergic diseases and we know this from different studies. In animal models, we know that when animals are not exposed to sufficient microbial stimuli early in life, their levels of immunoglobulin E are very high, and when challenged with an allergen, they exhibit a very strong response.

The other line of research is primarily based on epidemiological studies. For example, children who live in rural environments (e.g., farms) tend to have a lower risk of allergies. Similarly, children who are breastfed tend to have fewer allergies, as breast milk promotes the growth of certain bacteria. These findings suggest a connection between early-life microbial exposure and the risk of allergies.

Q. Could you describe the aims and design of the ACTIVATE study?

Cesarean delivery is known to increase the risk of allergies in predisposed infants, and a family history of allergy is also associated with higher risk. We also know that Cesarean-delivered (CD) infants start life with very different microbes compared to those who are delivered vaginally. Our hypothesis was that the increased risk of allergies in CD infants was a result of insufficient exposure to the right microbes.

ACTIVATE was a double-blind, placebo-controlled, randomized clinical trial. The aim of the study was to determine whether exposing CD infants at risk of developing allergies to certain microbes would help reduce the risk of food sensitization. In the study, we tried reintroducing maternal microbes in CD infants to determine whether that alone was sufficient to lower the risk of allergies.

There were three groups: CD infants exposed to maternal vaginal microbes, a placebo of CD infants not exposed to the vaginal seeding procedure, and we also had a group of infants born vaginally.

Q. What impact did vaginal seeding have on the infant gut microbiome?

A couple of days after birth, stool samples were collected. CD infants exposed to vaginal seeding showed much higher levels of Lactobacillus in their stool compared to the placebo. This finding indicates that the intervention successfully transfers Lactobacillus from the maternal vagina to CD infants, which is not observed in the placebo group.

At three months, when we examined the microbiomes again, we found that CD infants who had been vaginally seeded had microbiomes more similar to those of vaginally delivered infants compared to the placebo group. This suggests that, although the initially introduced microbes may not persist, the overall microbiome reroutes in a direction more similar to that of vaginally delivered infants..

Q. What microbes were associated with food sensitization at 12 months?

We saw several different microbes associated with sensitization. At 1 year of age, the infants were still very young, so the number with confirmed allergies remained relatively small. Instead we were looking at sensitization. We found different microbes depending on the allergen, for example eggs, milk, and peanuts. The microbe associated with sensitization to all three allergens was Ruminococcus gnavus (R. gnavus).

We saw that this association with sensitization was true, even after accounting for a number of potential confounders, including breastfeeding, maternal antibiotic use, and study group (whether the infants were in the seeding group or in the placebo group). We believe this represents a fairly robust association, suggesting that the intervention may prevent the overgrowth of this microbe. Without the intervention, there is an increased abundance of this bacteria, which is associated with sensitization to egg, milk, and peanut.

Q. What do you believe are the main clinical implications of these findings for allergy prevention in infants?

It is still too early to tell; this remains very much a work in progress, and I tried to emphasize that at AAAAI. For example, previous studies have already reported an association between R. gnavus and food allergies. Vaginal seeding is a relatively crude first approximation, and the goal is ultimately to identify the specific microbes that should be administered to infants to lower the probability of potentially pathogenic microbes later in life. There is some optimism that we are identifying microbes associated with sensitization and that we may be able to modulate these. However, this approach is not yet ready for clinical use.