Allergic diseases affect millions of people worldwide. Further, children in our society are increasingly at risk of developing a number of different allergic disorders. An increase in allergic disease prevalence has been attributed to alterations in the gut microbiome, i.e., the microorganisms and their genes within the gastrointestinal tract. While previous studies from our lab and others linked specific bacteria within the infant gut to individual diagnoses, we have now identified a common bacterial signature that may be universal to the development of several major childhood allergies. We looked at four distinct allergic diagnoses (asthma, food allergies, atopic dermatitis—or eczema—and allergic rhinitis—or hay fever). As similar as these disorders are at the cellular level, they each have their own unique symptoms and researchers have tended toward studying them individually. Our project is relatively unique because we decided to look at all four of the diseases together based upon the fact that they can share etiological origins, characterized by aberrant Type-2 inflammatory responses and elevated IgE, in the hope of finding a common link between their development and the early life microbiome.

Within this manuscript, we first showed, using deeply phenotyped participants in the CHILD birth cohort (n=1,115), that there are early-life influences, including antibiotic usage and breastfeeding, uniformly associated with four distinct allergic diagnoses at 5 years: atopic dermatitis (AD, n=367), asthma (As, n=165), food allergy (FA, n=136), and allergic rhinitis (AR, n=187). The CHILD study is a robust example of a longitudinal cohort aimed at characterizing important and targetable early-life factors that influence the onset of disease. Mothers were recruited during pregnancy and the families have subsequently brought in their children for evaluations at four different sites across Canada, in Vancouver, Winnipeg, Edmonton, and Toronto. The children are seen by CHILD teams who do their utmost to accurately record the children’s general health metrics and characteristics, their relevant responses to allergens, and any allergic symptoms that the participants may have developed. A key part of the success of CHILD is the active engagement of the community through frequent communication and interactive opportunities. This allows the participants to feel they are contributing to the progression of the study, as well as to the discoveries made that could improve the lives of children in the future.

Studies such by Arrietta et al. (1), Petersen et al. (2), Stokholm et al. (3), and Depner et al. (4), to name just a few seminal investigations of the maturing gut microbiome in the context of asthma and allergic disease, have revealed a clear link between gut microbiome and immune system development. Maturation of the infant immune system and gut microbiota occur in parallel; thus, the conformation of the microbiome may determine if tolerant immune programming arises within the infant. In our study, within a subset with shotgun metagenomic and metabolomic profiling (n=589), we discovered that impaired 1-year microbiota maturation may be universal to pediatric allergies (AD p = 0.000014; As p = 0.0073; FA p = 0.00083; and AR p = 0.0021). Extending this, we found a core set of functional and metabolic imbalances characterized by compromised mucous integrity, elevated oxidative activity, decreased secondary fermentation, and elevated trace amines, to be a significant mediator between microbiota maturation at age 1 year and allergic diagnoses at age 5 years (β_indirect = -2.281; p = 0.002).

Our paper builds upon previous literature by demonstrating common underlying microbial alterations between asthma and other allergic diseases. These commonalities may allude to similar mechanisms of action, or lack thereof, by an imbalanced microbiome that leads to the induction of immune dysregulation toward environmental or food antigens. Microbiota maturation thus provides a focal point to identify deviations from normative development to predict and prevent allergic disease. In the future, we may be able to use the bacteria and metabolites identified within this study for predictive and preventive therapeutic targets.

Our study has highlighted that distinct allergy diagnoses likely have a common origin, and it relates to the bacteria that colonize us as infants. These bacteria are important for supporting healthy development in childhood, especially for our immune system. This means that studying them not only can tell us when that development needs support, but also how we can help too.  By identifying infants with this signature, we may be able to provide early aid to prevent a broad array of allergies (not just one!) later in life.

References:

1. Arrieta, M. C., Stiemsma, L. T., Dimitriu, P. A., Thorson, L., Russell, S., Yurist-Doutsch, S., Kuzeljevic, B., Gold, M. J., Britton, H. M., Lefebvre, D. L., Subbarao, P., Mandhane, P., Becker, A., McNagny, K. M., Sears, M. R., Kollmann, T., CHILD Study Investigators, Mohn, W. W., Turvey, S. E., & Finlay, B. B. (2015). Early infancy microbial and metabolic alterations affect risk of childhood asthma. Science translational medicine, 7(307), 307ra152. https://doi.org/10.1126/scitranslmed.aab2271.
2. Petersen, C., Dai, D. L. Y., Boutin, R. C. T., Sbihi, H., Sears, M. R., Moraes, T. J., Becker, A. B., Azad, M. B., Mandhane, P. J., Subbarao, P., Turvey, S. E., & Finlay, B. B. (2021). A rich meconium metabolome in human infants is associated with early-life gut microbiota composition and reduced allergic sensitization. Cell reports. Medicine, 2(5), 100260. https://doi.org/10.1016/j.xcrm.2021.100260.
3. Stokholm, J., Blaser, M. J., Thorsen, J., Rasmussen, M. A., Waage, J., Vinding, R. K., Schoos, A. M., Kunøe, A., Fink, N. R., Chawes, B. L., Bønnelykke, K., Brejnrod, A. D., Mortensen, M. S., Al-Soud, W. A., Sørensen, S. J., & Bisgaard, H. (2018). Maturation of the gut microbiome and risk of asthma in childhood. Nature communications, 9(1), 141. https://doi.org/10.1038/s41467-017-02573-2.
4. Depner, M., Taft, D. H., Kirjavainen, P. V., Kalanetra, K. M., Karvonen, A. M., Peschel, S., Schmausser-Hechfellner, E., Roduit, C., Frei, R., Lauener, R., Divaret-Chauveau, A., Dalphin, J. C., Riedler, J., Roponen, M., Kabesch, M., Renz, H., Pekkanen, J., Farquharson, F. M., Louis, P., Mills, D. A., … Ege, M. J. (2020). Maturation of the gut microbiome during the first year of life contributes to the protective farm effect on childhood asthma. Nature medicine, 26(11), 1766–1775. https://doi.org/10.1038/s41591-020-1095-x.