Role of early-life gut microbiota maturation in the development of childhood allergy and obesity

Abstract

The human gut microbiome is an enormously complex community that is shaped by various exposures and interacts dynamically with the host, especially in early life. The assembly of gut microbiota in infancy has been characterized in studies with limited sample sizes, but its temporal ecological changes in the first year of life are yet to be explored. In line with the concept of “the developmental origins of health and disease”, there is increasing interest in improving our understanding on the role of gut microbiome maturation during infancy in the development of childhood allergies and obesity, two noncommunicable diseases that are global health concerns. Besides, the development of gut virome in early life and its role in these two diseases are understudied. To fill these research gaps, my thesis characterized gut microbiome (both gut bacteriome and virome) maturation, its influencing factors and its relationship with allergy and obesity outcomes, in large-scale cohorts. Using longitudinal data of the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort, we revealed different developmental trajectories of the gut microbiota in infancy. These trajectories were mainly shaped by birth mode, genetics and other early-life factors. They were discriminated by the relative abundance of Bacteroides and unclassified Enterobacteriaceae, as well as the capacity of sphingolipid synthesis and metabolism (Chapter 2). Most children belonged to three out of four identified trajectories. Compared to a trajectory in harmony with the natural shift in ecology and a trajectory with early-established Bacteroides, a trajectory characterized by persistently low levels of Bacteroides was associated to a higher risk of food sensitization at the age three years, with a greater risk for infants born to Asian mothers (Chapter 3). Furthermore, this trajectory with persistently low Bacteroides significantly mediates the ethnicity associations with food sensitization (Chapter 3). In an independent cohort, the DIABIMMUNE Microbiome Project, the natural ecological trajectories of both the bacteriome and virome were also consistently shown to be protective against food sensitization (Chapter 5). In another subset of the CHILD cohort, we reported that the increased abundance of Firmicutes members mediates the effect of maternal prenatal smoking on childhood obesity. An early maturation in gut microbiota characterized by increased diversity of Firmicutes and abundance of its members may play an obesogenic role via enhanced butyrate production (Chapter 4). In agreement with this finding, children at-risk of being overweight at age three years in the DIABIMMUNE cohort had an early gut microbiome maturation in infancy, also characterized by greater Firmicutes diversity and higher abundance of Firmicutes members and capacity for butyrate production (Chapter 5). These consistent observations across different population cohorts strongly suggest a potentially obesogenic role of excessive butyrate production in infancy. These series of findings outlined above iteratively emphasize the importance of having a natural gut microbiome development in early life, in terms of both timely ecological changes and confinement of disease-driving components. With mechanisms being clarified, these findings would also support the future development of microbiota-based disease predictions and preventive or therapeutic intervention strategies for childhood food allergies and obesity.