Microbiota, epigenetics, and trained immunity. Convergent
drivers and mediators of the asthma trajectory from pregnancy to
childhood

The prevalence of allergy and asthma has increased significantly over the past several decades, especially in industrialized nations where environmental exposures and lifestyles have rapidly diverged from those with which humans evolved. Developing effective interventions for precision treatment and prevention of allergy and asthma requires a deeper understanding of their origins and underlying mechanisms. This Perspective proposes a trans-generational framework for future studies that integrates microbiome, immunology, genetics and epigenetics research in human populations and model systems. We suggest that environmental exposures during pregnancy shape maternal microbiomes and immune function, which in turn influence fetal immune and microbiome development in the context of the child's genetic makeup. Relying on epigenetic mechanisms, these interacting influences train the neonate's innate immune system and regulate its ability to respond to the stimuli provided by microbes vertically transmitted from the mother that initially colonize neonatal body habitats. Depending on their composition and functional properties, these pioneer microbes shape immune function which controls the rate and types of exogenous microbes accumulated into these body habitats during the first year of life, thereby determining trajectories of microbiota development, innate and adaptive immune development, and ultimately asthma risk. One critical implication of the framework we propose is that hitherto independent research tracks should converge to determine how very early life microbes in the context of extrinsic and intrinsic factors direct the accumulation of environmental microbes in early life, and how the composition and metabolic capacity of the child's microbiome at various body habitats, shaped by these interacting influences, controls immune development and asthma risk.