The epigenetic-immune-microbiome axis in early life: reprogramming the origins and endotypes of pediatric asthma

Pediatric asthma is a highly heterogeneous inflammatory syndrome characterized by distinct immune endotypes. The inception of asthma predominantly occurs during the first 1,000 days of life, a critical window of immunological plasticity. Within this critical window, the developing immune system is continuously shaped by dynamic interactions between environmental exposures, the microbiome, and host genetics. Recent advances highlight the epigenetic-immune-microbiome axis as the central mechanism orchestrating these interactions. This review provides a comprehensive synthesis of how prenatal maternal imprinting (including maternal immune activation, nutrition, and psychological stress) and postnatal "second hits" (such as respiratory viral infections and gut-lung microbial dysbiosis)trigger the epigenetic reprogramming of airway epithelial cells and innate/adaptive immune cells. We specifically emphasize the paradigm of "trained immunity" in macrophages and dendritic cells, alongside the hyperactivation of group 2 innate lymphoid cells (ILC2s), as fundamental drivers of asthma pathogenesis. In parallel, we outline the epigenetic and metabolic networks (immunometabolism) that govern T-cell polarization (Th1/Th2/Th17/regulatory T cells) and airway mucosal barrier dysfunction. Finally, we evaluate the translational potential of these multi-omics signatures, discussing how non-invasive approaches like nasal epigenomic profiling may eventually aid in stratifying clinical endotypes and inform the development of future mechanism-based therapeutics.