<p>Adverse Childhood Experiences (ACEs) are strongly associated with an increased risk of major chronic diseases in adulthood. Early exposure to adversity imposes a toxic stress load that disrupts stress physiology, immune responses, brain development, and behavior. These alterations accumulate across the lifespan, contributing to elevated risks of chronic disease, mental illness, and premature mortality. Although many studies have examined associations between ACEs and biological markers using diverse methods, the evidence remains fragmented, and potential pathways to later outcomes are not well integrated. This gap limits our ability to delineate shared risk processes and to design coordinated preventive and therapeutic interventions. This narrative review paper focuses on a potential stress mechanism and biomarkers associated with ACEs, particularly those associated with the HPA axis, gene methylation, and the gut microbiome, which has emerged as a cross-cutting biomarker across multiple disease domains. A core innovation of this review is the proposed integrated cross-system model of development and interactions among the hypothalamic-pituitary axis, epigenetic alterations, and the gut microbiome.</p>