A Hypothesis Linking Early-Life Adversity to Altered Synaptic Connectivity Through Disrupted Gut Microbiome-Microglia Communication.

Childhood adversity is a major risk factor for the development of numerous psychiatric and medical disorders later in life. Individuals exposed to early adversity also tend to experience more severe, treatment-resistant, and highly comorbid conditions, suggesting that childhood adversity represents a distinct pathophysiological entity requiring specialized diagnostic and therapeutic approaches. However, the biological mechanisms underlying these diverse long-term outcomes remain poorly understood. Recent studies have implicated disruptions of the gut-immune-brain axis and persistent low-grade inflammation in mediating the long-term consequences of childhood adversity. Here, we propose a complementary and novel, but still speculative, hypothesis that shifts the focus away from chronic low-grade neuroinflammation and instead emphasizes the direct crosstalk between the gut microbiome and glia-mediated synaptic pruning during critical periods of brain development. Specifically, we hypothesize that alterations in microbiome-derived signals disrupt the normal maturation and function of glial cells, leading to aberrant synaptic pruning, long-lasting changes in neural circuit connectivity, and persistent deficits in cognition and emotional regulation. Although several lines of evidence are consistent with individual components of this model, direct evidence linking these processes into a causal pathway is currently limited. We therefore discuss the experimental findings that provide a rationale for this hypothesis, identify important gaps in the current literature, and propose specific experimental strategies to rigorously test its central predictions. If validated, this framework could transform our understanding of how childhood adversity becomes biologically embedded and provide a foundation for the development of novel diagnostic biomarkers and targeted therapeutic interventions.