Liver-brain axis-related transcriptomic signatures associated with vulnerability or resilience in adult males exposed to prenatal stress

Early life stress (ELS), particularly prenatal stress (PNS), profoundly impacts mental and metabolic health, contributing to the development of psychiatric and metabolic comorbidities. However, not all individuals exposed to ELS develop these conditions, and the molecular mechanisms underlying vulnerability or resilience remain incompletely understood. The liver-brain axis, a bidirectional system linking peripheral metabolic processes with central nervous system (CNS) function, plays a key role in mediating this comorbidity. In the current study, we used the PNS model to investigate how ELS affects the liver-brain axis by characterizing transcriptomic changes associated with vulnerability or resilience. Differential expression analysis with DESeq2 and weighted gene co-expression network analysis (WGCNA) were conducted to profile gene expression in the ventral hippocampus and liver of adult male rats exposed to PNS. Our findings reveal distinct transcriptomic signatures associated with vulnerability and resilience in both organs in male adult animals. In the ventral hippocampus, vulnerable animals showed disrupted synaptic plasticity, along with dysregulation of energy and lipid homeostasis, whereas resilient animals exhibited activation of immunomodulatory and plasticity-related pathways. In the liver, vulnerable animals presented impaired stress responses, while resilient animals displayed enhanced cholesterol biosynthesis and immune modulation. WGCNA identified co-expression modules with altered preservation in both tissues, highlighting shifts in mitochondrial function, energy metabolism, and cellular processes as key features distinguishing vulnerability from resilience. These findings offer new insights into the molecular pathways linking ELS to mental and metabolic comorbidities, highlighting the liver-brain axis as a potential therapeutic target to mitigate the long-term consequences of ELS.