Emerging evidence indicates that paternal environmental factors can influence offspring
development through epigenetic and metabolic mechanisms operating in the germline. Recent
studies have demonstrated that paternal gut microbiota dysbiosis alters sperm molecular
composition and leads to placental dysfunction and impaired offspring growth. However, the
mechanistic mediators linking paternal microbiome alterations to developmental outcomes
remain poorly understood. In this study, we propose and investigate a mechanistic framework describing a paternal gut–germline–placenta axis in which microbiome-driven metabolic changes alter leptin signaling, reshape testicular metabolite profiles, and remodel sperm small RNA cargo. Using integrative analysis combining microbiome profiling, metabolomics, sperm RNA sequencing, and placental transcriptomics, we identify candidate causal pathways responsible for intergenerational transmission of paternal physiological states. Our findings suggest that sperm-borne regulatory RNAs and metabolite-mediated signaling pathways collectively influence placental development and fetal growth trajectories. This work provides mechanistic insights into paternal epigenetic inheritance and highlights potential targets for preventing adverse developmental outcomes associated with paternal metabolic dysfunction.
