DNA Methylation in Bovine Mastitis: Regulatory Mechanisms, Shared Networks, and Translational Prospects

Bovine mastitis is a multifactorial inflammatory disease shaped by interactions among host genetics, physiological state, environmental exposure, management, and pathogen characteristics. DNA methylation is an important regulatory mechanism linking these factors with changes in mammary immunity, metabolism, and secretory function. This review synthesizes evidence from methylome and integrated methylome–transcriptome studies in blood cells, mammary tissue, and milk somatic cells. Mastitis associated with Staphylococcus aureus, Escherichia coli, Streptococcus uberis, Staphylococcus chromogenes, Streptococcus agalactiae , and Prototheca spp. shows distinct but overlapping methylation changes affecting cytokine signaling, leukocyte recruitment, antigen processing, epithelial integrity, and mammary metabolism. Recurrent methylation–expression relationships across studies suggest shared regulatory features despite pathogen- and tissue-specific responses. The review further examines the influence of nutrition, heat stress, and physiological state, while addressing key interpretative challenges, including analytical thresholds, platform heterogeneity, genomic context, cellular composition, and limited longitudinal validation. Emerging applications include methylation-based biomarkers, integrated disease-monitoring panels, epigenetically informed breeding, targeted epigenome editing, and trained-immunity-based interventions. Translation will require harmonized analytical approaches, independent multiherd validation, and functional confirmation of candidate loci across populations and disease contexts. Overall, DNA methylation provides a mechanistic framework for understanding mastitis as a dynamic host–pathogen–environment interaction and for developing biologically informed strategies for disease management.