Bovine mastitis is generally viewed as a localized intramammary infection, but the extent to which microbial, metabolic, and mammary tissue alterations covary with disease severity remains unclear. We tested whether healthy control (HC), subclinical mastitis (SCM), and clinical mastitis (CM) cows exhibit coordinated changes across the rumen, hindgut, circulation, milk, and mammary gland, and whether 5-androstene-3β,17β-diol (5-AED) is an integrative marker of this response.