Gut microbiota induces mammary gland sIgA production to alleviate S. aureus mastitis

Mastitis threatens dairy cow health and public safety. While gut dysbiosis increases mastitis susceptibility, the mechanism is unclear. We hypothesized that gut dysbiosis exacerbates Staphylococcus aureus (S. aureus)-induced mastitis by reducing milk secretory immunoglobulin A (sIgA). In mice, vancomycin-induced gut dysbiosis reduced sIgA and IgA⁺ B cells in milk, gut, and Peyer's patches, impairing the blood-milk barrier and worsening mastitis, effects reversed by fecal microbiota transplantation. Dysbiosis specifically reduced intestinal M. intestinale abundance and GABA levels. Supplementing with M. intestinale or GABA restored sIgA, increased IgA⁺ B cells, and alleviated mastitis. We identified an NADP-specific glutamate dehydrogenase (GDH) in M. intestinale; a GDH-expressing E. coli-produced glutamate, elevating gut GABA, enhancing sIgA, and mitigating mastitis. Mechanistically, GABA activated the mTOR pathway to drive macrophage M2 polarization and B cell differentiation. Thus, M. intestinale-derived GABA boosts sIgA to protect against mastitis, offering novel prevention strategies.