The rumen and its microbiome play essential roles in supplying key nutrients, such as energy, protein, minerals and vitamins, to the host and also shapes the cow’s immune system. Rumen health disorders, such as subacute ruminal acidosis, cause ruminal dysbiosis provoking epithelial barrier dysfunction and inflammation. These conditions facilitate rumen- and hindgut-derived lipopolysaccharides (LPS) to translocate into the blood stream, thereby compromising systemic metabolism and immune response. This chapter summarizes new research related to rumen health, LPS exposure, and their role in modulating the systemic metabolome and liver health. The chapter reviews the effects of prolonged rumen acidosis episodes on udder health due to the long-term exposure of LPS, highlighting the systemic role of LPS in impairing the blood-milk barrier and invading mammary gland tissue.