Dairy cows are frequently immune challenged, and obvious infections include metritis and mastitis. An often-unrecognized source is compromised gastrointestinal tract (GIT) integrity; a consequence of stressors including dietary changes, hind-gut acidosis, systemic inflammation, heat stress, psychological stress, and feed restriction. Immunoactivation begins when immune cells recognize invading pathogens, eliciting inflammatory cytokine response(s) culminating in an acute phase response characterized by fever, leukocytosis, and hepatic acute phase protein synthesis. Paradoxically, endotoxemia (a catabolic condition) either causes insulin (a potent anabolic hormone) secretion or markedly enhances glucose stimulated insulin secretion. We recently demonstrated an in vivo lipopolysaccharide (LPS)-activated immune system consumes >1 kg of glucose within 12 h; a finding consistent with activated immune cells requiring glucose primarily for fuel and as a biosynthetic precursor. Despite increased glucose requirements, anorexia accompanies immunoactivation, which decreases diet-derived glucose precursors. Inflammation decreases milk synthesis and this presumably represents a strategy to spare glucose for the immune system. To further ensure an adequate fuel supply for the immune system, hepatic glucose output increases via both glycogenolysis and gluconeogenesis. Simultaneously, peripheral insulin resistance develops leading to decreased glucose uptake by skeletal muscle and adipose tissue. These metabolic adaptations are indicative of altered homeorhetic partitioning toward a new dominant physiological state of immunoactivation. GIT-derived endotoxin is also likely a key contributor to infertility as LPS and/or LPS-induced hyperinsulinemia markedly disrupts follicular, ovarian and uterine physiology. Additionally, gut-derived LPS also negatively affects the mammary epithelial barrier and causes hypocalcemia. Thus, leaky gut may be a common denominator that explains why transition cow disorders are strongly correlated with each other. It is becoming increasingly clear that GIT barrier dysfunction negatively affects many economically important dairy phenotypes.