An intact intestinal epithelium allows efficient transepithelial transport across cells (transcellular transport) and between cells (paracellular transport) via (1) channels directly embedded in the membrane such as SGLT (sodium-dependent glucose transporter), ion channels, and aquaporins and (2) control of gap junctions, adherens junctions, desmosomes, and tight junctions between epithelial cells. EHS risk factors including hyperthermia, exercise, dehydration, sleep deprivation, drugs, and diet are known to increase intestinal permeability via multiple independent mechanisms. When intestinal barrier integrity is compromised, increased permeability results in bacterial or endotoxin translocation into circulation. Bacterial components may stimulate an immune response that results in signaling that promotes positive feedback of inflammation and inflammation-associated symptoms such as fever. Simultaneously, stress or tissue injury also may signal to enhance proinflammatory immune responses via gut-independent signals such as DAMPs (danger-associated molecular patterns) including heat shock protein 60, which are increased during cell/tissue stress. SNS, sympathetic nervous system; AVP, arginine vasopressin; HPA, hypothalamic-pituitary-adrenal.