The gastrointestinal mucosa serves as the interface between the luminal contents, including nutrients and injurious substances, and submucosal structures. Secreted gastric acid is one of the principal injurious components of the luminal contents. To be protected against harm from this acid, the epithelium has an "early warning" system that can activate potent defense mechanisms. We studied the mechanisms that defend the epithelium against luminal acid-induced injury, including the regulation of epithelial intracellular pH (pHi), blood flow, and mucus gel secretion in the perfused rat duodenum, and the pathways involved in the activation and regulation of these mechanisms. Physiological concentrations of luminal acid acidified the epithelial cells and increased blood flow (hyperemic response) and mucus gel thickness. The hyperemic response to acid was abolished by inhibitors of the Na+/H+ exchange, vanilloid receptors (VR), calcitonin gene-related peptide (CGRP) receptors, and nitric oxide (NO) synthase, and also by sensory afferent denervation, but not by pretreatment with a nonselective cyclooxygenase (COX) inhibitor. Mucus secretion in response to luminal acid was delayed by an interruption to the capsaicin pathway, which includes VR, capsaicin-sensitive afferent nerves, CGRP, and NO, and was abolished by COX inhibition. These observations support the hypothesis that the capsaicin pathway is an acid-sensing pathway that promotes hyperemia and mucus secretion in response to luminal acid. The COX pathway is a secondary regulatory system for mucus secretion. A similar acid-sensing capsaicin pathway is also present in the colon, suggesting that the gastrointestinal mucosa "tastes" luminal acidity through epithelial-VR communication.