It is now well established that patients with gastroesophageal reflux disease - both erosive and non-erosive forms - have on esophageal biopsy a lesion in esophageal stratified squamous epithelium known as 'dilated intercellular spaces (DIS). This lesion has importance because it reflects an increase in paracellular permeability due to acid damage to the tight junctions [1]. Moreover, the increase in paracellular permeability in non-eroded esophageal epithelium provides a plausible explanation for why heartburn occurs during episodes of acid reflux (or esophageal acid perfusion) in those with nonerosive reflux disease (NERD) but not in healthy subjects, and that is because luminal acid is now able to diffuse between cells in quantities sufficient to acidify the intercellular space [2]. Further, the lowering of intercellular pH is the likely trigger for heartburn by its ability to stimulate pain-sensing neurons (nociceptors) within the esophageal mucosa; with the signal from these neurons being transmitted to the CNS for heartburn perception. Clinical and experimental evidence support these concepts in that antacid ingestion relieves and proton pump inhibitors (PPIs) prevent heartburn in most patients and when PPIs control heartburn, they also lead to resolution of DIS in squamous epithelium [3]. Moreover, it is increasingly likely that many NERD patients classified as PPI-partial responders develop heartburn through the same mechanism as PPI-complete responders with NERD. This is because PPIs only raise gastric pH to ~pH 5, and even such 'weakly-acidic' refluxates have been shown to be associated with heartburn [4]. The reason for this is that in the presence of a broken epithelial barrier, weakly acidic refluxates are still able to acidify the intercellular space to levels sufficient to activate the nociceptors - the latter the case since the nociceptors can be activated even at pHs as modestly acidic as pH 6.0-pH 7.0 (see below).