| dc.description.abstract | As the first line of defence against noxious luminal contents, the oesophageal mucosa plays an important role in the pathogenesis of gastroesophageal reflux disease (GORD). We hypothesised that the heterogeneity of symptom perception between heartburn patients may be dependent on the interactions between neuronal and inflammatory cells in the oesophageal mucosa. Studies were conducted with endoscopic oesophageal biopsies from GORD patients (N=83) to characterise the phenotype of afferent mucosal nerve endings by assessing expression of ion channels TRPV1, ASIC3, and TRPM8 involved in pain transduction. Neuro-immune interactions in the oesophageal mucosa of heartburn patients and healthy individuals (N=14) was studied by assessing the expression of inflammatory cytokine receptors CXCR2, TNFR1, IL1R, IL6R, and RAMP1. Infiltration of immune cell populations was characterised among GORD groups. Mast cell co-expression of NGF was also studied. Cytokine release profiles were measured in supernatant from mucosal biopsies from ERD patients and healthy controls exposed to acid using a multiplex assay. RNA extracted from mucosal GORD biopsies and healthy controls were bulk-sequenced to assess the differences in the molecular gene signature between patients with heartburn and asymptomatic subjects, and among GORD phenotypes. TRPV1 was expressed only on mucosal superficial sensory afferent nerve endings of NERD patients, while ASIC3 was most frequently expressed on oesophageal epithelial cells in NERD and ERD patients. CXCR2 was localised on epithelial cells surrounding the papillae in all GORD phenotypes and healthy controls, but was also detected on deep sensory afferent nerves innervating papillae in FH patients. NGF expression was significantly higher in mast cells in patients with GORD compared to healthy controls, and these mast cells were detected in close proximity to sensory deep afferent nerves in patients with ERD. IL8 secretion was increased with acid exposure in both healthy control oesophageal mucosa and ERD, while NGF was released at higher levels with acid exposure from ERD oesophageal mucosa. RNA sequencing detected important differences in expression of genes with structural and regenerative roles between NERD, ERD and BO oesophageal mucosa and asymptomatic subjects. We demonstrated distinct sensory phenotypes in the oesophageal mucosa of patients with ERD, NERD, BO, FH, and healthy controls. These phenotypes include differences in mucosal afferent innervation, immune cell profiles, cytokine release when challenged with acid, and gene expression signatures. Collectively, these findings may contribute to heartburn pathogenesis in the oesophageal epithelium of GORD patients. Improved understanding of mucosal targets identified in this study, including TRPV1, ASIC3, and NGF, in functional studies will enable development of targeted topical treatments to alleviate heartburn symptoms. | en_US |
