Gastroesophageal reflux disease (GERD) is a major health problem in the United States, impacting over 20% of the population. In at least a quarter of these patients, symptoms caused by GERD such as heartburn and chest pain cannot be controlled by gastric acid suppression with proton pumps inhibitors (PPIs). This population of patients with PPI-refractory GERD have no effective medical treatment options. Failure to understand mechanisms of persistent symptoms in this condition is a major knowledge gap, and limits clinical therapeutic options. One potential cause of persistent symptoms in PPI-refractory GERD patients is weakly acidic (pH>5.0) reflux. This can cause activation of pain- mediating nerves (C-fiber nociceptors) in esophageal mucosa, but the molecular mechanisms have not been clearly elucidated. Furthermore it is not clear whether bile acid also directly activates esophageal C-fibers and mediates nociceptive symptoms in GERD. Our overall hypothesis is that the refluxates in PPI-refractory GERD (mild acid and bile acids) activate esophageal nociceptive C-fiber subtypes and contribute to persistent symptoms in refractory GERD. Determining the identity of the afferent nerve subtype(s) and the key receptor(s) responsible for PPI refractory symptoms are crucial for development of specific targets for this population. Over the past decade, we have identified 3 types of C-fibers in the esophagus which express differential receptors and neurotransmitters and have different central projections. Intriguingly, we have developed new data which demonstrated that two factors in weakly acidic refluxate robustly stimulate esophageal C-fibers: 1) bile acids (that are quite often found in the refluxates on PPI therapy), and 2) acid in low proton concentrations (pH=6.0, termed here mild acid). Our published papers and preliminary data suggest that the key receptors TGR5 and TASK1/ASIC3 are likely involved. Based on these progresses, we will first determine in aim 1 the subtypes of nociceptive afferent nerve terminals in esophagus mucosa which are more vulnerable to refluxates. We will then elucidate receptors mediating C-fiber activation by mild acid in aim 2. We will address the hypothesis that mild acid activates C-fiber subtypes via combination of inhibition of potassium two-pore domain (K2P) family channel (TASK1) and activation of cationic channels from the ASIC family (ASIC3).
In aim 3, we will elucidate receptors mediating C-fiber activation by bile acids. We hypothesize that bile acids activate C- fiber subtype(s), which is mediated by the bile acid receptor TGR5. We will apply the approaches of gene expression analysis, patch clamp recordings, and recordings of nerve activity originating in the C-fiber nerve terminals. Studies will be carried out in in animal models in which neuron-selective gene knockdown by our validated in vivo shRNA silencing strategy. Elucidation of the mechanisms by which bile acids and mild acid activate C-fibers will help to develop novel targets for PPI--refractory GERD.
Heartburn and non-cardiac chest pain are the most common complaints in which patients experience painful and burning sensations when stomach contents reflux into the esophagus. Acid inhibition medications are usually helpful to relieve such symptoms, but there are still more than 20% of patients who do not respond well to even potent anti-acid drugs such as proton pump inhibitors. This project will study the underlying mechanism of how reflux content (both acid and non-acid) activates esophageal sensory nerve to induce painful sensation, which may lead to novel treatment approaches for these common but difficultly managed clinical problems.
| Hennel, Michal; Harsanyiova, Jana; Ru, Fei et al. (2018) Structure of vagal afferent nerve terminal fibers in the mouse trachea. Respir Physiol Neurobiol 249:35-46 |
| Han, Liang; Limjunyawong, Nathachit; Ru, Fei et al. (2018) Mrgprs on vagal sensory neurons contribute to bronchoconstriction and airway hyper-responsiveness. Nat Neurosci 21:324-328 |
| Kollarik, M; Sun, H; Herbstsomer, R A et al. (2018) Different role of TTX-sensitive voltage-gated sodium channel (NaV 1) subtypes in action potential initiation and conduction in vagal airway nociceptors. J Physiol 596:1419-1432 |
