PIs: Professor Daniel Sifrim, Professor Qasim Aziz

Heartburn is one of the commonest GI symptoms and it is a typical symptom of gastro-oesophageal reflux disease (GORD), with a population prevalence of up to 40% at one time or another, and weekly in 20%. The pathophysiology of GORD is multifactorial involving 1) motility disorders of the stomach, lower oesophageal sphincter and oesophageal body, 2) increased exposure of the oesophageal mucosa to gastric juice 3) altered defence mechanisms in the oesophageal mucosa and 4) oesophageal hypersensitivity. While in most patients with GORD, symptoms settle with lifestyle measures or acid suppression therapy, in a proportion (10 – 30%) symptoms continue despite adequate conventional treatment. Most research in GORD aims to understand the mechanisms of refractoriness and to develop new strategies for management of GORD patients, refractory to standard treatment. Transient lower oesophageal sphincter relaxations (TLOSRs) are the main motor pattern that allows GOR. The mechanisms of triggering TLOSRs and the factors that favour reflux during TLOSRs are under current intense investigation. Drugs that reduce the frequency of TLOSRs are already reaching the clinical setting. Current evidence suggests that peripheral mechanisms related to permeability of oesophageal mucosa, central sensitisation of spinal dorsal horn neurones and psychological factors contribute to persistence of symptoms in these patients. There are, therefore, several areas of active research in GORD that aim to provide an answer to unmet clinical needs. One limitation for investigating GORD is the fact that most diagnostic methods are invasive and require naso-oesophageal intubation. We focus our research in GORD in the following areas

• Diagnostic techniques
  development of non-invasive diagnosis of GORD (e.g. saliva assessment for acid and/or bile); improvement of reflux monitoring using impedance-pHmetry; cortical evoked potentials to distinguish persistence of symptoms due to neuronal sensitisation and/or psychological factors)
• Pathophysiology
  analysis of factors responsible for triggering of TLOSRs and reflux during TLOSRs (gastric contents distribution and acid pocket), the role of altered oesophageal mucosal permeability on perception of GORD symptoms (in preclinical and clinical models as well as in vitro human oesophageal tissue), role of peripheral, central sensitisation and psychological factors mediating reflux symptoms.
• Treatment
  tailoring treatment according to phenotype, based on anatomy, motility, acid secretion, mucosal integrity, and presence of hypersensitivity; Clinical trials testing, new prokinetics, reflux inhibitors, mucosal protectors and modulators of oesophageal perception.

Strengths

1. Studies will be performed in healthy volunteers and patients with GORD
2. The upper GI physiology unit is a referral centre in the UK for GORD patients not responding to PPI treatment
3. Physiological studies will allow to recruit large cohorts of carefully phenotyped patients for clinical pharmacological trial
4. A dedicated oesophageal “in vitro” laboratory will perform studies on oesophageal mucosa integrity and muscle function. This lab will work with both human biopsies and human oesophageal tissue from surgical specimens

References:

1. Sifrim D, Holloway R, Silny J, Xin Z, Tack J, Lerut A, Janssens J. Acid, nonacid, and gas reflux in patients with gastroesophageal reflux disease during ambulatory 24-hour pH-impedance recordings. Gastroenterology 2001; 120: 1588-98.
2. Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux. Gut 2004; 53: 1024-31.
3. Lopez-Alonso M, Moya MJ, Cabo JA, Ribas J, del Carmen Macyas M, Silny J, Sifrim D. Twenty-four-hour esophageal impedance-pH monitoring in healthy preterm neonates: rate and characteristics of acid, weakly acidic, and weakly alkaline gastroesophageal reflux. Pediatrics 2006; 118: e299-308.
4. Farre R, De Vos R, Geboes K, Verbecke K, Vanden Berghe P, Depoortere I, Blondeau K, Tack J, Sifrim D. Critical role of stress in increased oesophageal mucosa permeability and dilated intercellular spaces. Gut 2007; 56: 1191-7.
5. Kahrilas PJ, Sifrim D. High-resolution manometry and impedance-pH/manometry: valuable tools in clinical and investigational esophagology. Gastroenterology 2008; 135: 756-69.
6. Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut 2009; 58: 295-309.
7. Farre R, Fornari F, Blondeau K, Vieth M, De Vos R, Bisschops R, Mertens V, Pauwels A, Tack J, Sifrim D. Acid and weakly acidic solutions impair mucosal integrity of distal exposed and proximal non-exposed human oesophagus. Gut 2010; 59: 164-9.
8. Boeckxstaens GE, Beaumont H, Mertens V, Denison H, Ruth M, Adler J, Silberg DG, Sifrim D. Effects of lesogaberan on reflux and lower esophageal sphincter function in patients with gastroesophageal reflux disease. Gastroenterology 2010; 139: 409-17.
9. Woodland P, Sifrim D. The refluxate: the impact of its magnitude, composition and distribution. Best Pract Res Clin Gastroenterol 2010; 24: 861-71.
10. Farre R, Blondeau K, Clement D, Vicario M, Cardozo L, Vieth M, Mertens V, Pauwels A, Silny J, Jimenez M, Tack J, Sifrim D. Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique. Gut 2011; 60: 885-92.