P2. Gastrointestinal physiopathology: inflammatory disease and motility disorders

Coordinator: Pere Clavé

Clinical and scientific relevance of the areas covered in the programme  

This research programme includes a group of digestive disease of great prevalence and impact on the health and quality of life of the general population structured in three major lines of Research: a) Oesophageal-gastroduodenal pathology; b) Inflammatory Bowel Disease; and c) Neuro-gastroenterology and functional digestive disorders. The aim of the programme is to improve knowledge about the physiopathology, diagnosis, epidemiology, prevention and treatment of these diseases by means of a high level of cooperative and multidisciplinary investigation between researchers and research groups with a clinical, basic and epidemiological approach; and the development of type I and II translational research.

a). Oesophageal-gastro-duodenal pathology

Gastroesophageal reflux disease (GERD) is highly prevalent in the general population (15%). The research performed is intended to find out the determining factors of development into oesophagitis, Barrett’s oesophagus and its potential neoplasic progress, and the implementation of clinical practice guides to enable optimising the pharmacological treatment of both patients with erosive forms and patients with symptoms in spite of antisecretory treatment (NERD). This approach also includes the diseases associated with infection by Helicobacter pylori, the gastrointestinal effects of cyclooxygenases COX-1 and COX-2 (NSAIDs and acetyl-salicylic acid, used by roughly 25% of the adult population) and disorders connected with secretion of gastric acid. The prevalence of infection by H. pylori in Spain is high, roughly 50% in the general population and constitutes the main cause of chronic gastritis, gastroduodenal ulcers and gastric cancer. The aim of the research is the development of new diagnostic methods of infection by HP and new therapeutic modes of eradication; the study of environmental and genetic determining factors associated with the physiopathology of these diseases and the reduction of the associated gastrointestinal complications (perforation, haemorrhages).

b). Inflammatory Bowel Disease

This line of research addresses the primary causes of immune dysfunction - in particular the role of innate immunity and dendritic cells – against certain microbial species identifiable by means of mass sequencing, the recognition of the genetic and environmental determining factors conditioning the phenotypic development of each chronic IBD, and finding out the epidemiology of each phenotype. The age of diagnosis of IBD in our environment stands at 16 to 35 years and it is common for there to be a delay in diagnosis of roughly 3.5 years from when the symptoms start. Diagnosis and early treatment improve patients’ response rates spectacularly and this requires the implementation of methods enabling the early differential diagnosis of IBD as compared with other processes such as the irritable bowel syndrome IBS by the use of faecal biomarkers. In Crohn’s disease (CD) the value of magnetic resonance for objective monitoring of the therapeutic response is being examined.    

As regards the optimisation of treatment, in CD the aim is to use biomarkers to identify the patients who are going to present incomplete responses to anti-TNF drugs and the optimum handling of patients to prevent the loss of efficiency, refractoriness and relapse; its possible withdrawal in some patients undergoing remission; the application of cell therapy (transplant of stem cells) for patients with extensive, refractory or surgically operable forms; and the effect of the least invasive treatments (dilation or prosthesis with local injection of anti-TNFs) in patients with stenosing forms of CD. Different studies in this area appraise the safety of drugs used in IBD in the clinical practice and the study of disorders of immune response in these patients (in particular against the VHB vaccine). The translation of this progress to the clinical level will enable improving the definition of the minimum structure and the appropriate standards for handling IBD (IBD Care Units), clinical practice guides, as well as the study of the social and employment repercussions of these diseases.

This area also includes research projects connected with celiac disease, which is considered to possibly affect 5% of the general population. Studies cover its physiopathology, the origin of symptoms, diagnosis in the forms with few histological changes, strategies for improving compliance of gluten free diet, and the natural history of the disease and identification of genetic cell and molecular markers connected with the appearance of tolerance.

c) Neuro-gastroenterology and functional digestive disorders

The prevalence of IBS is 15% of the general population and Oropharyngeal Dysphagia (OD) affects 50% of the patients who have undergone an ictus, neurodegenerative diseases and frail elderly patients and is associated with a high morbidity-mortality due to nutritional and respiratory complications. In spite of these disorders being properly recognised by the World Health Organisation, they seriously affect the health and quality of life of the patients concerned, in most cases there are not yet any standardised diagnosis procedures nor specific treatments.

In this line of research we are going to study a number of critical aspects to improve the way patients are handled: 1) the mechanisms for control of motility through both the enteric nervous system and through the CNS and the neuronal plasticity phenomena associated with the disease and their treatment; 2) the impact of new diagnostic methods such as high resolution manometry, intraluminal impedance, capsule endoscopy, evoked potentials, and other emerging technologies in the phenotypic classification of patients with primary and secondary motor disorders; 3) humoral immune activation in the intestinal mucus, and the role of molecular alterations of the proteins involved in the regulation of intestinal permeability; 4) the role of stress and of sex/gender; 5) the development of new experimental models of disease; 6) the development of new biomarkers and pharmacological targets for the diagnosis and treatment of these alterations; and 7) the role of intestinal microbiota in its physiopathology in different sections of the digestive tract.

The aims of this area of research include the development of a completely new pharmacological treatment of neurogenic dysphagia and dysphagia associated with aging (TRPV1, TRPA1 and TRPM8 agonists), the use of magnetic and electric stimulation techniques of the CNS and the evaluation of their effect on the biomechanics of swallowing and on cortical activation (cortical plasticity). The development of multi-centre studies will enable finding out the epidemiology of the phenotypes of oesophageal achalasia and motor disorders and the development of more specific CPGs. On the basic level, the study of the physiopathology of intestinal motility disorders is based on the analysis of in vitro motility patterns, electrophysiological, histological and molecular changes in samples from surgically operated patients and to facilitate access to this tissue by mixed teams of clinical and basic researchers committed to the study of the origin and potential new channels of treatment of these patients.

The origin and physiopathological mechanisms of functional digestive disorders has not been established although a large amount of evidence indicates that both the chronic psychological stress and gastrointestinal infections could be key factors in particular in the female sex with IBS. The alteration of the intestinal microbiota and the epigenetic modifications in the mediators of the stress response could affect the intestinal epithelial barrier in diseases such as GERD, functional dyspepsia and IBS. The mastocytes of the intestinal mucus would be a key cell in the modulation of the response of the intestinal barrier to stress in disorders such as IBS-D or post-operatory ileus and would be the basis of both new pharmacological targets; with the local and humoral immunity activation as the basis of development of specific biomarkers. The area also includes research lines of great clinical significance such as the origin of mechanisms of abdominal distension (diet, metabolism of intestinal gas, intestinal microbiota and visceral sensitivity), functional constipation and faecal incontinence in different phenotypes of patients, with potential transfer to the development of clinical practice guides for these groups of patients.

Program Group Members

Main ResearcherConsortium InstitutionCCAADetails
Fernando Azpiroz Fundación Hospital Universitario Vall D´hebron - Institut De Recerca (VHIR) Cataluña View Group
Belén Beltrán (grupo vinculado) Fundación para la Investigación Hospital La Fe Valencia View Group
Eduard Cabré Fundación Instituto de Investigacion Germans Trias i Pujol Cataluña View Group
Xavier Calvet Corporación Sanitaria Parc Taulí Cataluña View Group
Pere Clavé (Coordinador de Programa) Fundación Privada Salud del Consorcio Sanitario del Maresme Cataluña View Group
Juan Vicente Esplugues Universidad de Valencia Valencia View Group
María Esteve (Grupo Vinculado) Fundació per la Docència i Recerca Mútua Terrassa Cataluña View Group
Francisco Guarner Fundación Hospital Universitario Vall D´hebron - Institut De Recerca (VHIR) Cataluña View Group
Ángel Lanas Instituto Aragonés de Ciencias de la Salud Aragón View Group
Julià Panés Hospital Clínico y Provincial de Barcelona Cataluña View Group
Javier Pérez Gisbert Servicio Madrileño de Salud Madrid View Group
Fermín Sánchez de Medina Universidad de Granada Andalucía View Group