AN EXPLORATION OF THE MECHANISMS OF VISCERAL HYPERSENSITIVITY IN THE HUMAN GASTROINTESTINAL TRACT IN HEALTH AND DISEASE

Lead Research Organisation: Queen Mary, University of London
Department Name: Unlisted

Abstract

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Technical Summary

Background:
Functional Gastrointestinal Disorders (FGID) affect 9-12% of the UK population. The commonest symptom experienced by FGID patients is pain, however, the heterogeneity of the group and lack of effective clinical investigations has prevented identification of its aetiology.

Visceral hypersensitivity is the most consistent experimental finding in FGID patients and two main hypothesise regarding its mechanism exist. The first states that sensitisation of peripheral and/or central afferents develops as a result of previous inflammation or injury. The second states that aberrant processing of visceral sensation occurs within the brain as a result of psychological abnormalities.

I have investigated human brain-gut interactions using a combination of imaging techniques and have designed several models of oesophageal hypersensitivity which have utilised both psychological modulation and central/peripheral sensitisation of which I have explpored pharmacologically. Based on my observations I have developed a conceptual model of the mechanisms of visceral hypersensitivity and I now wish to test the validity of this model in health and disease.

Objectives:
To differentiate between the putative mechanisms of visceral hypersensitivity in patients with unexplained GI pain.

Design:
Whole human studies in healthy subjects and patients with visceral hypersensitivity.

Methodology:
Study 1: In healthy subjects I will use Magnetoencephalography and Cortical Evoked Potentials to investigate the effects that peripheral/central sensitisation and heightened vigilance have on the cortical regions that process the sensory discriminatory and affective/cognitive aspects of visceral pain processing.
Study 2: In healthy subjects I will determine the effects of repeated acid exposure on the development and severity of oesophageal hypersensitivity.
Study 3: In healthy subjects I will determine the effects of NMDA receptor blockade on the development of oesophageal hypersensitivity induced by either peripheral/central sensitisation or psychological manipulation.
Study 4: In healthy subjects and patients with unexplained oesophageal pain or oesophagitis, oesophageal biopsies will be taken to look for the expression of biological markers of hypersensitivity and these findings compared to physiological measures of oesophageal sensitivity. The study will be repeated after six weeks of gastric acid suppression.
Study 5: Using data obtained in my initial studies, I will test my conceptual model of visceral hypersensitivity in a cohort of patients with unexplained oesophageal pain.

Outcome:
A detailed understanding of the mechanisms of visceral hypersensitivity will facilitate the development of novel treatments which specifically target the appropriate pathophysiology, resulting in benefits to the well being of patients and increased efficiency in healthcare utilisation.

Publications

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Al Omran Y (2014) Functional brain imaging in gastroenterology: to new beginnings. in Nature reviews. Gastroenterology & hepatology

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Al Omran Y (2014) The brain-gut axis in health and disease. in Advances in experimental medicine and biology

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Albusoda A (2018) What drives the hypoalgesic effect of neurostimulation? in The lancet. Gastroenterology & hepatology

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Anand P (2007) Peripheral and central mechanisms of visceral sensitization in man. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

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Aziz Q (2016) Functional Esophageal Disorders. in Gastroenterology

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Brock C (2017) Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

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Bulmer DC (2015) Evidence of a role for GTP cyclohydrolase-1 in visceral pain. in Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society

 
Description Brain imaging guidelines for visceral pain
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact The guidelines provide information on optimal methods for functional brain imaging of visceral pain.
 
Description CLINICAL GUIDELINES FOR IBS
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
Impact These guidelines were commissioned by the BSG were publisHed in GUT which is one of the major gastroenterology journals. These quidelines are used internationally for the management of Irritable Bowel Syndrome patients
 
Description Co Lead for the International Association For the Study of Pain's Global Year Programme against Visceral Pain
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact Provided information and education about different types of visceral pain in health and disease and this led to 1st world congress on visceral pain in Amsterdam in 2013
 
Description Education Committee of UEG
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact As a member of the education committee of the united European Gastroenterology Federation I have influenced policy regarding education across Europe in particualar related to Neurogastroenterology and Motility. This has led to development of workshops; international conferences etc which has disseminated best practice guidelines to trainees and gastroenterologists across Europe.
 
Description International Association for the Study of Pain - Chair Special Interest Group for Abdominal and Pelvic Pain
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact In this role I am in charge of organising educational activities for abdominal and visceral pain and am participating in the IASPs Global Year in Pain Education. This will include webinars and development of written material. I am also organising the educational activities around visceral and abdominal pain for the forthcoming World Pain Congress in Boston USA in September 2018 and The World Congress of Abdominal and Pelvic Pain in London in 2019. In these congresses we will be disseminating new classification criteria for visceral pain developed as part of WHO-ICD 11 visceral pain new codes development. I am also in the process of writing a review article for 'Pain Reports' on the new WHO 11 pain classification which will have a world wide impact.
 
Description Member and lead for education for European Society of Neurogastroenterology and Motility
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact Involved in designing educational platforms for trainees and gastroenterologists across Europe
 
Guideline Title Functional oesophageal disorders
Description ROME CRITERIA FOR FUNCTIONAL GUT DISORDERS
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
URL http://www.romecriteria.org
 
Guideline Title ROME IV - Oesophageal Disorders
Description ROME IV Criteria for Functional Oesophageal Disorders
Geographic Reach South America 
Policy Influence Type Citation in clinical guidelines
Impact I was first author of a paper on Functional oesophageal disorders which describes the new classification criteria for these disorders and provides best practice guidelines. I wrote the classification of a new category called 'Reflux Hypersensitivity' in this manuscript. The new criteria will now be used in the diagnosis of functional oesophageal disorders worldwide and these criteria will be mandatory for clinical trials in these conditions
URL https://www.sciencedirect.com/science/article/pii/S0016508516001785?via%3Dihub
 
Description Butterfield Awards for UK-Japan collaboration in medical research and public health practice
Amount £22,500 (GBP)
Organisation The Great Britain Sasakawa Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2013 
End 01/2015
 
Description CLINICAL RESEARCH FELLOWSHIP
Amount £60,000 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2017 
End 11/2018
 
Description EFFICACY MECHANISM EVALUATION GRANT
Amount £2,323,053 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 02/2018 
End 02/2022
 
Description INNOVATIVE MEDICINES INITIATIVE
Amount € 2,000,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 09/2018 
End 08/2021
 
Description Large Grants Scheme
Amount £459,956 (GBP)
Organisation Barts Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 08/2013
 
Description MRC Experimental Medicine Call II
Amount £390,224 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2008 
End 08/2010
 
Description MRC Project Grant
Amount £634,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2007 
End 08/2010
 
Description MRC Translational Medicine Grant
Amount £535,200 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2009 
End 08/2011
 
Description NeuroGut- European Training in Neural Regulation of Intestinal Function; FP7-PEOPLE-2013-ITN. Marie Curie Actions- Initial Training Networks (ITN)
Amount € 3,600,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 09/2014 
End 08/2017
 
Description PHD STUDENTSHIP
Amount £75,000 (GBP)
Organisation Bowel & Cancer Research 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 03/2021
 
Description PROGRAMME GRANT
Amount £2,233,960 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 02/2018 
End 02/2021
 
Description Aston collaboration 
Organisation Aston University
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided the financial, intellectual and man power in helping to establish this collaborations. Funding provided by MRC allowed the collaborations to advance the joint research programmes.
Collaborator Contribution Our collaborator from Clinical Neuroimaging School of Life and Health Sciences Aston University Birmingham has made significant intellectual contribution to our brain imaging and gut brain neurophysiology programme and also provided access to equipment and personnel to support research programme. Some of the studies were conducted at Aston University.
Impact Aston: 19118573;18410265;16401471
 
Description Genetics collaboration 
Organisation Karolinska University Hospital
Country Sweden 
Sector Hospitals 
PI Contribution a collaboration has been established to study the genetics of functional gut disorders - we will provide patient samples from our clinic
Collaborator Contribution Genetic analysis will be done in sweden and they will also look at existing data bases to see if there is a link between joint hypmermobility and functional gut disorders
Impact none at present. very early phase
Start Year 2016
 
Description Institute of Psychiatry Collaboration 
Organisation King's College London
Department Institute of Psychiatry, Psychology & Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided the financial, intellectual and man power in helping to establish this collaborations. Funding provided by MRC allowed the collaborations to advance the joint research programmes.
Collaborator Contribution Our collaborator has been instrumental in developing our functional magnetic resonance imaging. He has provided us with access to scanning facilities and has provided intellectual input at all stages of the brain imaging projects
Impact 19582887;18848558;17395900;
 
Description Maastricht Collaboration 
Organisation Maastricht University (UM)
Country Netherlands 
Sector Academic/University 
PI Contribution We have provided expertise and training
Collaborator Contribution Provided research fellow for 6 months to visit our department
Impact Working of collaborative projects which should lead to publications and EU grants
Start Year 2014
 
Title Oesophageal thermal probe 
Description Development of a peltier probe to stimulate the oesophaus with a thermal stimulus 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted 2010
Licensed No
Impact A auccessful grant applicaiton was obtained from NIHR to study of the clinical utiltiy of the probe and a grant applicaiton to the Wellcome Trust is now underway to develop this for commercial purposes
 
Title Transcutaneous Vagal Nerve Stimulation for managing oesophageal hypersensitivity 
Description We are using a commercially available device to non-invasively stimulate the vagus nerve to determine its efficacy in a model of health human acid induced oesophageal hypersensitivity. The study is now nearing completion 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact Depending on final results the intervention may have an impact on treatment of mild to moderate visceral pain non-pharmacologically. 
 
Title pregablin in visceral hypersensitivity 
Description We have used pregablin in a model of oesopahgeal hypersensitivity and shown efficacy 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2011
Development Status Actively seeking support
Clinical Trial? Yes
Impact Has allowed us to apply for NIHR EME grant. Awaiting outcome 
URL http://www.controlled-trials.com/ISRCTN40924266
 
Description Advisory board meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I have been invited by pharmaceutical companies to speak at sponsored symposia as well as advisory board meetings

collaboration with pharma and funding of research drug trials.
Year(s) Of Engagement Activity 2006,2007,2008,2010,2011
 
Description Meet the investigator meetings 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Our medical School through has an active dissemination programme for local school children. This allows particular scheme allows investigators to speak to school children about their reserach programme in lay language to inform and encourage children about medical research

One student and one teacher went on to undertake work experience in our department as a direct result of my talk
Year(s) Of Engagement Activity 2009
 
Description PATIENT EDUCATION 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact patients were educated about the causes and management of IBS. Which generated a lot of discussion. There were a lot of interactive sessions and group work to which I contributed.

Similar activities are planned for each year and will take place around the country and I will be involved in these.
Year(s) Of Engagement Activity 2012
 
Description work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact during work experience of student from local school and teacher they were given explanation and were shown experiments related to this grant.

student has decided to persue a career in medicine
Year(s) Of Engagement Activity 2009
 
Description work experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact as mentioned for other grants, we regularly host students and on one occasion even a teacher from a local and regional school for work experience and the work being conducted on the current grant was explained to them.

student has decided to study medicine
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description work experience 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact One teacher and one student from local school did work experience where they were able to see reserach being carried out on projects relevant to the MRC funded project.

The student has decided to study medicine
Year(s) Of Engagement Activity 2009