Magnetic Resonance Imaging of Motility in Crohn's 1
Condition: Healthy
Study type: Interventional

Summary: 
      Crohn's disease (CD) is becoming more common. One of the main features of this disease is
      weight loss and malnutrition with symptoms such as tummy aches and bloating. These problems
      have a strong negative effect on the patients' quality of life but the causes of these
      problems are not well understood.

      Enteroendocrine cells are nutrient sensors in the bowel that secrete special chemicals
      (called hormones) that control appetite and the movements all the gut. The investigators
      think that this control mechanism goes wrong in Crohn's patients and they have set off to do
      more research on this. Looking at the inside work of the gut has always been difficult and at
      times unpleasant for patients, however recent developments in magnetic resonance imaging
      (MRI) are allowing the investigators to study the workings of the gut in greater detail and
      without discomfort for the patients.

      Before studying the Crohn's patients it is necessary to run a set of pilot experiments in
      healthy volunteers using a test meal and subsequent MRI imaging to look at the motion of the
      gut. This validation stage of the methodology is essential before embarking in more detailed
      studies in the patients.
    

Detailed description: 
      Background: Poor nutrition in Crohn's disease (CD) is common but poorly understood. Apart
      from disease burden and repeated surgery, reduction in appetite might be an aetiological
      factor.

      Enteroendocrine cells (EC) are intraluminal nutrient sensors. They play a pivotal role in
      orchestrating physiological functions in the gastrointestinal tract. Sensing the nutrient
      content of the lumen, they secrete multiple peptides and amines that control gut secretory
      and motor functions. CD patients with small bowel inflammation show increased expression in
      EC peptides with exaggerated postprandial responses in anorectic EC hormones. This is
      associated with symptoms of nausea and anorexia, with EC-peptide expression decreasing to
      normality in remission.

      There has been a longstanding interest on the effect of CD on gastric emptying and
      gastrointestinal motility.

      Recent technological advances have allowed us to use magnetic resonance imaging (MRI) to
      measure both disease activity, intestinal motility and whole gut transit.

      Reduced intestinal motility has been recently shown in CD patients with active terminal ileal
      disease. A significant negative correlation is observed between terminal ileal motility and
      histological, biochemical and radiological measures of disease activity. Intestinal
      hypomotility may be observed in proximal unaffected segments of small bowel as well.

      An increase in EC activity could potentially lead to altered appetite and symptoms of nausea
      through delayed gastric emptying and most importantly delayed small bowel transit. This
      mechanistic link has not been described and present findings have not been correlated to
      patient symptoms. This work can potentially open a new therapeutic pathway in CD therapy.
      Optimisation studies in healthy volunteers (HV) are urgently needed.

      Aims & Hypothesis: In intestinal inflammation due to CD, the observed up-regulation of
      fasting and postprandial EC peptides may correlate with a delayed whole gut transit
      specifically small bowel transit and gastric emptying. This optimization study in HV aims to
      validate a test meal and optimize themethodology in assessing gastric emptying, small bowel
      transit and whole gut transit.

      Experimental protocol and methods: 15 healthy volunteers will be recruited. Standard MRI
      exclusion criteria will apply. Volunteers should not have a history of inflammatory bowel
      disease, history of smoking, a history of bowel resections or any gastric surgery, history of
      pancreatic insufficiency, thyroid disease, diabetes, protein-pump inhibitor usage or any
      medication that affects gastric emptying or small bowel transit.

      This study will have an open-label design. Subjects will be asked to swallow five MRI marker
      capsules (20 x 7 mm) at 09:00 am, 24 h before undergoing an MRI scan. The subjects will be
      asked to fast from 2000 h. They will be asked to fill in a questionnaire to ensure adherence
      to the study day restrictions.

      On the day of the scan, they will only be allowed a small glass of water on waking. They will
      undergo a baseline fasting scan at 0900 hours (defined at t = -45 min time point), together
      with a fasting baseline blood sample. At 0925 hours, they will be asked to eat their test
      meal within a maximum time of 20 min so that at 0945 hours the subjects will undergo a first
      immediate postprandial scan (defined as t = 0 min). This will be followed with data
      collection (MRI, questionnaire data and blood samples) time points every 15 min for the first
      60 min and every 30 min up to 270 min.

      At each time point, the positioning of the subject, setup and data collection will take
      ~15min. After the first 60 min, at completion of data collection at each time-point, the
      volunteers will be kept sitting upright in a quiet lounge next to the scanner. At each time
      point, volunteers will fill a 100mm Visual Analogue Scale (VAS) symptoms questionnaire
      scoring their feeling of fullness, bloating, distension, abdominal pain/discomfort and
      nausea. The VAS anchors were from 'not' to 'extremely'. Participants will be given a meal at
      the end of the study.

      MRI scanning will be carried out supine on either a 1.5T or 3.0 T Philips Achieva MRI scanner
      (Philips Healthcare, Best, The Netherlands) depending on availability. Fasting and
      post-prandial plasma tests: On the morning of the test, a 10 ml fasting blood sample will be
      drawn in aprotonin/EDTA tubes (BD-361017, BD Diagnostics, Oxford). Samples will be measured
      every 45 min to 270 min. Samples will be centrifuged at 4000 rpm for 5 min and stored on ice.
      Measurement of plasma peptides: All EC peptides (GLP-1, PYY) will be analysed through ELISA
      techniques (Millipore, UK). Serum CCK will be measured by RIA (Euro Diagnostic Products,
      Sweden). Total EC plasma peptide response will be presented as per individual time points and
      compositely as area under the curve (AUC).
    

Intervention name(s): Soup meal
Intervention type(s): Other
Intervention description(s): Soup meal as above
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Motility; MRI; Gut peptides; Feeding