Magnetic Resonance Imaging of Motility in Crohn's 1

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).