Inflammatory Bowel Disease (IBD)
IBD Leader: Dr Gordon Moran
Deconstructing the gut-brain axis in adult Crohn's disease using fMRI methodology
Collaborators: Susan Francis, Luca Marciani, Ian Macdonald (UoN); John Mclaughlin (University of Manchester); Graham Finlayson (University of Leeds); Tony Goldstone (Imperial College).
We have shown that in intestinal inflammation due to Crohn’s disease (CD), upregualtion in the tissue and plasma levels of GI peptides (GLP-1 and PYY)1, 2 is correlated to key patient symptoms of nausea and bloating. In CD, we hypothesise an accentuated homeostatic responses and loss of hedonic drives to food intake, exerting negative influences on eating behaviour. We have started a study in CD subjects with active inflammation to assess the CNS response to food intake using fMRI. This work will serve as a platform for future mechanistic studies that will highlight the importance of pharmacological modulation of the EC pathway in active CD. Findings from this work may be transferrable to other diseases such as obesity or anorexia, thus addressing one of the MRC research priorities: understanding how lifestyle and our environment can affect our health.
*These studies are funded through the MRC and the BROAD research Foundation.
Functional MRI image of the brain showing cortical activation in response to a fat meal in a Crohn’s patient.
Motility in Crohn’s disease
Collaborators: Luca Marciani, Penny Gowland, Aseel Khalaf, Caroline Hoad, Robin Spiller (UoN); Stuart Taylor, Alex Menys (University College, London).
GLP-1, PYY and CCK have an effect on GI motility as well by delaying gastric emptying3-6 and small bowel transit7, 8. The symptoms of nausea and bloating may thus be explained through a reduction in GI motility rather than alteration in the gut-brain axis. Some preliminary data has shown delayed gastric emptying6 and orocaecal transit time8 in CD subjects. The EC hyperplasia and the increase in postprandial plasma levels of anorectic EC peptides could potentially lead to altered appetite and symptoms of nausea and bloating through delayed small bowel motility and gastric emptying. To our knowledge this mechanistic link has not been described. We are presently undertaking a study investigating patient symptoms, gastric emptying, global small bowel motility, whole gut transit and EC peptide responses in the fasting and postprandial state. By investigating the physiological pathways that may be responsible for patient symptoms we may be able in the near future to specifically target these symptoms pharmacologically with specific GI peptide inhibitors.
*This work is funded through the NDDBRC and NUH Charity and Education Ministry in Kuwait.
Skeletal muscle metabolism in Crohn’s disease
Collaborators: Francis Stephens, Ian Macdonald (UoN)
Maintaining skeletal muscle mass is a tightly regulated process controlled by the fine balance between muscle hypertrophy and atrophy signalling pathways, and adult patients with active CD show a significant decrease in expression of hypertrophy signals with no change in the expression of atrophy signals. This latter finding is in keeping with theory that the inability to stimulate muscle protein synthesis in response to feeding, termed ‘anabolic resistance’, is thought to be a main driver for muscle loss observed in conditions such as ageing, critical illness, and disuse, but is as yet untested in CD. It is simply not known whether anabolic resistance contributes to the muscle loss and inability to gain muscle mass in CD, particularly in remission, or if physical activity plays an aetiopathological role in muscle loss or is just a mere effect of reduced muscle function. The purpose of the present study is to perform a detailed in vivo physiology study to investigate the skeletal muscle metabolic response to feeding in patients with CD vs. age and weight matched healthy controls before and after a period of increased physical activity and after medical treatment.
*This study is funded through a pilot grant from the UoN, Life Sciences, NUH charity and the CORE Foundation.