Investigating the physiological systems that regulate food intake and metabolic processes in the treatment of Obesity and other metabolic diseases

Crohn's disease and ulcerative colitis are chronic, incurable inflammatory bowel diseases. Diet, environmental factors, lifestyle, drugs, the microbiome and genetics all play a key role in driving unpredictable and disabling periods of 'flare' that have a cumulative damaging effect on the bowel. Current strategies for treating gastrointestinal conditions such as IBD are not believed to address the primary dysfunction of the host-microbial interactions that are likely to play a critical role in the disease pathophysiology. Furthermore until recently access to understanding how the molecular environment changes over time following the consumption of food in the human GIT has been difficult.

Work to date
1. We have obtained ethical permission to use the tube sampling techniques throughout the gastrointestinal tract. This has resulted in the initiation of a project that is sampling from stomach,
duodenum, ileum and ascending colon.
2. We have successfully taken samples from the ileum and ascending colon
Below is a initial summary table of NMR metabolomic differences in the ileum across three diets are shown below where diet 1 is highly refined and processed, diet 2 in minimally processed
where the food structures are intact and diet 3 is identical to diet 2 but with the cell structure disrupted. This bring highlights potential new molecule(s) that may be metabolically active such
as raffinose
3. We have also run analysis exploring the relationship exploring the relationship between the metabolite profile in the ileum an GLP-2 release. We demonstrate the ileum lactate relates to GLP-2 release.
Objectives
The current proposal outlines a 2 year research proposal focused on the identification of novel interactions between GPCRs and microbiome derived ligands in a defined patient population(s) healthy volunteer and inflammatory bowel disease). The objectives are:
1. to understand how the dietary molecular environment in the human GIT in healthy and IBD patients influences GPCR signalling systems to mediate key functions in the gut
(repair/regeneration, tight junction formation and gut hormone release e.g. GLP-2)
2. To develop a computational systems biology interactome GPCR pathway for multiple
dietary ligand signalling molecules and GPCRs