Project Reference: TRG27-IMS-FG1

Project title: Gut hormonal origins of human intestinal motility disorders

Project outline

Colonic motility is modulated by an interplay between local epithelial production of GLP-1, PYY, INSL5 (all from L-cells), and 5-HT (from enterochromaffin cells), acting on sensory neurones of the enteric nervous system. We have observed dysregulated hindgut hormone secretion in people with diarrhoea-predominant IBS and bile acid diarrhoea. This project will use intestinal organoids and colonic tissues to dissect the neurohormonal networks underlying gut motility disorders triggered by pathological microbial metabolites and bile acids. Human organoids will be modified by CRISPR-Cas9 to label specific enteroendocrine cell types or generate gene knockouts. These will be used for live cell imaging to investigate the molecular mechanisms underlying signalling events triggered by colonic metabolites, and pathways of cross-talk between enteroendocrine cell types and the enteric nervous system. Intestinal motility will be monitored in murine models including through video tracking of motility patterns, and will be used to investigate the importance of different mediators and signalling pathways. Overall the project will establish how hormones from the distal gut contribute to the pathophysiology of human intestinal motility disorders.

Principal Supervisor

Professor Fiona Gribble

Email address: fmg23@cam.ac.uk

Department / Partner Institute: Institute of Metabolic Science (IMS)

Website: https://www.mrl.ims.cam.ac.uk/staff/professor-fiona-gribble

BBSRC strategic theme

Bioscience for an integrated understanding of health