Proceedings of The Physiological Society
AstraZeneca (2010) Proc Physiol Soc 18, C02 and PC02
Enteroendocrine cells in human intestinal inflammation
G. W. Moran1, J. T. McLaughlin1
1. School of Translational Medicine, University of Manchester, Manchester, United Kingdom.
Appetite is often reduced in patients with gastrointestinal inflammation, but the precise biological basis for this is extremely unclear. Gastrointestinal satiety signals are produced by enteroendocrine cells (EEC), and signal to the brain to regulate food intake. Polypeptide YY (PYY) and glucagon like peptide-1 (GLP-1) are secreted by L cells and suppress food intake, probably physiologically. Recent animal model research has suggested that immune-regulated upregulation of EEC plays a mechanistic role in the appetite and feeding disturbance observed during gut inflammation (1,2). This has not been explored in humans: Crohn’s disease (CD) has been chosen as an exemplar for this, in order to assess EEC and related markers in human intestinal inflammation. Endoscopic terminal ileal biopsies were taken from CD patients with active intestinal inflammation, sampling small and large bowel (SB and LB respectively), and tissue from age/sex matched controls. Symptoms including appetite and satiety were quantified with validated visual analogue scores (VAS). EEC markers and transcription factors were studied by immunohistochemistry and quantitative polymerase chain reaction (qPCR). CD patients with active inflammation displayed a ~6-fold significant reduction in basal appetite as measured by VAS (unpaired t-test; N=18 vs 13; p<0.0001). Inflammation was graded independently with endoscopic, clinical, histological and biochemical scoring. GLP-1 cells were significantly increased 2.5-fold in SB CD (unpaired t-test; N=8 vs 11; p=0.04), while the general EEC marker chromogranin A showed a 1.5 fold increase in expression. However, PYY cell numbers were not significantly altered, with a trend to decreased numbers. Phox2b (3), a neural transcription factor associated with CD in a recent genome-wide association study, was co-localised to EEC through dual immunofluorescence and showed a 1.5-fold increase in SB CD compared to controls. At mRNA level, significant increases were noted for Chromogranin A (3.3-fold; Mann Whitney (MW) test; N=8; p=0.009), GLP-1 (MW test; N=8; 2.7-fold p=0.05), Ubiquitination protein 4a (Ube4a) (MW test; N=8; 2.2-fold p=0.02). However PYY was not significantly changed. Neurogenin 3, a NOTCH transcription factor central to EEC differentiation showed ~2 fold-upregulation (MW test; N=8; p=0.04). These preliminary results show that changes in EEC biology occur in CD, with differential effects on specific cell lineages. This is compatible with a potential role for EEC in appetite dysregulation in intestinal inflammation: enhanced EEC activity may directly suppress appetite in such patients through increased gut-brain signalling. It is now planned to further dissect the signalling pathways implicated.
Where applicable, experiments conform with Society ethical requirements