The small bowel and functional dyspepsia : peptide hormones and neurotransmitters

Functional dyspepsia (FD) is believed to be caused by pathophysiological changes in the upper gut. Gastro-intestinal motility, epithelial transport and signalling is associated with the metabolism of nutrients and the complex regulation of hunger and satiety. Glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) are considered “hot targets”. Both are anorexigenic, can induce nausea, and are involved in neuronal and hormonal feedback. Epithelial transport and signalling are partly controlled by the action of the neurotransmitter serotonin (5-HT). 5-HT forms the “link” between luminal stimulation and the enteric nervous system. We aimed at investigating if GLP-1, PYY and 5-HT are involved in the pathogenesis of FD.

In study I and II healthy subjects were given a radiolabelled omelette during intravenous infusion of saline, PYY1-36, or PYY3-36 (study I) and saline or the GLP-1 receptor antagonist Exendin(9-39)amide (study II) in a single-blinded, randomized design. Gastric emptying (scintigraphy), appetite ratings (VAS), and plasma concentrations of insulin, glucose, GLP-1, PYY and glucagon were studied.

In study III FD patients and controls consumed two liquid meals, first a fixed amount and then until maximal satiety. Gastric emptying (paracetamol absorption test) and plasma concentrations of GLP-1, glucose and insulin were assessed as well as appetite ratings and dyspeptic symptoms.

In study IV duodenal mucosal biopsies from FD patients and controls were studied for the number of 5-HT-containing cells (immunohistochemistry) and the expression of different 5-HT receptors by means of PCR. Biopsies were also mounted in Ussing chambers for evaluation of basal and 5-HT-stimulated short-circuit current.

In study V duodenal biopsies from non-patients with FD and controls from a population based upper endoscopy study were evaluated immunohistochemically for Chromogranin A (CGA) as endocrine cell marker and 5-HT. Individuals with FD were further divided into epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS).

PYY3-36 and PYY1-36 inhibits gastric emptying (PYY3-36 most effectively), and decreased the postprandial rise in insulin. PYY3-36 induced nausea and decreased prospective consumption. GLP-1 was involved in regulation of postprandial gastric motility, in insulin and glucose levels, and restrained glucagon secretion. Gastric emptying was not affected and we conclude that GLP-1 has a role as incretin hormone independent of gastric emptying. FD patients had normal postprandial glucose and GLP-1 concentrations. The FD-EPS subgroup had higher postprandial insulin levels compared to controls. Exogenous 5-HT induced lower short-circuit current and higher electrical resistance in FD. FD patients had higher gene expression of HTR3E and SERT and lower expression of HTR7 and TPH1. The number of 5-HT containing cells in duodenal mucosa was similar in FD patients and controls, and adults with FD had less endocrine cells and a normal number of 5-HT containing cells compared to controls. Endocrine cells was significantly decreased in the duodenal bulb in EPS but not PDS.

Our results provide new evidence that altered endocrine secretion in the small bowel is part of the disease mechanism in FD, with PYY and GLP-1 as key candidates. GLP-1 specifically contributes to the development of nausea. Furthermore, FD patients have abnormal 5-HT stimulated electrolyte secretion in the duodenum with possible involvement of the 5-HT receptors 3E and 7.

List of scientific papers

I. Differential effect of PYY1-36 and PYY3-36 on gastric emptying in man. Witte AB, Grybäck P, Holst JJ, Hilsted L, Hellström PM, Jacobsson H, Schmidt PT. Regulatory Peptides. 2009; 158(1-3): 57-62.
https://doi.org/10.1016/j.regpep.2009.07.013

II. Involvement of endogenous glucagon-like peptide-1 in regulation of gastric motility and pancreatic endocrine secretion. Witte AB, Grybäck P, Jacobsson H, Näslund E, Hellström PM, Holst JJ, Hilsted L, Schmidt PT. Scandinavian Journal of Gastroenterology. 2011; 46(4): 428-35.
https://doi.org/10.3109/00365521.2010.537680

III. Glucose homeostasis and GLP-1 in Functional Dyspepsia – relation to dyspeptic symptoms and satiety measures. Witte AB, Hilsted L, Holst JJ, Schmidt PT. [Manuscript]

IV. Duodenal epithelial transport in functional dyspepsia: Role of serotonin. Witte AB, D'Amato M, Poulsen SS, Laurent A, Knuhtsen S, Bindslev N, Hansen MB, Schmidt PT. World Journal of Gastrointestinal Pathophysiology. 2013; 4(2): 28-36.
https://doi.org/10.4291/wjgp.v4.i2.28

V. Decreased number of duodenal endocrine cells with unaltered serotonin containing cells in Functional Dyspepsia. Witte AB, Walker MM, Aro P, Ronkainen J, Marrazzo V, Talley NJ, Agréus L, Schmidt PT. [Manuscript]