Vasoactive intestinal peptide (VIP), a gut peptide hormone originally reported as a vasodilator in 1970, has multiple physiological and pathological effects on development, growth, and the control of neuronal, epithelial, and endocrine cell functions that in turn regulate ion secretion, nutrient absorption, gut motility, glycemic control, carcinogenesis, immune responses, and circadian rhythms. Genetic ablation of this peptide and its receptors in mice also provides new insights into the contribution of VIP towards physiological signaling and the pathogenesis of related diseases. Here, we discuss the impact of VIP on gastrointestinal function and diseases based on recent findings, also providing insight into its possible therapeutic application to diabetes, autoimmune diseases and cancer.

A substantial volume of the consultations requested of gastroenterologists are directed towards the evaluation of anemia. Since iron deficiency anemia often arises from bleeding gastrointestinal lesions, many of which are malignant, establishment of a firm diagnosis usually obligates an endoscopic evaluation. Although the laboratory tests used to make the diagnosis have not changed in many decades, their interpretation has, and this is possibly due to the availability of extensive testing in key populations. We provide data supporting the use of the serum ferritin as the sole useful measure of iron stores, setting the lower limit at 100 μg/l for some populations in order to increase the sensitivity of the test. Trends of the commonly obtained red cell indices, mean corpuscular volume, and the red cell distribution width can provide valuable diagnostic information. Once the diagnosis is established, upper and lower gastrointestinal endoscopy is usually indicated. Nevertheless, in many cases a gastrointestinal source is not found after routine evaluation. Additional studies, including repeat upper and lower endoscopy and often investigation of the small intestine may thus be required. Although oral iron is inexpensive and usually effective, there are many gastrointestinal conditions that warrant treatment of iron deficiency with intravenous iron.

Key points: Luminal lipid in the duodenum modulates gastroduodenal functions via the release of gut hormones and mediators such as cholecystokinin and 5‐HT. The effects of luminal short‐chain fatty acids (SCFAs) in the foregut are unknown. Free fatty acid receptors (FFARs) for long‐chain fatty acids (LCFAs) and SCFAs are expressed in enteroendocrine cells. SCFA receptors, termed FFA2 and FFA3, are expressed in duodenal enterochromaffin cells and L cells, respectively. Activation of LCFA receptor (FFA1) and presumed FFA3 stimulates duodenal HCO₃⁻ secretion via a glucagon‐like peptide (GLP)‐2 pathway, whereas FFA2 activation induces HCO₃⁻ secretion via muscarinic and 5‐HT₄ receptor activation. The presence of SCFA sensing in the duodenum with GLP‐2 and 5‐HT signals further supports the hypothesis that luminal SCFA in the foregut may contribute towards the generation of functional symptoms. Intraduodenal fatty acids (FA) and bacterial overgrowth, which generate short‐chain FAs (SCFAs), have been implicated in the generation of functional dyspepsia symptoms. We studied the mechanisms by which luminal SCFA perfusion affects duodenal HCO₃⁻ secretion (DBS), a measure of mucosal neurohumoral activation. Free fatty acid receptor (FFAR) 1 (FFA1), which binds long‐chain FA (LCFA), and SCFA receptors FFA2 and FFA3 were immunolocalised to duodenal enteroendocrine cells. FFA3 colocalised with glucagon‐like peptide (GLP)‐1, whereas FFA2 colocalised with 5‐HT. Luminal perfusion of the SCFA acetate or propionate increased DBS, enhanced by dipeptidyl peptidase‐IV (DPPIV) inhibition, at the same time as increasing GLP‐2 portal blood concentrations. Acetate‐induced DBS was partially inhibited by monocarboxylate/HCO₃⁻ exchanger inhibition without affecting GLP‐2 release, implicating acetate absorption in the partial mediation of DBS. A selective FFA2 agonist dose‐dependently increased DBS, unaffected by DPPIV inhibition or by cholecystokinin or 5‐HT₃ receptor antagonists, but was inhibited by atropine and a 5‐HT₄ antagonist. By contrast, a selective FFA1 agonist increased DBS accompanied by GLP‐2 release, enhanced by DPPIV inhibition and inhibited by a GLP‐2 receptor antagonist. Activation of FFA1 by LCFA and presumably FFA3 by SCFA increased DBS via GLP‐2 release, whereas FFA2 activation stimulated DBS via muscarinic and 5‐HT₄ receptor activation. SCFA/HCO₃⁻ exchange also appears to be present in the duodenum. The presence of duodenal fatty acid sensing receptors that signal hormone release and possibly signal neural activation may be implicated in the pathogenesis of functional dyspepsia.