Ghrelin, motilin in health and disease

Abstract

Ghrelin is a 28 amino-acid peptide produced predominantly by the stomach. Two main isoforms of ghrelin are currently known (octanoyl- and desoctanoyl ghrelin). It functions as a circulating orexigenic hormone In addition, it has an effect on the nervous, cardiovascular and immune system. Current data suggest that ghrelin may have beneficial anti-inflammatory effects. Chapter 3 in this thesis primarily examines the relationship between ghrelin and inflammation in Crohn’s disease (CD). Modulation of inflammation with infliximab, a powerful anti-TNFα antibody therapy, can increase total ghrelin concentration by 25%. In addition, a normal physiological post-prandial decrease in ghrelin following a meal is restored when infused with infliximab, suggesting a dysregulation of ghrelin in CD patients with active inflammation. At cellular level, there is evidence that ghrelin may have an immunosuppressive effect on activated T-lymphocytes. Chapter 4 of this thesis examines the effect of ghrelin, a manufactured agonist and des-octanoyl ghrelin on NFκB activation on a human Blymphocyte cell line. This study demonstrated that exposure to octanoyl ghrelin confers an initial increase of NFκB activation in inactivated cells of up to 50% which suggests a pro-inflammatory effect. However, NFκB activation appears to decrease at much higher concentrations of octanoyl ghrelin, which may indicate toxicity at supra-physiological levels. Ghrelin is also involved in the regulation of gastric motility and has structural similarities to motilin. Symptoms of delayed gastric emptying can occur long after cancer chemotherapy has ended. Chapter 5 of this thesis compares the contractility and pro-motility neurotransmitter expression in chemotherapy and non-chemotherapy exposed stomach tissues obtained from patients undergoing surgery for oesophagogastric cancers. Chemotherapy exposed tissues have reduced contractility to carbachol and apparent destruction of the cholinergic activity. The tendency for ghrelin receptors to increase suggests an attempt to upregulate compensating systems. In conclusion, ghrelin can be altered by inflammation and may have beneficial effects on gastric motility