Adrenomedullin regulates intestinal physiology and pathophysiology

Abstract

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are 2 biologically active peptides produced by the same gene, ADM, with ubiquitous distribution and many physiological functions. Adrenomedullin is composed of 52 amino acids, has an internal molecular ring composed by 6 amino acids and a disulfide bond, and shares structural similarities with calcitonin gene-related peptide, amylin, and intermedin. The AM receptor consists of a 7-transmembrane domain protein called calcitonin receptor-like receptor in combination with a single transmembrane domain protein known as receptor activity–modifying protein. Using morphologic techniques, it has been shown that AM and PAMP are expressed throughout the gastrointestinal tract, being specially abundant in the neuroendocrine cells of the gastrointestinal mucosa; in the enterochromaffin-like and chief cells of the gastric fundus; and in the submucosa of the duodenum, ileum, and colon. This wide distribution in the gastrointestinal tract suggests that AM and PAMP may act as gut hormones regulating many physiological and pathologic conditions. To date, it has been proven that AM and PAMP act as autocrine/paracrine growth factors in the gastrointestinal epithelium, play key roles in the protection of gastric mucosa from various kinds of injury, and accelerate healing in diseases such as gastric ulcer and inflammatory bowel diseases. In addition, both peptides are potent inhibitors of gastric acid secretion and gastric emptying; they regulate the active transport of sugars in the intestine, regulate water and ion transport in the colon, modulate colonic bowel movements and small-intestine motility, improve endothelial barrier function, and stabilize circulatory function during gastrointestinal inflammation. Furthermore, AM and PAMP are antimicrobial peptides, and they contribute to the mucosal host defense system by regulating gut microbiota. To get a formal demonstration of the effects that endogenous AM and PAMP may have in gut microbiota, we developed an inducible knockout of the ADM gene. Using this model, we have shown, for the first time, that lack of AM/PAMP leads to changes in gut microbiota composition in mice. Further studies are needed to investigate whether this lack of AM/PAMP may have an impact in the development and/or progression of intestinal diseases through their effect on microbiota composition.