guanylin and Inflammatory-Bowel-Diseases

Guanylate cyclase C (GC-C) receptor is a transmembrane receptor, predominantly expressed in intestinal epithelial cells, which is considered to play a main role in homeostasis and function of the digestive tract. The endogenous ligands for this receptor are the paracrine hormones uroguanylin and guanylin. Upon ligand binding, GC-C receptors increase cyclic guanosine monophosphate (cGMP) levels, regulating a variety of key cell-type specific processes such as chloride and bicarbonate secretion, epithelial cell growth, regulation of intestinal barrier integrity and visceral sensitivity. It has been suggested that GC-C acts as an intestinal tumor suppressor with the potential to prevent the initiation and progression of colorectal cancer. In fact, loss of ligand expression is a universal step in sporadic colorectal carcinogenesis. Interestingly, the role of GC-C is not limited to the digestive tract but it has been extended to several other systems such as the cardiovascular system, kidney, and the central nervous system, where it has been involved in a gut-hypothalamus endocrine axis regulating appetite. Objetive: In this review we summarize the physiology of the GC-C receptor and its ligands, focusing on newly developed drugs like linaclotide, and their suggested role to reverse/prevent the diseases in which the receptor is involved.. Available data points toward a relationship between uroguanylin and guanylin and their receptor and pathological processes like gastrointestinal and renal disorders, colorectal cancer, obesity, metabolic syndrome and mental disorders among others. Recent pharmacological developments in the regulation of GC-receptor may involve further improvements in the treatment of relevant diseases.

Topics: Animals; Colorectal Neoplasms; Cyclic GMP; Gastrointestinal Hormones; Guanylate Cyclase; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Kidney Diseases; Natriuretic Peptides; Obesity; Protein Binding; Protein Transport; Receptors, Peptide; Signal Transduction

Functional gastrointestinal disorders (FGID) and inflammatory bowel diseases (IBD) are the most frequent pathologic conditions affecting the gastrointestinal (GI) tract and both significantly reduce patients' quality of life. Recent studies suggest that guanylyl cyclase C (GC-C) expressed in the GI tract constitutes a novel pharmacological target in the treatment of FGID and IBD. Endogenous GC-C agonists - guanylin peptides: guanylin and uroguanylin, by the regulation of water and electrolyte transport, are involved in the maintenance of homeostasis in the intestines and integrity of the intestinal mucosa. Linaclotide, a synthetic agonist of GC-C was approved by Food and Drug Administration and European Medicines Agency as a therapeutic in constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC). Lately, several preclinical and clinical trials focused on assessment of therapeutic properties of synthetic agonists of uroguanylin, plecanatide, and SP-333. Plecanatide is currently tested as a potential therapeutic in diseases related to constipation and SP-333 is a promising drug in ulcerative colitis treatment.. Here, we discuss the most recent findings and future trends on the development of GC-C agonists and their use in clinical trials.

Topics: Clinical Trials as Topic; Constipation; Female; Gastroenterology; Gastrointestinal Diseases; Gastrointestinal Hormones; Humans; Inflammatory Bowel Diseases; Male; Natriuretic Peptides; Peptides; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Signal Transduction

Guanylin is a recently discovered peptide hormone that activates intestinal guanylate cyclase (GC-C) and thereby stimulates intestinal chloride secretion. Immunohistochemistry showed its presence in enterochromaffin (EC) cells of the gut. In vitro studies suggested that guanylin plays an important role in the endogenous modulation of intestinal salt and water secretion. In the present study the concentration of circulating immunoreactive (IR)-guanylin in plasma of patients with intestinal diarrhoea due to chronic bowel inflammation and patients with carcinoid tumours were measured with a specific radioimmunoassay. In 22 patients with Crohn's disease and eight patients with ulcerative colitis, plasma concentrations of IR-guanylin were 44 +/- 3 and 42 +/- 4 fmol mL-1, respectively. Levels were not different from that in 44 healthy volunteers suggesting that the circulating hormone is not involved in diarrhoea of these patients. In 17 patients with symptomatic carcinoid tumors the median concentration of circulating IR-guanylin was significantly enhanced (94 +/- 16 fmol mL-1, range 37-312 fmol mL-1). Immunohistochemistry revealed the presence of immunoreactive guanylin in carcinoid tissues, suggesting that these tumours co-release guanylin along with their usual resident hormone, serotonin. Enhanced local secretion of guanylin may play a causal role in diarrhoea of these patients and its elevation in plasma may be of diagnostic value in this type of endocrine tumours.

Topics: Adult; Aged; Carcinoid Tumor; Diarrhea; Digestive System Neoplasms; Female; Gastrointestinal Hormones; Humans; Immunohistochemistry; Inflammatory Bowel Diseases; Male; Middle Aged; Natriuretic Peptides; Peptides; Radioimmunoassay