uroguanylin and Irritable-Bowel-Syndrome

The uroguanylin system is a newly discovered endocrine/paracrine system that may have a role in the regulation of salt balance, appetite and gut health. The precursor pro-uroguanylin is predominantly synthesized in the gut, although there may be other sites of synthesis, including the kidney tubules. Products from pro-uroguanylin may mediate natriuresis following oral consumption of a salt load through both GC-C (guanylate cyclase C)-dependent and -independent mechanisms, and recent evidence suggests a role in appetite regulation. Local paracrine effects in the gut through GC-C stimulation may have tumour-suppressing actions through the regulation of cell proliferation and metabolism. Although most information on this system has been derived from knockout models, recent human studies have indicated possible roles in heart failure and renal failure. An improved understanding of the nature of its natriuretic, appetite and tumour-suppressing actions may facilitate the discovery of new therapies for heart failure, obesity and cancer prophylaxis.

Topics: Amino Acid Sequence; Appetite Regulation; Colonic Neoplasms; Endocrine System; Heart Failure; Humans; Hypertension; Intestinal Mucosa; Irritable Bowel Syndrome; Kidney; Models, Biological; Molecular Sequence Data; Natriuretic Peptides; Paracrine Communication; Receptors, Guanylate Cyclase-Coupled; Signal Transduction; Species Specificity

Linaclotide is a minimally absorbed agonist of guanylate cyclase-C (GUCY2C or GC-C) that reduces symptoms associated with irritable bowel syndrome with constipation (IBS-C). Little is known about the mechanism by which linaclotide reduces abdominal pain in patients with IBS-C.. We determined the effects of linaclotide on colonic sensory afferents in healthy mice and those with chronic visceral hypersensitivity. We assessed pain transmission by measuring activation of dorsal horn neurons in the spinal cord in response to noxious colorectal distention. Levels of Gucy2c messenger RNA were measured in tissues from mice using quantitative reverse transcription polymerase chain reaction and in situ hybridization. We used human intestinal cell lines to measure release of cyclic guanosine-3',5'-monophosphate (cGMP) by linaclotide. We performed a post-hoc analysis of data from a phase III, double-blind, parallel-group study in which 805 patients with IBS-C were randomly assigned to groups given an oral placebo or 290 μg linaclotide once daily for 26 weeks. We quantified changes in IBS-C symptoms, including abdominal pain.. In mice, linaclotide inhibited colonic nociceptors with greater efficacy during chronic visceral hypersensitivity. Intra-colonic administration of linaclotide reduced signaling of noxious colorectal distention to the spinal cord. The colonic mucosa, but not neurons, was found to express linaclotide's target, GC-C. The downstream effector of GC-C, cGMP, was released after administration of linaclotide and also inhibited nociceptors. The effects of linaclotide were lost in Gucy2c(-/-) mice and prevented by inhibiting cGMP transporters or removing the mucosa. During 26 weeks of linaclotide administration, a significantly greater percentage of patients (70%) had at least a 30% reduction in abdominal pain compared with patients given placebo (50%).. We have identified an analgesic mechanism of linaclotide: it activates GC-C expressed on mucosal epithelial cells, resulting in the production and release of cGMP. This extracellular cGMP acts on and inhibits nociceptors, thereby reducing nociception. We also found that linaclotide reduces chronic abdominal pain in patients with IBS-C.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Animals; Caco-2 Cells; Cell Line; Colon; Cyclic GMP; Disease Models, Animal; Double-Blind Method; Female; Guanylate Cyclase; Humans; Irritable Bowel Syndrome; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Natriuretic Peptides; Nociceptors; Peptides; Receptors, Atrial Natriuretic Factor; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Treatment Outcome; Trinitrobenzenesulfonic Acid

Prouroguanylin (ProUGN) in the intestine is cleaved to form uroguanylin (UGN), which stimulates guanylate cyclase C (GUCY2C), inducing cyclic guanosine monophosphate signaling. Paracrine release regulates fluid secretion, contributing to bowel function, whereas endocrine secretion evoked by eating forms a gut-brain axis, controlling appetite. Whereas hormone insufficiency contributes to hyperphagia in obesity, its contribution to the pathophysiology of constipation syndromes remains unexplored. Here, we compared circulating ProUGN and UGN in healthy subjects and in patients with chronic idiopathic constipation (CIC) and patients with irritable bowel syndrome with constipation (IBS-C).. Circulating ProUGN and UGN levels were measured in 60 healthy subjects, 53 patients with CIC, and 54 patients with IBS-C. After an overnight fast, the participants ingested a standardized meal; blood samples were drawn at fasting and at 30, 60, and 90 minutes thereafter, and hormone levels were quantified by enzyme-linked immunosorbent assay.. Fasting ProUGN levels were >30% lower in patients with CIC and those with IBS-C compared with healthy subjects regardless of age, sex, or disease state. After eating, ProUGN levels increased compared with fasting levels, although the rate of change was slower and maximum levels were lower in patients with CIC and those with IBS-C. Similarly, fasting UGN levels were lower in patients with CIC and those with IBS-C compared with healthy subjects. However, unlike ProUGN levels, UGN levels did not increase after eating.. These observations support a novel pathophysiologic model in which CIC and IBS-C reflect a contribution of ProUGN insufficiency dysregulating intestinal fluid and electrolyte secretion.. This study suggests that CIC and IBS-C can be treated by oral GUCY2C hormone replacement. Indeed, these observations provide a mechanistic framework for the clinical utility of oral GUCY2C ligands like plecanatide (Trulance) and linaclotide (Linzess) to treat CIC and IBS-C.

Topics: Adult; Case-Control Studies; Constipation; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Guanylyl Cyclase C Agonists; Humans; Irritable Bowel Syndrome; Male; Middle Aged; Natriuretic Peptides; Nucleotides, Cyclic; Peptides; Protein Precursors; Receptors, Atrial Natriuretic Factor

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation, and intestinal dysfunction. Durable expression of GUCY2C, guanylin, and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess; Trulance) to prevent and treat RIGS in cancer therapy and nuclear disasters.

Topics: Animals; Apoptosis; Cell Proliferation; Colonic Neoplasms; Female; Gamma Rays; Gastrointestinal Hormones; Gastrointestinal Tract; Humans; Irritable Bowel Syndrome; Lymphoma; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Natriuretic Peptides; Paracrine Communication; Radiation Injuries, Experimental; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Signal Transduction; Tumor Cells, Cultured