Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Synergy Pharmaceuticals, New York City, New York, USA.
Clin Transl Gastroenterol. 2019 Jul;10(7):e00016. doi: 10.14309/ctg.0000000000000016.
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.
肠道中的促尿钠排泄肽（ProUGN）被切割形成尿鸟苷素（UGN），后者刺激鸟苷酸环化酶 C（GUCY2C），诱导环鸟苷酸单磷酸信号转导。旁分泌释放调节液体分泌，有助于肠道功能，而进食引起的内分泌释放形成肠-脑轴，控制食欲。虽然激素不足会导致肥胖症患者摄食过多，但它对便秘综合征病理生理学的贡献仍未得到探索。在这里，我们比较了健康受试者、慢性特发性便秘（CIC）患者和便秘型肠易激综合征（IBS-C）患者的循环 ProUGN 和 UGN。
测量了 60 名健康受试者、53 名 CIC 患者和 54 名 IBS-C 患者的循环 ProUGN 和 UGN 水平。禁食一夜后，参与者摄入标准化餐；在禁食和此后 30、60 和 90 分钟时抽取血液样本，并通过酶联免疫吸附试验定量激素水平。
无论年龄、性别或疾病状态如何，CIC 患者和 IBS-C 患者的空腹 ProUGN 水平均低于健康受试者，高出>30%。进食后，ProUGN 水平与空腹水平相比有所增加，尽管 CIC 患者和 IBS-C 患者的变化速度较慢，最大水平较低。同样，CIC 患者和 IBS-C 患者的空腹 UGN 水平低于健康受试者。然而，与 ProUGN 水平不同，UGN 水平在进食后不会增加。
这些观察结果支持一种新的病理生理模型，其中 CIC 和 IBS-C 反映了 ProUGN 不足对肠道液体和电解质分泌的调节紊乱。
该研究表明，CIC 和 IBS-C 可以通过口服 GUCY2C 激素替代治疗。事实上，这些观察结果为口服 GUCY2C 配体（如 plecanatide（Trulance）和 linaclotide（Linzess））治疗 CIC 和 IBS-C 的临床应用提供了一个机制框架。
