OBJECTIVES 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). METHODS 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. RESULTS 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. DISCUSSION 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. TRANSLATIONAL IMPACT 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.

中文翻译：

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慢性便秘中钝性诱发的鸟嘌呤鸟嘌呤内分泌。

目的肠中的鸟嘌呤鸟苷（ProUGN）被裂解形成尿鸟嘌呤（UGN），后者刺激鸟苷酸环化酶C（GUCY2C），诱导环鸟苷单磷酸信号。旁分泌释放调节体液分泌，促进肠功能，而进食引起的内分泌分泌形成肠脑轴，控制食欲。尽管激素不足会导致肥胖症的食欲亢进，但其对便秘综合征病理生理的影响尚待探索。在这里，我们比较了健康受试者以及慢性特发性便秘（CIC）和肠易激惹综合征便秘（IBS-C）患者的循环ProUGN和UGN。方法在60例健康受试者，53例CIC患者和54例IBS-C患者中测量循环ProUGN和UGN水平。一夜禁食后，参与者摄入了标准餐；禁食时以及此后30、60和90分钟抽取血样，并通过酶联免疫吸附测定定量激素水平。结果与健康受试者相比，无论年龄，性别或疾病状况如何，CIC和IBS-C患者的空腹ProUGN水平均降低30％以上。进食后，尽管CIC患者和IBS-C患者的变化速度较慢且最大水平较低，但ProUGN水平较禁食水平有所提高。同样，与健康受试者相比，CIC和IBS-C患者的空腹UGN水平较低。但是，与ProUGN水平不同，进食后UGN水平没有增加。讨论这些观察结果支持一种新型的病理生理模型，其中CIC和IBS-C反映了ProUGN功能不全引起肠道液和电解质分泌失调。翻译影响这项研究表明，口服GUCY2C激素替代可以治疗CIC和IBS-C。实际上，这些观察结果为口服GUCY2C配体（如plecanatide（Trulance）和linaclotide（Linzess））用于治疗CIC和IBS-C的临床实用性提供了一个机制框架。