Blunted Evoked Prouroguanylin Endocrine Secretion in Chronic Constipation

Area of Science:

• Gastroenterology
• Endocrinology
• Molecular Biology

Background:

• Prouroguanylin (ProUGN) is cleaved to uroguanylin (UGN), stimulating guanylate cyclase C (GUCY2C) and cyclic guanosine monophosphate signaling.
• UGN regulates intestinal fluid secretion and appetite via gut-brain axis.
• UGN insufficiency is linked to hyperphagia in obesity, but its role in constipation is unknown.

Purpose of the Study:

• To investigate circulating ProUGN and UGN levels in healthy individuals, patients with chronic idiopathic constipation (CIC), and patients with irritable bowel syndrome with constipation (IBS-C).
• To explore the potential contribution of ProUGN insufficiency to the pathophysiology of constipation syndromes.

Main Methods:

• Measured fasting and postprandial (30, 60, 90 min) circulating ProUGN and UGN levels in 60 healthy subjects, 53 CIC patients, and 54 IBS-C patients using enzyme-linked immunosorbent assay.
• Participants consumed a standardized meal after an overnight fast.

Main Results:

• Fasting ProUGN levels were over 30% lower in CIC and IBS-C patients compared to healthy subjects.
• Postprandial ProUGN levels increased in all groups but showed a slower rate of change and lower maximum levels in CIC and IBS-C patients.
• Fasting UGN levels were also lower in CIC and IBS-C patients, and UGN levels did not increase postprandially in these patients.

Conclusions:

• Reduced circulating ProUGN and UGN levels in CIC and IBS-C patients suggest ProUGN insufficiency contributes to altered intestinal fluid and electrolyte secretion.
• These findings support a novel pathophysiological model for CIC and IBS-C.
• This provides a mechanistic basis for the efficacy of oral GUCY2C agonists in treating CIC and IBS-C.