Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation

Abstract

IntroductionIncreased intestinal hydration by activation of the epithelial enzyme linked receptor guanylate cyclase C (GC-C) is a pharmacological principle for treating constipation. Activating mutations in the GUCY2C gene encoding GC-C cause Familial GUCY2C diarrhea syndrome (FGDS) which has been diagnosed with severe dysmotility.AimTo investigate gut motility and hormones before and after a meal in FGDS patients and compare with healthy controls (HC).Subjects and methodsBristol stool chart and stool frequency was assessed. Before and after a meal occlusive and non-occlusive contractions were obtained using ultrasound. A wireless motility capsule (WMC) recorded gut transit time, pH, contractions and pressure. Plasma levels of selected gut hormones were measured at different time points.ResultsThe FGDS patients had 4 (range 1–10) loose stools/day and prolonged total gut transit time compared to HC, 55.5 h vs 28.5 h, respectively,with significantly increased colon transit time. In FGDS patients, pH in duodenum, small bowel and colon was increased and the number of contractions and the intraluminal pressure were significantly decreased, measured by WMC. Ultrasound showed in small bowel increased number of non-occlusive contractions in the FGDS patients. Serotonin (5-HT) plasma levels in the HC peaked 30 min after the meal, while the FGDS patients had no response.ConclusionDespite having diarrhea, the FGDS patients have prolonged transit time through the gut compared to HC, particularly in colon. The reduced number of intestinal contractions and lack of 5-HT release after a meal in FGDS patients surprisingly resemble colonic motility disturbances seen in patients with constipation.

Guanylate Cyclase C Activation Shapes the Intestinal Microbiota in Patients with Familial Diarrhea and Increased Susceptibility for Crohnʼs Disease

“…211 We have indeed verified that the intestinal lumen is more alkaline in FGDS compared to healthy controls, suggesting another factor linking GC-C activation and the intestinal microbiota. 175,211 Taken together our findings align with mounting evidence in human as well as animal studies indicating that GC-C signalling may serve important host benefits, including the defence against pathogens by regulation of the intestinal microbiota. 212,213 The involvement of GC-C in intestinal immune function has been suggested by studies in Gucy2c knock-out mice, which show increased susceptibility to invasive enteric infections, malignancy and inflammation.…”

“…174,175 Patients with FGDS display increased non-occlusive small bowel contractions and delayed colonic transit. 174,175 Intestinal motility is regulated through a complex and still insufficiently understood crosstalk involving mechanoand chemo-sensors in the gut, the entero-endocrine as well as the autonomic and the enteric nervous system. 193 Supporting that the GC-C pathway interacts with the enteric nervous system, FGDS patients display different circulating levels of the neurotransmitter serotonin than healthy following a meal.…”

“…193 Supporting that the GC-C pathway interacts with the enteric nervous system, FGDS patients display different circulating levels of the neurotransmitter serotonin than healthy following a meal. 175 However the GC-C activating ligands stored in various cell types throughout the gut show little degree of co-localization with serotonin-secreting cells. 194 Intestinal dysmotility has to our knowledge not previously been linked with GUCY2C, and this finding emphasizes the multiple functional impacts of this gene.…”

Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility

“…Moreover, even if the link between the observed transit time delay in zebrafish and congenital diarrhea disease is not obvious, prolonged intestinal transit and diarrhea have been already observed in the familial GUCY2C diarrhea syndrome (FGDS), a rare autosomal-dominant inherited disease. 34 More studies are needed to fully understand the physio pathological basis of the diarrhea in O2HE.…”

The Guanylate Cyclase C—cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia

“…The most apparent role of cGMP signaling in the intestine can be appreciated from human populations harboring mutations in GUCY2C, resulting in hyper- or hypo-secretion syndromes. In the recently described familial GUCY2C diarrhea syndrome (FGDS), a single missense mutation in the catalytic domain of GUCY2C produces hyperactivation of the receptor in response to ligand ( 9 , 59 , 60 ). This rare autosomal dominant disorder (initially reported in 32 members of a Norwegian family) is clinically characterized by loose stools, inflammation resembling irritable bowel disease with diarrhea (IBS-D), a doubling of intestinal transit time, and elevated intestinal pH.…”