Linaclotide increases cecal pH, accelerates colonic transit, and increases colonic motility in irritable bowel syndrome with constipation.

BACKGROUND: Linaclotide is efficacious in the management of irritable bowel syndrome with constipation (IBS-C), yet relatively little is known regarding its effect on human gastrointestinal physiology. The primary aim of the study was to examine the effect of linaclotide on change in pH across the ileocecal junction (ICJ), a proposed measure of cecal fermentation, and its relationship to symptoms and quality of life (QoL) in IBS-C. METHODS: A total of 13 participants with Rome III IBS-C underwent a standardized wireless motility capsule (WMC). Stool consistency was measured using the Bristol stool form scale (BSFS) and frequency with spontaneous bowel movements (SBM). Gastrointestinal symptoms and QoL were assessed using validated questionnaires. The WMC and questionnaires were repeated after 28 days of linaclotide 290 g po od. KEY RESULTS: Linaclotide reduced the change in pH across the ICJ (-2.4 ± 0.2 vs -2.1 ± 0.4, P = 0.01) as a function of a relative alkalinization of the cecum (5.2 ± 0.2 vs 5.5 ± 0.3, P = 0.02). Linaclotide accelerated colonic transit time (2650 minutes (2171-4038) vs. 1757 (112-3011), P = 0.02), increased colonic log motility index (15 ± 1.8 vs. 16.5 ± 1.8, P = 0.004) but had no effect of gastric emptying or small bowel transit. Change in pH across the ICJ correlated with improvement in symptom intensity, unpleasantness, and visceral sensitivity index (r = 0.62, P = 0.03, r = 0.63, P = 0.02, r = 0.62, P = 0.02) and with increases in BSFS type and SBM (r = 0.9, P < 0.0001, r = 0.6, P = 0.02). CONCLUSIONS & INFERENCES: Linaclotide's effects are confined to the colon where it increases cecal pH, potentially representing a reduction in cecal fermentation and accelerates colonic motility.

[Distribution and localization of nitric oxide containing neural elements in the digestive tract]. / Nitrogén-monoxid-tartalmú idegelemek megoszlása és lokalizációja a tápcsatornában.

Nitric oxide free radical is a presumed neurotransmitter of the gastrointestinal tract. It can play an important role in the relaxation of the smooth muscles. We used nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and the localization and morphology of the NADPH-d positive neural elements of the different areas were compared in the cat. NADPH-d positive neurons could be found mainly in the myenteric plexus but some of them were located in the submucous plexus and in the inner circular muscle layer as well as around the blood vessels. The greatest number of the positive neuronal cell bodies could be seen in the myenteric plexuses of the sphincter regions. Stained nerve fibers were seen mainly in the inner circular muscle layer. These results suggest that the positive neurons of the sphincter regions can have an important role in the relaxation. NADPH-d positive neuronal elements of the submucous plexus were located around blood vessels and can regulate the blood flow and secretion of the glands or it is also possible that they belong to the sensory neurons.

Localization of nitric oxide synthase in canine ileocolonic and pyloric sphincters.

The distribution of neurons containing NAD-PH-diaphorase (NADPH-d) activity and nitric oxide synthase-like immunoreactivity (NOS-LI) in the canine pyloric and ileocolonic sphincters was studied. Cells within the myenteric and submucosal ganglia were positive for NADPH-d. These cells generally had the morphology of Dogiel type-I enteric neurons, however, there was some diversity in the morphology of NADPH-d-positive neurons in the myenteric plexus of the pylorus. Intramuscular ganglia were observed in both sphincters, and NADPH-d was found in a sub-population of neurons within these ganglia. Dual staining with an antiserum raised against nitric oxide synthase (NOS) demonstrated that almost all cells with NOS-LI were also NADPH-d positive. Varicose fibers within ganglia and within the circular and longitudinal muscle layers also possed NOS-LI and NADPH-d activity. Dual staining with anti-VIP antibodies showed that some of the NADPH-d-positive cells in the myenteric and submucosal ganglia also contained VIP-LI, but all VIP-LI-positive cells did not express NADPH-d activity. These data are consistent with recent physiological studies suggesting that nitric oxide serves as an inhibitory neurotransmitter in the pyloric and ileocolonic sphincters. The data also suggest that VIP is expressed in a sub-population of NADPH-d-positive neurons and may therefore act as a co-transmitter in enteric inhibitory neurotransmission to these specialized muscular regions.