Novel role of zonulin in the pathophysiology of gastro-duodenal transit: a clinical and translational study

We examined the relationship between zonulin and gastric motility in critical care patients and a translational mouse model of systemic inflammation. Gastric motility and haptoglobin (HP) 2 isoform quantification, proxy for zonulin, were examined in patients. Inflammation was triggered by lipopolysaccharide (LPS) injection in C57Bl/6 zonulin transgenic mouse (Ztm) and wildtype (WT) mice as controls, and gastro-duodenal transit was examined by fluorescein-isothiocyanate, 6 and 12 h after LPS-injection. Serum cytokines and zonulin protein levels, and zonulin gastric-duodenal mRNA expression were examined. Eight of 20 patients [14 years, IQR (12.25, 18)] developed gastric dysmotility and were HP2 isoform-producing. HP2 correlated with gastric dysmotility (r = − 0.51, CI − 0.81 to 0.003, p = 0.048). LPS injection induced a time-dependent increase in IL-6 and KC-Gro levels in all mice (p < 0.0001). Gastric dysmotility was reduced similarly in Ztm and WT mice in a time-dependent manner. Ztm had 16% faster duodenal motility than WT mice 6H post-LPS, p = 0.01. Zonulin mRNA expression by delta cycle threshold (dCT) was higher in the stomach (9.7, SD 1.4) than the duodenum (13.9, SD 1.4) 6H post-LPS, p = 0.04. Serum zonulin protein levels were higher in LPS-injected mice compared to vehicle-injected animals in a time-dependent manner. Zonulin correlated with gastric dysmotility in patients. A mouse model had time-dependent gastro-duodenal dysmotility after LPS-injection that paralleled zonulin mRNA expression and protein levels.

Gastric peroral endoscopic pyloromyotomy for decompensated gastroparesis: comprehensive motility analysis in relation to treatment outcomes

Background and study aims There are no reliable data to predict which patients with gastroparesis (GP) would benefit the most from gastric peroral endoscopic pyloromyotomy (G-POEM). The aim of the present study was to assess whether antro-duodenal motility patterns and pyloric distensibility can predict the outcome of G-POEM in patients with decompensated GP. Patients and methods In an open-label study, patients with GP and refractory symptoms were eligible for treatment with G-POEM if treatment attempts according to a standardized stepwise protocol had failed. Baseline assessment included Gastroparesis Cardinal Symptom Index (GCSI), C13-octanoic gastric emptying breath test and high-resolution antro-duodenal manometry. Pyloric distensibility using EndoFlip measurements was assessed at baseline and 3 months after the procedure. Explorative analyses were performed on potential predictors of response using logistic regression analyses. Results Twenty-four patients with decompensated GP underwent G-POEM. At baseline, 78.3 % and 61.9 % of patients showed antral hypomotility and neuropathic motor patterns, respectively. The technical success rate was 100 % (24/24). Mean GCSI improved significantly at 3, 6, and 12 months after G-POEM (P = 0.01). Median distensibility index (DI) improved significantly as compared with baseline (7.5 [6.9;11.7] vs. 5.3[3.1;8.1], P = 0.004). A significant correlation was found between clinical response at 6 months and pyloric DI improvement (P = 0.003). No potential predictors of clinical response after G-POEM could be identified in an explorative analysis. Conclusions G-POEM improved pyloric distensibility patterns in patients with decompensated GP. Clinical response at 6 months after G-POEM was associated with pyloric distensibility improvement. However, no potential predictors of response could be identified from either antro-duodenal motility patterns or pyloric distensibility.

Stomach Region Stimulated Determines Effects on Duodenal Motility in Rats

Gastric electrical stimulation (GES) is used clinically to promote proximal GI emptying and motility. In acute experiments, we measured duodenal motor responses elicited by GES applied at 141 randomly chosen electrode sites on the stomach serosal surface. Overnight-fasted (H2O available) anesthetized male rats (n = 81) received intermittent biphasic GES for 5 min (20s-on/40s-off cycles; I = 0.3mA; pw = 0.2ms; 10 Hz). A strain gauge on the serosal surface of the proximal duodenum of each animal was used to evaluate baseline motor activity and the effect of GES. Using ratios of time blocks compared to a 15-min pre-stimulation baseline, we evaluated the effects of the 5-min stimulation on concurrent activity; on the 10-min immediately after the stimulation, and on the 15-min period beginning with the onset of stimulation. We mapped the magnitude of the duodenal response (3 different motility indices) elicited from the 141 stomach sites. Post hoc electrode site maps associated with duodenal responses suggested three zones similar to the classic regions of forestomach, corpus and antrum. Maximal excitatory duodenal motor responses were elicited from forestomach sites, whereas inhibitory responses occurred with stimulation of the corpus. Moderate excitatory duodenal responses occurred with stimulation of the antrum. Complex, weak inhibitory/excitatory responses were produced by stimulation at boundaries between stomach regions. Patterns of GES efficacies coincided with distributions of previously mapped vagal afferents, suggesting that excitation of the duodenum is strongest when GES electrodes are situated over stomach concentrations of vagal intramuscular arrays, putative stretch receptors in the muscle wall.

Assessment of abdominal organ motion using cine magnetic resonance imaging in different gastric motilities: a comparison between fasting and postprandial states

This study assessed abdominal organ motion induced by gastroduodenal motilities in volunteers during fasting and postprandial states, using cine magnetic resonance imaging (cine-MRI). Thirty-five volunteers underwent cine-MRI while holding their breath in the fasting and postprandial states. Gastric motility was quantified by the amplitude and velocity of antral peristaltic waves. Duodenal motility was evaluated as the change of duodenal diameter. Abdominal organ motion was measured in the liver, pancreas and kidneys. Motion was quantified by calculating maximal organ displacement in the left–right, antero–posterior and caudal–cranial directions. Median antral amplitude and velocity in the fasting and postprandial states were 7.7 and 15.1 mm (P &lt; 0.01), and 1.3 and 2.5 mm/s (P &lt; 0.01), respectively. Duodenal motility did not change. Median displacement for all organs ranged from 0.9 to 2.9 mm in the fasting state and from 1.0 to 2.9 mm in the postprandial state. Significant increases in abdominal organ displacement in the postprandial state were observed in the right lobe of the liver, pancreatic head and both kidneys. Differences in the median displacement of these organs between the two states were all &lt;1 mm. Although the motion of several abdominal organs increased in the postprandial state, the difference between the two states was quite small. Thus, our study suggests that treatment planning and irradiation need not include strict management of gastric conditions, nor the addition of excess margins to compensate for differences in the intra-fractional abdominal organ motion under different gastric motilities in the fasting and postprandial states.

The human duodenal mucosa harbors all components for a local renin angiotensin system

The renin-angiotensin system (RAS) is present in the gastrointestinal (GI) tract but remains to be fully characterized, particularly in man. The duodenum plays a role in both the upper and lower GI regulation, as well as in distant organs. The present study investigates the presence and functional potential of RAS in the human duodenal mucosa of healthy individuals. Endoscopically acquired mucosal biopsies from healthy volunteers were examined using western blot, immunohistochemistry, and ELISA. Functionality was examined by using Ussing chambers and recording duodenal transmucosal potential difference (PD) and motility in vivo. Angiotensinogen, Angiotensin II (AngII) and its receptors (AT1R, AT2R) as well as to the RAS associated enzymes renin, ACE, and neprylisin were detected in all samples of duodenal mucosa. Migrating motility complex induced elevations of transmucosal PD were significantly larger after per-oral administration of the AT1R receptor antagonist candesartan. Fasting duodenal motility per se was not influenced by candesartan. The epithelial current produced by duodenal mucosae mounted in Ussing chambers increased significantly after addition of AngII to specimens where the AT1R was blocked using losartan. The epithelial current also increased after addition of the AT2R-selective agonist C21. Immunostaining and pharmacological data demonstrate the presence of a local RAS in the human duodenal mucosa with capacity to influence epithelial ion transport by way of particulary the AT2R.