Society: AGA

Introduction: Patients with upper gastrointestinal (UGI) symptoms of abdominal pain, nausea, vomiting, and bloating often complain within the postprandial period. These symptoms overlap in gastroparesis (GP) and functional dyspepsia (FD), with the only distinction of gastric emptying delay being the main facet in clinical evaluation that separates the two entities. The small bowel postprandial response, an increase in contractile activity following meal intake, is known to be blunted in GP compared to healthy volunteers (HV) as measured by wireless motility capsule (WMC). This neuro-mediated reflex has not been evaluated in those with FD. The primary aim of the study was to assess the small bowel postprandial response in FD compared to GP and HV.
Methods: WMC data of HV and subjects with UGI symptoms suggestive of GP from prior clinical trials were analyzed. A gastric emptying time (GET) cut-off of 5 hours was used to classify symptomatic subjects as GP or FD. All subjects ingested a 250 cc standardized Ensure® meal after a 6-hour fast post-WMC ingestion. Area under the pressure curve (AUC), a measure of both contractile frequency and amplitude, data was extracted from a 20 minutes pre-prandial baseline and three consecutive 20-minute postprandial time periods to allow for granular assessment of contractility during the first 60-minute postprandial period. Comparison of postprandial windows to baseline and comparison of respective windows between subject groups was performed using a paired and unpaired t-tests, respectively. Significance level was defined as p< 0.05.
Key Results: 107 HV, 18 FD and 24 GP subjects were analyzed. All subjects showed a significant postprandial increase in AUC in all periods compared to baseline (p < 0.05). HV showed a robust meal response from meal ingestion to 40 minutes which expectedly decreases from 40 to 60 minutes postprandially (Figure 1). GP had a blunted meal response in all post-prandial time periods compared to HV (Figure 1). FD had a postprandial response pattern distinct from HV and GP, showing some intermediate blunting immediately after the meal but with distinctly increased contractile activity later compared to GP (Figure 1).
Conclusion: FD subjects have small bowel motor component abnormalities during the meal response without delayed gastric emptying. The patterns appear to be intermediate blunting (within the first 20-minutes postprandially) of the small bowel meal response in between a healthy and gastroparetic pattern. These motility abnormalities in the small bowel could be contributing to symptoms in FD or be a consequence of neuro-enteric dysfunction in FD patients.

Figure 1. Comparison of the area under the curve (AUC) of the small bowel pressure profile before and after a standardized meal intake between healthy, functional dyspepsia (FD), and gastroparesis (GP) subjects.

Background and aims: Epigastric pain is one of the major symptoms in patients with functional dyspepsia (FD) that affects up to 16% of the general population. Currently treatment options for epigastric pain in FD are limited. Our previous studies have shown promising effects of auricular vagus nerve stimulation (aVNS) for treating pain in both animal model of gastric hyperalgesia (GH) and patients with FD. Duodenal epithelial barrier impairment and immune activation are believed to play an important role in the pathogenesis of FD. This study aimed to explore analgesic effects and autoimmune mechanisms of aVNS in treating visceral pain in a rodent model of GH.
Methods: GH was induced by the gastric iodoacetamide (IA) treatment in the neonatal stage. Control rats (n=5) received neonatal vehicle treatment. The IA-treated rats in adulthood were randomized to Sham (no stimulation output, n=10) or aVNS (n=10), 1 hour daily for 10 days using parameters previously shown to suppress visceral pain. Gastric visceromotor reflex to graded gastric distensions (GD) was assessed by electromyogram (EMG). Autonomic functions were assessed by the spectral analysis of heart rate variability (HRV) to derive the low frequency (LF, reflecting mainly sympathetic activity) and high frequency (HF, reflecting vagal activity) components. Duodenal tissues were collected for the assessment of mucosal barrier function by the measurement of transepithelial electrical resistance (TEER) and the measurement of tight junction protein expression using Western blot. Duodenum mast cell activity was accessed by tryptase concentration normalized with tissue weight.
Results: 1) Compared with sham-aVNS, aVNS resulted in a decrease in the EMG response to GD, at 40, 60 and 80mmHg (P<0.01 for all) and mast cell activity accessed by tryptase concentration (10.3±3.6 vs. 14.9±5.0 ug/ml/mg, P=0.05), and an increase in duodenum mucosal integrity assessed by TEER (49.6±14.1 vs. 33.2±13.5 Ω.cm², P=0.03), the expression of duodenal tight junction ligandins occludin by 4.5 fold (P=0.026) and vagal efferent activity (HF: 0.52±0.24 vs. 0.33±0.13, P<0.05; LF/HF: 1.30±1.05 vs. 2.52±1.47, P<0.05) in the IA-treated rats. 2) Moreover, the aVNS-treated GH rats showed values comparable to the normal controls in mast cell activity (10.3±3.6 vs. 10.4±2.9 ug/ml/mg, P=0.94), TEER (49.6±14.1 vs. 50.6±5.5, P=0.87), protein expression of occludin (P=0.36) and vagal activity (HF: 0.52±0.24 vs. 0.58±0.17, P=0.62; LF/HF: 1.30±1.05 vs. 0.89±0.73, P=0.41), suggesting normalization of these activities/functions.
Conclusion: aVNS ameliorates gastric hypersensitivity by improving duodenal barrier function and structure possibly mediated via the autoimmune mechanisms.

Introduction:
Female gender has been shown to be a risk factor for gastroparesis, functional dyspepsia, and GERD. There was evidence that estrogen and progesterone can contribute to delayed gastric emptying. However, it is unclear if oral contraceptives (OCP) and hormone replacement therapy (HRT) would increase the risks of gastroparesis (GP) and functional dyspepsia (FD). The aim of the study was to evaluate the risks of developing common upper gastrointestinal disorders in patients who were on OCP and HRT.

Material and Methods:
A population based cohort analysis was performed using TriNetX. We selected adult female patients who were taking oral contraceptives. We also selected female patients aged 50 and above who were on HRT. The control group consists of adult female patients who received intrauterine device (IUD) for birth control. Propensity score matching was performed to adjust for age, race, ethnicity, diabetes, BMI and hemoglobin A1C. We compared the incidence of GP, FD, gastroesophageal reflux disease (GERD), Barrett’s esophagus (BE), esophagitis in OCP cohort with IUD cohort. Similar comparison was performed for HRT cohort and IUD cohort.

Results:
We identified a total of 3,065,444 patients who were taking OCPs, 240,420 patients who were on HRT, and 513,883 patients who received IUD insertion. Patients who were on OCPs were at higher risks for developing GP (OR 1.37-1.64), FD (OR 1.11-1.23), GERD (OR 1.15-1.20), BE (1.03-1.40), and esophagitis (OR 1.03-1.15) than patients who received IUD insertion. Similarly, patients who received HRT were also at higher risks for developing GP (OR 1.64-2.60), FD (OR 1.40-1.83), GERD (OR 1.65-1.86), BE (1.17-2.05), and esophagitis (OR 1.55-2.03) than patients who received IUD insertion.

Conclusions:
Oral contraceptives and hormone replacement therapy are associated with higher risks of developing upper gastrointestinal disorders than patients who received IUD insertion. Further research would be necessitated to determine the role of estrogen and progesterone on the upper gastrointestinal tract.

Table 1 Upper gastrointestinal disorders in patientson OCP and HRT

Table 1 Upper gastrointestinal disorders in patientson OCP and HRT

Background
Gastric emptying testing (GET) is used to assess gastric motility, however is non-specific and insensitive for neuromuscular disorders. Gastric Alimetry® is a new medical device combining non-invasive gastric electrophysiological mapping and validated symptom profiling. This study assessed patient-specific phenotyping using Gastric Alimetry with comparison to GET.
Methods
Patients with chronic gastroduodenal symptoms underwent simultaneous GET and Gastric Alimetry. Tests comprised a 30-minute baseline, 99mTC-labelled egg meal, and 4-hour postprandial recording. Results were referenced to normative ranges. Symptoms were profiled in the validated Gastric Alimetry App, phenotyped with rule-based criteria, and compared to questionnaires. Three symptom profiles were phenotyped: i) continuous (symptoms do not correlate with meal or gastric activity); ii) gastric sensorimotor (symptoms increase within 30 minutes of the meal and decay as gastric activity decreases); and iii) Other (symptoms that do not fit the other two symptom profiles).
Results
75 patients with chronic gastroduodenal symptoms were assessed; 77% female, median age 43, median BMI 24.0. Motility abnormality detection rates (Figure 1A) were: GET 22.7% (14 delayed, 3 rapid); Gastric Alimetry spectral analysis 33.3% (14 dysrhythmic / low amplitude; 5 high amplitude; 6 abnormal frequency); combined yield 42.7%. All groups showed similar symptom profiles and did not correlate with specific Rome criteria or health psychology (p>0.05). Gastric Alimetry symptom phenotypes (Figure 1A) were: gastric sensorimotor 17%; continuous 30%; other 53%. The sensorimotor phenotype correlated strongly with gastric amplitude (median r=0.61 vs r=0.08 and r=0.06 respectively; p=0.0002). Only the continuous phenotype correlated with depression and anxiety (p<0.05), while Rome IV Criteria did not correlate (p>0.05). Delayed emptying was not predictive of specific Gastric Alimetry phenotypes (Figure 1B).
Conclusion
Gastric Alimetry generated a higher yield for motility abnormalities than GET in patients with chronic gastroduodenal symptoms. Gastric Alimetry also identified patient-specific symptom phenotypes, showing correlations with health psychology variables not observed with Rome IV and GET. GET and Gastric Alimetry assess different aspects of gastric function, indicating these tests may have complementary roles.

Background: Gastric sensorimotor disorders are prevalent. Gastric emptying tests, either scintigraphy or a breath test, provide only a brief “snapshot” of gastric myoelectrical activity, and no information on small bowel or colon myoelectrical activity. Prolonged ambulatory recording may provide novel information in patients with symptoms of functional dyspepsia (FD), nausea, vomiting and gastroparesis.
Methods: Consecutive adult patients (age >18 years) referred to the nuclear medicine department at Mayo Clinic Jacksonville for a 4-hour, solid phase, scintigraphic gastric emptying scan were eligible for study inclusion. Patients were excluded if they: had prior foregut surgery; surgery to the GI tract within the last 60 days; were on opioids or other medications known to affect gastric emptying; had a HgbA1C > 10; or were recently hospitalized for complications of diabetes mellitus. Demographics were obtained. 3 wireless motility patches were applied to the skin prior to scintigraphy. After the gastric emptying scan was complete, patients wore the patches for 6 days while recording meals and bowel movements (rated “satisfactory” or “unsatisfactory”) using an iPhone app. Patients were asked to consume three meals per day without in-between meal snacks.
Results: 23 adults (87% women; mean age = 43.9 yrs.; mean BMI = 26.7 kg/m²) were enrolled. Data from 1 patient were not available due to accidentally stopping the iPhone app. Mean recording time was 4.8 days across subjects. A gastric histogram revealed 3 types of gastric myoelectric activity: weak, moderate, and strong (see figure 1a). Patients with FD (n=4) had lower gastric and intestinal myoelectric activity; those with nausea and vomiting (n=7) had higher intestinal activity (see figure 1b). Those with delayed gastric emptying (% emptying >75%) at 4 hours also had lower gastric myoelectrical activity. Patients with FD had reduced meal response in the stomach, intestine and colon compared to those with nausea alone or vomiting alone (see figure 1c). A trend towards lower nighttime to daytime colonic activity ratio was observed in patients with predominant “unsatisfactory” bowel movements (see figure 1d). One patient reported a rash around one of the patches which quickly resolved with topical hydrocortisone cream.
Conclusions: An ambulatory wireless motility patch system is well tolerated, safe and demonstrates novel information on gastrointestinal myoelectrical activity. Patients with FD, and those with delayed gastric emptying, had unique patterns. Reduced postprandial pan-intestinal myoelectric activity may explain symptoms of FD in some patients. Recording gastrointestinal activity over a prolonged period in the outpatient setting has the potential to identify unique pathophysiologic patterns and meal related activity that distinguishes patients with distinct gastric sensorimotor disease states.

Figure 1A Histogram showing the distribution of gastric activity reveals 3 types of gastric activity: weak, moderate, and strong. B. Plot of total gastric, intestine and colon activity across diagnosis groups shows patients with functional dyspepsia had lower gastric and intestine activity while patients with nausea & vomiting had higher intestinal activity. C Plot of postprandial activity for the 17 patients that had recorded meals shows patients with functional dyspepsia had lower meal response across all organs. D. Plot for recorded bowel movement activity shows a trend towards lower nighttime to daytime colonic activity ratio in patients with predominant “unsatisfactory” bowel movements.

Figure 1A Histogram showing the distribution of gastric activity reveals 3 types of gastric activity: weak, moderate, and strong. B. Plot of total gastric, intestine and colon activity across diagnosis groups shows patients with functional dyspepsia had lower gastric and intestine activity while patients with nausea & vomiting had higher intestinal activity. C Plot of postprandial activity for the 17 patients that had recorded meals shows patients with functional dyspepsia had lower meal response across all organs. D. Plot for recorded bowel movement activity shows a trend towards lower nighttime to daytime colonic activity ratio in patients with predominant “unsatisfactory” bowel movements.

Introduction
Chronic gastroduodenal symptoms are common but management can be challenging due to non-specific symptom labels and tests. High resolution body surface gastric mapping, Gastric Alimetry (GA), is a new test of gastric neuromuscular function which is correlated to symptoms via a validated App. GA subgroups patients with neuromuscular dysfunction and symptom profiling aids symptom origin.¹ Reference ranges guide interpretation.² The aims of this study were to: i) propose a framework for implementation of GA in the management of chronic gastroduodenal disorders; and ii) assess the impact of this framework in a consecutive case series.
Methods
The framework integrated GA, Gastric Emptying Tests (GET) and existing management guidelines (Figure 1A). This was applied with reference to individual patient histories, clinical work-up and comorbidities, while accepting that phenotypes may overlap. 50 consecutive patients were examined at two New Zealand specialist motility centers. All patients underwent standardised GA testing (30 minute fasted baseline followed by a 480kCal meal and 4 hour post prandial recording with symptom logging). Positive impacts in management were defined by an independent assessor as a new diagnosis or altered management (medication, endoscopic intervention, feeding).
Results
Within the sample 90% were female, median age 30 years, predominant symptoms of nausea/vomiting 72%. 70% had previous GET. Primary diagnoses prior to GA were gastroparesis/other dysmotility in 46%, or disorder of gut-brain interaction (CNVS/FD) in 54%. GA aided management in 78%. 40% of patients changed primary diagnosis, typically being a switch from a primary motility disorder to a primary DBGI/sensory disorder of vice-versa, or to a small bowel phenotype, as based on GA analysis (Figure 1B).¹ Therapeutic changes favoured neuromodulators in 36%, prokinetics in 28%, with 2 patients receiving pyloric interventions, and other medications in 14%. Of 9 patients on invasive nutrition prior to evaluation, 5 were successfully weaned from PN, and 3 from enteral feeding, after diagnosis and medication changes facilitated tolerance of oral diet. Conversely, nasojejunal feeding was initiated in one patient with a new diagnosis of a neuromuscular disorder.
Conclusions
This real-world data reports the introduction of GA into clinical care pathways and shows GA can inform management decisions in a majority of patients with gastroduodenal disorders. The most significant changes were altered diagnosis from neuromuscular dysfunction to DGBI or vice-versa, justified by the specificity of GA spectral analysis vs gastric emptying.¹ Prospective studies showing additional patient outcome data are now a priority.
Gharibans AA et al. Sci Transl Med. 2022;14(663):eabq3544.
Varghese C, et al. Am J Gastroenterol; In Press; doi:10.1101/2022.07.25.22278036

Chris Cederwall

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