Introduction

Diabetes is associated with a variety of gastrointestinal disorders, including altered gastric emptying, which can be rapid, slow, or transient.
These changes can significantly influence gastrointestinal symptoms and potentially impact blood glucose levels. DA-9701 (motilitone), a known prokinetic agent derived from Corydalis tuber and Pharbitis seed, is employed in Korea to manage functional dyspepsia due to its noted anti-inflammatory and gastrointestinal motility-enhancing effects. This study aims to investigate the potential of DA-9701 in addressing altered gastric emptying and glycemic control in diabetic rats, thereby validating its broader clinical utility.

Aims & Methods

Diabetes mellitus was induced in rats by streptozotocin injection. Post-diabetes development, rats received oral administration of DA-9701 daily for two weeks. Evaluations included serum glucose levels, gastric emptying rates for liquids and solids, plasma insulin levels, and serum malondialdehyde concentration. Immunoblot assays assessed the expression of c-Kit, the Ogg1 gene, and phosphorylated extracellular signal-regulated kinase (p-ERK).

Results

Diabetic rats exhibited blood glucose levels three to four times higher than nondiabetic control rats at weeks 3 and 4. Gastric emptying, initially accelerated by week 2 and persisting until week 4, was linked to increased interstitial cells of Cajal (ICC) activity driven by hyperglycemia-induced oxidative stress. The expression of c-Kit, an ICC marker, was elevated in the gastric tissues of diabetic rats by weeks 3 and 4 but reduced following two weeks of DA-9701 administration. Oral administration of DA-9701 (6 mg/kg) not only normalized gastric emptying but also improved blood glucose levels through increased serum insulin concentrations by weeks 3 and 4. Oxidative stress markers, including Ogg1, p-ERK, and serum malondialdehyde concentrations, initially upregulated, were reduced post-treatment.

Conclusion

Two weeks of DA-9701 treatment attenuated accelerated gastric emptying and reduced elevated blood glucose levels in diabetic rats. Normalized gastric emptying contributed to improved glucose homeostasis by reducing oxidative stress. Additionally, an unexpected increase in serum insulin levels post-treatment suggests that DA-9701's regulatory effects extend beyond gastric dynamics to direct modulation of blood glucose. These findings underscore DA-9701's significant potential in managing both gastrointestinal dysfunction and glucose control in diabetes mellitus.

References

1. Goyal RK. Gastric Emptying Abnormalities in Diabetes Mellitus. N Engl J Med. 2021;384(18):1742-51.
2. Goyal RK, Cristofaro V, Sullivan MP. Rapid gastric emptying in diabetes mellitus: Pathophysiology and clinical importance. J Diabetes Complications. 2019;33(11):107414.
3. Oh JH, Pasricha PJ. Recent advances in the pathophysiology and treatment of gastroparesis. J Neurogastroenterol Motil. 2013;19(1):18-24.
4. Hayashi Y, Toyomasu Y, Saravanaperumal SA, Bardsley MR, Smestad JA, Lorincz A, et al. Hyperglycemia Increases Interstitial Cells of Cajal via MAPK1 and MAPK3 Signaling to ETV1 and KIT, Leading to Rapid Gastric Emptying. Gastroenterology. 2017;153(2):521-35.e20.
5. Kishi K, Kaji N, Kurosawa T, Aikiyo S, Hori M. Hyperglycemia in the early stages of type 1 diabetes accelerates gastric emptying through increased networks of interstitial cells of Cajal. PLoS One. 2019;14(10):e0222961. E
6. Jin M, Son M. DA-9701 (Motilitone): A Multi-Targeting Botanical Drug for the Treatment of Functional Dyspepsia. Int J Mol Sci. 2018;19(12). Epub 20181213.
7. Jung HK, Lee KJ, Choi MG, Park H, Lee JS, Rhee PL, et al. Efficacy of DA-9701 (Motilitone) in Functional Dyspepsia Compared to Pantoprazole: A Multicenter, Randomized, Double-blind, Non-inferiority Study. J Neurogastroenterol Motil. 2016;22(2):254-63.

Introduction

Gastroparesis (GP) is defined as symptomatic delayed gastric emptying. The most frequent etiologies are diabetes mellitus, after esophageal or gastric surgery and about a third of patients have idiopathic GP. The gastric emptying study by using a scintigraphy scintigraphy (GES) is considered as a principal diagnostic method. Endoscopic pyloromyotomy (G-POEM) is a method improving symptoms in about 60-70% of patients with GP. Its effect on gastric emptying remains controversial.

Aims & Methods

We performed a retrospective single-center analysis to assess the clinical efficicacy of G-POEM based on GES parameters. Between 2016 – 2024, a total of 72 patients with GP (confirmed by scintigraphy) underwent G-POEM and were later invited for clinical as well as scintigraphic assessment after 3, 12 and 36 months. Of these patients, 4 were excluded for missing data, incomplete follow-up data or non-standard testing meal. GES was always performed using the standardized 4 hours protocol with the standard testing meal mixed with 99Tc-DTPA. For this study, all GES were reanalyzed and the following parameters were established : residual activity after 2 hours, residual activity after 4 hours, biological halftimes of ingested activity and proximal-to-distal count ratio for time 0 (PDCR0).

Results

Mean value of GCSI before G-POEM was 3.1 and decreased to 1.6, 1.0 and 0.7 after 3, 12 and 36 months. Median value of GES after 2 hours was 60.2% before G-POEM and 38%, 32.6% and 24.2% after 3, 12 and 36 months. Median value of GES after 4 hours was 21.9% before G-POEM and 7.8%, 6.5% and 3.9% after 3, 12 and 36 months. Correlation index was weakly positive for GCSI and GES after 4 hours only for the first follow-up visit and negative for all remaining visits.
The residual activity after 2 hours and residual activity after 4 hours decreased after G-POEM during all follow-up visits (p<0,001). Mean decrease of residual activity after 4 hours was 12.89%, 15.13% and 6.7% after 3, 12 and 36 months.
Biological halftime also decreased after the procedure with statistically significant results with the mean halftime before G-POEM being 150 min and 86 min, 78.4 min and 65.8 min after 3, 12 and 36 months.
There was a difference between the diabetic and non-diabetic groups, with higher residual activity after 2 hours [median 29.6% before G-POEM, 9.0% after 3 months (p<0.001) and 11.0% after 12 months (p=0.005)] and 4 hours [median 64.8% before G-POEM, 39.4% after 3 months (p<0.001) and 37.7% after 12 months (p=0.012)] respectively in patients with diabetes.
The predictive value of PDCR0 for treatment success after G-POEM was only calculated for the first follow-up visit but was not statistically proved (p=0,712).

Conclusion

In our group of patients there is a weak correlation between the decrease of GCSI and GES early after G-POEM. The decrease in GES parameters tends to be lower in patients with diabetes compared to non-diabetic patients. Based on our data, predicting clinical success of G-POEM using PDCR0 cannot be recommended.

Introduction

Gastroparesis is a disorder characterized by delayed gastric emptying without mechanical obstruction, leading to symptoms such as nausea, vomiting, abdominal pain, and bloating. Cannabis and its active compounds are thought to interact with the gastrointestinal system through cannabinoid receptors, influencing motility, sensation, and inflammation. Nevertheless, data pertaining to the interactions between cannabis use, gastric motility and gastrointestinal (GI) symptoms is still scant¹.

Aims & Methods

The aim of the current study was to compare GI symptoms and gastric motility in a cohort of patients referred for gastric emptying breath test (GEBT). In this prospective study, all consecutive patients referred for motility testing in a tertiary hospital were recruited. Following obtaining written informed consent, questionnaires, including ROME, SCL-90-R and SF36 were filled out by the patients. Carbon-13 spirulina GEBT was done performed according to protocol, following consumption of a standardized meal. Patients with ongoing (regular or occasional) cannabis use were compared with non-cannabis users for all symptoms, quality of life and GEBT testing results. An additional healthy cohort of volunteers was recruited for validation of GEBT cut-off values and comparison to the symptomatic cohort.

Results

A total of 88 patients and 14 healthy volunteers were included in the current study. Among patients, 15 (17%) were identified as cannabis users, and these were compared with 73 non-users. Mean age and gender did not differ between users and non-users (52.4 vs 43.0, and 21% vs 33% males, respectively, p=NS). Gastric emptying breath test results did not significantly differ between groups, both in terms of mean values (t^1/2 127.2 vs 129.2 minutes, users versus non-users, respectively; p=NS) and in the proportion of delayed gastric emptying (26.7% versus 32.9%, users versus non-users, respectively; p=NS). None of the healthy volunteers displayed delayed gastric emptying results. Cannabis users demonstrated a higher gastrointestinal symptom burden and a greater number of diagnosed disorders of gut-brain interaction (DGBI) compared to non-users.

Conclusion

In our cohort of patients referred for gastric emptying breath tests, gastric emptying was similar between cannabis users and non-users. This is in line with previous studies suggesting that cannabis does not improve delayed gastric emptying. Nevertheless, previous studies suggested that cannabis may alleviate gastroparesis-associated symptoms². In this context, our results show that cannabis use was rather associated a more severe and systemic symptomatic manifestation of gut-brain disorders, in contrast to a more localized upper gastrointestinal involvement seen in non-users. Although causality cannot be established, we do note that despite ongoing cannabis use, treatment response was sub-optimal in the user patient group. Factors contributing to these differences, such as physiological or psychological constructs, should be further explored.

References

¹Parkman HP et al. Marijuana Use in Patients with Symptoms of Gastroparesis: Prevalence, Patient Characteristics, and Perceived Benefit. Dig Dis Sci. 2020
²Barbash, B et al. Cannabinoids Lead to Significant Improvement in Gastroparesis—Related Abdominal Pain: 1204. American Journal of Gastroenterology 2018.

Introduction

Ethanol-induced gastric ulcers are common and the treatment options are limited. Escin, a extract from the horse chestnut plant, has been proven to have therapeutic effects in improving inflammation, edema, and vascular permeability. However, its effects and mechanisms on ethanol-induced gastric mucosal injury are not yet clear.

Aims & Methods

This study aims to explore the protective effect of Escin on ethanol-induced gastric mucosal injury and its potential mechanisms, providing a new drug choice for the treatment of ethanol-induced gastric ulcers. For this purpose, a control, ethanol, ethanol+Escin , and ethanol+omeprazole groups were established in male SD rats to compare and analyze the ulcer index and histopathological scores of each group. The network pharmacology approach was used to predict potential targets of Escin related to gastric ulcers. Apoptotic proteins, NF-κb inflammatory pathway proteins, inflammatory factors, and related mRNA expression were analyzed by methods such as Immunofluorescence (IF), Immunohistochemistry (IHC), Western Blot (WB), real-time quantitative fluorescence PCR (q-PCR), and enzyme-linked immunosorbent assay (Elisa). Furthermore, an ethanol-induced GES-1 cell injury model was established to evaluate the protective effect of Escin. Finally, Transcriptomic sequencing was performed to identify key regulatory genes.

Results

The study found that Escin significantly reduced the damage of ethanol to gastric mucosal tissues. Network pharmacology analysis predicted that Escin is closely related to inflammatory pathways such as NF-κb in the treatment of gastric ulcers. IHC and WB results showed that Escin reduced the loss of gastric mucosal surface markers MUC5AC, TFF2, and gastric mucosal barrier protein O-ccludin, inhibited the expression of inflammatory factors IL-1β, IL-6, TNF-α, and apoptosis-related proteins BAX, Caspase-3, and promoted the expression of anti-apoptotic protein BCL-2. IF further revealed that Escin prevented the nuclear translocation of NF-κb, thereby inhibiting the activation of the NF-κb pathway. Elisa results showed a decrease in inflammatory factor levels in the plasma of rats in the Escin group, while q-PCR results demonstrated that Escin downregulated the expression levels of inflammatory factor mRNA in gastric tissues. Cell proliferation experiments also confirmed the protective effect of Escin against ethanol-induced damage. Finally, Transcriptomic analysis revealed significant upregulation of 27 inflammation-related genes in ethanol-treated gastric tissues. Notably, nine genes—Birc3, Bcl3, SOCS1, SOCS3, Ccl2, Cx3cl1, Pim1, SGK1, and OSMR—were identified as positive regulators of the TNF-α/NF-κB signaling axis through functional annotation and pathway enrichment analysis.

Conclusion

Escin exerts a protective effect on ethanol-induced gastric mucosal damage by inhibiting the TNF-α/NF-κB pathway, reducing the expression of inflammatory factors and the level of cell apoptosis. Escin, as a novel therapeutic drug for ethanol-induced gastric ulcers, has certain clinical translational application value, but further clinical trials are needed to confirm the results.

Introduction

Gastroparesis is common in patients with Diabetes mellitus, especially in those with poor glycemic control. Due to this association, diabetic patients are at risk of prolonged gastric transit time (PGTT) when undergoing small-bowel capsule endoscopy (SBCE).

Aims & Methods

In this investigation we aimed to assess if there was an association between hemoglobin A1c levels and PGTT in diabetic patients undergoing SBCE.
We have conducted a single-center retrospective study including all consecutive diabetic patients undergoing SBCE for two years. Patients without a valid hemoglobin A1c measurement within 3 months from SBCE were excluded. The assessed outcome was PGTT (defined as SBCE remaining in the stomach for >1h, requiring prokinetic administration and/or endoscopically assisted capsule delivery into the duodenum). Possible confounders – age, gender, inpatient status, smoking habits, diagnosis of IBD, thyroid disease, prokinetics or antidepressants regular usage - were also assessed.

Results

Final sample included 77 patients, 40 (51.9%) of them males, with a mean age of 70±10 years. PGTT occurred in 33 (42.9%) individuals. Mean hemoglobin A1c levels were significantly higher in diabetic patients with PGTT (7.4±0.8% vs 6.5±0.8%; p<0.001). In a multivariate analysis including significant confounders, hemoglobin A1c levels were still an independent predictor of PGTT (B=1.35; p<0.001). Single-handedly, hemoglobin A1c levels demonstrated very good acuity in predicting PGTT (AUC=0.80; p<0.001), with an optimal cut-off of HbA1c ≥6.8% (sensitivity 81% and specificity 73%).

Conclusion

Hemoglobin A1c levels significantly influenced the occurrence of PGTT in diabetic patients undergoing SBCE. This may eventually allow the performance of preemptive measurements to avoid PGTT in diabetic patients with poor glycemic control.

Introduction

Gastric emptying (GE) of liquids and solids is differentially regulated. GE of liquids follows an exponential kinetic and mainly depends on fundic tone, GE of solids requires trituration by antral contractions for passage through the adequately opened pylorus into the duodenum. Adler et al. showed that liquid GE was more often delayed in systemic sclerosis patients compared with GE of solids (Rheumatology 2022), but knowledge on the association between GE of solids and liquids in dyspeptic patients, in general, is limited.

Aims & Methods

To investigate this association and the correlation of GE times with symptoms, we compared results of breath tests using 13C-acetate (13C-ABT, GE-liquids) and 13C-octanoic acid (13C-OBT, GE-solids) in consecutive dyspeptic patients undergoing both tests (Keller et al. UEG J 2021). Normal ranges at our institution for 13C-ABT are 20-35 min (T lag-liquids), for 13C-OBT 50-150 min (T ½-solids). All patients additionally answered the gastroparesis cardinal symptom index questionnaire (GCSI, Revicki APT 2003).

Results

302 patients were included (230 women, age 45.9 (31.7-59.5) yrs, median(IQR)). Median T lag-liquids was 25 (20-35) min, median T ½-solids 78 (60-104) min. T lag-liquids and T ½-solids were weakly associated (R=0.165, p=0.002). Both were indirectly correlated with age (R=-0.280, p<0.0001 and R=-0.179, p=0.0009, resp), and similar in men and women. Concordant results for both tests were achieved in 172 subjects (57.6%): Both were normal in 161 (53.3%), both showed accelerated GE in 10 (3.3%) and both delayed GE in 3 (1%) subjects. Discrepant results were observed in 128 subjects (42.4%), in the vast majority of these, one of the tests was normal, but in 7 subjects (2.3%), GE was accelerated in one test, delayed in the other. 67 patients (22.2%) had delayed GE in at least one of the tests. Only in this subgroup, GE time correlated significantly with GCSI (R=0.242, p=0.024), in particular with the nausea/vomiting subscale (p=0.009).

Conclusion

In a large group of dyspeptic patients, more than 45% had disturbances of liquid and/or solid GE. In less than 5% of the total group both tests were found to be either accelerated or delayed in the same patient. Instead, measurements of liquid and solid GE often differred. In patients with delayed GE in at least one of the tests, severity of gastroparesis symptoms was associated with GE time. Thus, measurements of liquid and solid GE may be complementary and identify patients with different pathomechanism leading to GE disturbances and symptoms.

Introduction

Opioids are commonly prescribed medications known to cause a range of gastrointestinal (GI) side effects, including nausea and delayed gastric emptying. Naloxegol is a peripherally acting mu-opioid receptor antagonist, currently approved for the treatment of opioid-induced constipation, but with presumed effects throughout the entire GI tract. We aimed to elucidate further the mechanisms of opioid-mediated GI dysfunction and naloxegol's effects using a novel magnetic resonance imaging (MRI) approach to assess changes in gastric motility and gastric content volumes in healthy volunteers (HVs).

Aims & Methods

15 HV will be invited for three study visits, separated by ≥1 week washout. During each visit, five abdominal MRI scans are taken (each 20 min.), with 30 min. in between the scans, comprising one baseline fasted MRI, one MRI after the intake of either of the three drug combinations: 25 mg naloxegol + 60 mg codeine, 60 mg codeine + placebo, or double placebo, one after a standardized meal with 44 g oatmeal and 100 mL Nutridrink (313 kCal), followed by an MRI scan after a second dose of either 30 mg codeine or placebo, and a final scan after a bisacodyl 10 mg suppository administration. Gastric motility scores were obtained using the GIQuant score (Motilent, London, UK) of each of the 5 MRI scans. Both motility scores of the whole stomach and the antrum, defined below the angular incisura, were analyzed. Gastric content volumes were quantified from all MRI scans. Symptom scores were recorded by HVs at 13 time points during each visit: one before baseline scan, three after scan 1, 2, and 3, two after scan 4, and one after scan 5. P-values <0.05 are considered statistically significant. Adjusted p-values are used in case of post-hoc analysis.

Results

Interim results from 10 HVs (mean age 34±4y, 70% females) are displayed in Table 1. The codeine + placebo group showed a significantly higher median gastric content volume at the fifth MRI scan (average 129 minutes postprandially) compared to the placebo group (p=0.036). Moreover, there were significant differences in stomach volumes between the scans in all 3 groups. Although there was a significant difference in whole stomach motility score between the 3 groups (p=0.035), and more specifically between the naloxegol+codein group and the double placebo group at the second scan (median GIQuant 215 vs 288 respectively, p=0.046), there were no significant differences in motility scores for the antrum between scans.

Conclusion

Interim analysis of 10 HVs using cine-MRI revealed significant codeine-induced delays in gastric emptying compared to placebo. However, no significant differences were currently observed between codeine with and without naloxegol, and this will be reassessed on the entire study sample size. Nevertheless, gastric motility revealed only a tendency toward more contractility of the whole stomach but not of the antrum with placebo. Expansion to the full number of subjects will provide definitive insights into the gastric responses to opioids and potential reversal by naloxegol.