Introduction

The “incretin effect”, the concept that gut hormones amplify insulin secretion, has been around for decades. In the 1960’s, it was discovered that oral glucose leads to greater circulating insulin response than IV glucose(1). This was later attributed to gut hormones, such as GLP-1 and GIP. Activation of their receptors on pancreatic β-cells raises cAMP, accounting for amplified insulin secretion. This study aimed to determine if incretin and related metabolic analytes consistent with the incretin effect are detectable during SmartPill® wireless motility capsule (WMC) investigations. These increasingly common investigations represent a convenient resource to study metabolism and relate this to gut physiology.

Aims & Methods

Healthy volunteers (n=41) arrived following overnight fasting. They consumed a standardized 270 kcal mixed meal breakfast. Details of methods including validation of motility data have been published (2). Blood was tapped -10, 0, 10, 20, 30, 40, 50, 60, 90, 120, 180 and 240 min into the meal. Protease inhibitors, including DPP4 inhibitor KR-62436, were added and plasma was prepared. Glucose was measured by the clinical chemistry unit. Active GLP-1, total GIP, acyl-ghrelin and insulin were measured by multiplex ELISA (MesoScale Discovery, USA). Glucagon was measured by ELISA (Mercodia, Sweden). Statistics for comparing pairs of peak or trough timing was done by rank-sum test. Data is presented as median ±SD.

Results

Following meal ingestion, the GLP-1 peak (30 ± 11 min) preceded those of glucose (40 ± 16 min), insulin (40 ± 12 min) and GIP (50 ± 26 min)(p<0.01, all comparisons). Glucose peaked about same time as insulin and before GIP (p<0.01). However, the rising phase of insulin and GIP overlapped somewhat, with no statistical difference in time to peak. GLP-1 peaked before insulin in 68% (28/41) of subjects, at the same time in 29% (12/41) of subjects, and after insulin in only 2% (1/41) cases in which insulin appeared to peak at 10 min and GLP-1 at 30 min. GIP peaked before insulin in 20% of subjects (8/41), at the same time as insulin in 49% of subjects (20/41), and after insulin in 32% of cases (13/41). Ghrelin and glucagon deflected downward at 30 min. Ghrelin reached trough at 60 ± 31 min, which was later than peaks of GLP-1 (p<0.01), glucose (p<0.01), insulin (p<0.01) and GIP (p<0.05). Glucagon reached trough at 55 ± 44 min, which was also later than peaks of GLP-1 (p<0.01), glucose (p<0.01), insulin (p<0.01) and GIP (p<0.05). GLP-1 peaked before glucagon reached trough in 95% of cases (38/40)(p<0.01) and at the same time or after glucagon in only 5% (2/40) of cases. GIP peaked before glucagon reached trough in 75% (30/40) of cases (p<0.01). Expulsion of the WMC from the stomach (gastric emptying time 185 ± 72 min) occurred after all peaks and troughs were reached in 95% (39/41) of subjects (p<0.001).

Conclusion

GLP-1 rise to peak is detectable as an early event during SmartPill® WMC investigation, usually preceding peaks or troughs of any of the other analytes. This is consistent with GLP-1 raising intracellular cAMP in pancreatic β-cells to prime them for insulin secretion. GIP rise to peak trails GLP-1, implying a later, prolonged action that parallels insulin. Ghrelin and glucagon start to decline when GLP-1 peaks, tending to reach trough after other hormones peak. Studies of these events require blood taps at a number of time points during a meal.

References

1. Unger RH & Eisentraut AM. Arch Intern Med. 123(3):261–6. 1969
2. Diaz Tartera HO, et al. Neurogastroenterol Motil. 29(10):e13107:1-9. 2017

Introduction

Functional dyspepsia (FD) is one of the most frequent disorders of the gut-brain interaction with a worldwide prevalence of around 7%.¹ Our group showed that a diet excluding fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) improved symptoms in the majority of FD patients.² FODMAPs have been studied in irritable bowel syndrome, where poor intestinal absorption may lead to osmotic effects and fermentation, contributing to symptoms. However, this has not been studied in FD to date. In this study, we assessed pathophysiological parameters after ingestion of mannitol and a control meal in FD patients and healthy volunteers (HV).

Aims & Methods

FD patients (N=11) that responded to the low FODMAP diet and showed symptom triggers by mannitol during reintroduction were recruited. Also, 11 HV participated in this trial. FD and HV had a similar age (47 (24-55) vs. 25 (21-46), p=0.14) and BMI (22 (21-31) vs. 23 (21-25), p=0.85), but FD cohort included more females (100% vs 55%, p=0.04). After an overnight fast, abdominal magnetic resonance imaging (MRI) was performed in patients and HV. MRI images, gastrointestinal (GI) symptoms and blood samples were collected at baseline and at six separate time points after a challenge meal (0, 15, 30, 45, 60, 120, 240 min). The meal was an oat porridge breakfast containing either mannitol or glucose, as a control, in a randomized, double blind cross-over fashion. MRI images were analyzed for gastric emptying T_1/2 (GE T_1/2), duodenal volume, small bowel water content (SBWC) and colonic gas volume. Blood samples were analyzed for glucose like peptide-1 (GLP-1), peptide YY (PYY), and GIP.

Results

FD patients exhibited more FD symptoms compared to HV after consuming both the glucose-rich meal (54 ± 10 vs 24 ± 7, p=0.02) and the mannitol-rich meal (64±13 vs 23±7, p=0.01). No differences were found for GE T_1/2 in FD and HV, as indicated in Table 1. Colonic gas volume was significantly increased in patients compared to HV. Duodenal volumes tended to increase more after intake of mannitol compared to glucose in both groups, but reached significance only in HV. SBWC was increased after mannitol in both HV (p=0.01) and FD (p=0.01). After intake of mannitol, postprandial GLP-1 levels were significantly lower in FD compared to HV, after 15 (p=0.02) and 30 min (p=0.001). Also, the AUC of GLP-1 was significantly lower in FD versus HV after mannitol (p=0.04), as well as after glucose-rich (p=0.04) meal. In FD, AUC of GIP levels was significantly lower after mannitol versus glucose (p=0.002). GI symptom scores did not correlate with PYY, GLP-1, and GIP levels. GLP-1 and GIP values did not correlate with GE T_1/2.

Conclusion

In this pilot study no difference in symptom triggering in FD was observed between mannitol and glucose (control) supplemented meals, but compared to HV the meals were associated with higher symptom burden, lower release of GLP-1 and GIP, and larger colonic gas volumes. The mechanisms underlying decreased peptide hormone release and their relevance to symptom generation deserve further studies.

References

1. Sperber AD, Bangdiwala SI, Drossman DA, Ghoshal UC, Simren M, Tack J, Whitehead WE, Dumitrascu DL, Fang X, Fukudo S, Kellow J, Okeke E, Quigley EMM, Schmulson M, Whorwell P, Archampong T, Adibi P, Andresen V, Benninga MA, Bonaz B, Bor S, Fernandez LB, Choi SC, Corazziari ES, Francisconi C, Hani A, Lazebnik L, Lee YY, Mulak A, Rahman MM, Santos J, Setshedi M, Syam AF, Vanner S, Wong RK, Lopez-Colombo A, Costa V, Dickman R, Kanazawa M, Keshteli AH, Khatun R, Maleki I, Poitras P, Pratap N, Stefanyuk O, Thomson S, Zeevenhooven J, Palsson OS. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology. 2021 Jan;160(1):99-114.e3. doi: 10.1053/j.gastro.2020.04.014. Epub 2020 Apr 12. PMID: 32294476.
2. Van den Houte K. et al. OUTCOME OF A LOW FODMAP ELIMINATION DIET WITH BLINDED REINTRODUCTION IN FUNCTIONAL DYSPEPSIA / POSTPRANDIAL DISTRESS SYNDROME. Under review Gut 2025

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.

Introduction

The pathophysiology of disorders of gut-brain interaction is complex and incompletely understood. In functional dyspepsia, increased gut permeability and low-grade mucosal inflammation with eosinophils and mast cells have been reported. Stress as well as exogenously administered corticotropin-releasing hormone (CRH) have been shown to increase small bowel permeability in vivo in a mast-cell dependent fashion. Moreover, eosinophil-derived CRH has been implicated in mast cell activation.

Aims & Methods

The aim of the current study was to evaluate whether acute CRH administration can induce increased duodenal mucosal permeability and immune activation in healthy volunteers (HVs).
HVs without gastrointestinal symptoms were recruited. The use of drugs such as NSAIDs, mast cell stabilizers or corticoids was prohibited. An i.v. bolus of 100 µg CRH or placebo (NaCl 0.9%) was administered in a crossover, double blind, randomized fashion with a 1-week washout period. Two hours after injection a gastroscopy with duodenal biopsies was performed. Duodenal permeability was evaluated in Ussing chambers measuring trans-epithelial electrical resistance (TEER) and the flux of a fluorescence-labeled dextran of 4kDa (FITC-D4). Duodenal biopsies were incubated at 37°C in culture medium for 24h. Sandwich ELISA was performed on supernatant for eosinophil derived neurotoxin (EDN), tryptase and chymase, corrected for biopsy weight. Analysis was performed using marginal mixed models in SAS. Correlation analysis was performed using Pearson correlation coefficient. Results are described as mean ± SEM. P-values < 0.05 were considered significant after correction for multiple testing.

Results

Twenty HVs (65% women, 27±1 years, BMI 23.2 ± 0.6 kg/m²) completed the study. Tryptase release in supernatant was significantly lower after CRH exposure, 6.06±0.88 ng/mL vs 4.03±0.46 ng/mL after CRH exposure (n=16, p= 0.031). Chymase release however, was not significantly different between both conditions (2805.82 ± 447.85 pg/mL/mg for placebo vs 2001.19±365.91 for CRH pg/mL/mg; p=0.27, n=15). There was a trend towards a decrease in EDN, after CRH exposure (13.3±2.05 µg/L/mg for placebo vs 8.96±1.11 µg/L/mg for CRH; p=0.061; n=16). Correlation analysis of delta values showed a significant correlation between ∆ tryptase and ∆ chymase (r 0.79, p=0.0062, n=10) and ∆ tryptase and ∆ EDN (r 0.60, p=0.019, n=15). No significant correlation was found between ∆ chymase and ∆ EDN (r 0.36, p=0.30, n=10).
A trend towards an decreased mucosal permeability was observed after CRH administration for TEER (25.75 ± 0.91 Ω.cm² for placebo vs 27.20 ± 1.44 Ω.cm² for CRH; p=0.056). Likewise, FITC-D4 flux was significantly lower in the CRH condition (41.4 ± 5.6 pmol for placebo vs 33.0 ± 2.7 pmol for CRH, p<0.0001). There was no significant correlation of delta values of FITC-D4 flux or TEER with delta values of supernatant for tryptase, chymase or EDN secretion.

Conclusion

Acutely administered CRH in vivo decreased tryptase release in supernatant of duodenal biopsies, suggesting an increased tryptase release in vivo, and decreased duodenal permeability in healthy subjects. However, no correlation between permeability and tryptase release was found.

Introduction

Avoidant/restrictive eating is common in people with neurogastroenterology disorders including functional dyspepsia (FD). There is debate on whether avoidant/restrictive food intake disorder (ARFID) is an expected response to severe symptoms or simply a common comorbid disorder. To address this, among adults with FD, we aimed to contrast those with and without ARFID on FD symptoms, quality of life, psychosocial factors, nutrient tolerance, and gut transit.

Aims & Methods

Adults with Rome-IV confirmed FD and healthy controls (HC) from an ongoing study participated. ARFID diagnosis was assigned based on a semi-structured DSM-5 diagnostic interview. Surveys: Patient Assessment of GI Disorders Symptom Severity Index (PAGI-SYM), Short Form Nepean Dyspepsia Inventory (SF-NDI), Nine-Item ARFID Screen (NIAS), Fear of Food Questionnaire (FFQ), Visceral Sensitivity Index (VSI), and Hospital Anxiety/Depression Scale (HADS). Nutrient Drink Test (NDT) measured gastric tolerance—liquid nutrient ingestion at 30mL/minute until subject reported unbearable fullness. Wireless Motility Capsule (WMC) measured gut transit. Height/weight was measured for body mass index (BMI).

Results

Sample (80% female, M_age=37.1±14.4y) included 37 FD+ARFID, 14 FD only, and 18 HC. Groups did not significantly differ in sex or age. Adjusted pairwise comparisons showed small (r=.1-.2) non-significant differences between FD and FD+ARFID on FD symptoms by PAGI-SYM and SF-NDI (Table 1). However, FD+ARFID had significantly worse scores compared to FD with medium effects (r=.3-.4) on: FD-related quality of life by SF-NDI, Fear of Food by NIAS-Fear and FFQ, GI-anxiety by VSI, and anxiety by HADS. FD+ARFID vs FD also had small differences (rs=.2) on: feeling more bothered by FD symptoms on SF-NDI, worse depression by HADS, lower BMI, and less NDT consumption. Compared to HC, FD and FD+ARFID had significantly worse survey scores with large effects for FD+ARFID (r=.6-.8) and medium effects for FD vs HC (r=.3-4). For the NDT, FD+ARFID consumed significantly less than HC with large effect (r=.6) but with a trend medium effect for FD consuming less than HC (r=.3). Groups did not significantly differ in WMC transit times.

Conclusion

Our findings suggest ARFID, when present in FD, does not reflect a response to more severe FD symptoms. Thus, ARFID is a legitimate secondary condition in FD. ARFID may reflect more profoundly altered distress around symptoms (e.g., fear of symptoms, anxiety sensitivity) and greater negative impacts (e.g., FD-related quality of life, lower liquid nutrient tolerance).

Introduction

STW 5, a herbal medicinal product with well characterized pharmacological action, has been shown in several RTCs to be an effective treatment in disorders of the gut-brain interaction (DGBI) as functional dyspepsia (FD) [1, 2]. The aim of the present study was to examine whether changes in gut microbiota induced in an experimental model of FD could be prevented by STW 5.

Aims & Methods

FD was induced in rats by subjecting them to neonatal maternal separation followed by subjecting them to restraint stress for 90 minutes/day for one week. During that week, one group (8 animals) was treated with the liquid form of STW 5 (5 ml/Kg) and one with its vehicle at the same dose level. Animals were sacrificed 24 h after the last drug administration. Fecal samples were taken from the cecum. Genomic DNA was isolated and changes in selected bacterial phyla and genera were assessed using quantitative Real Time-PCR (qPCR). The main phyla studied under the influence of stress in the model were the Bacteroidetes, Firmicutes, Fusibacterium and Actinobacteria.

Results

FD led to a 50% drop in the Lactobacilli population but to a two-fold rise in Proteobacteria abundance but did not affect significantly the changes in Bacteroidetes. Furthermore, the Methanobrevibacter population was raised more than two-fold while the genomic DNA concentration in Bifidobacterium dropped from ca. 3 ng/g feces to nearly nil.

Conclusion

In general, STW 5 tended to ameliorate and protect against the changes induced by the stress model. The results lend further support to the use of STW 5 in FD and IBS by providing evidence that it acts at least in part through influencing beneficially the changes in intestinal microbiota induced by stress. Taken together, the findings shed more light on mechanisms involved in the therapeutic action of STW 5 in gastro-intestinal disorders.

References

1. Malfertheiner P. STW 5 (Iberogast) Therapy in Gastrointestinal Functional Disorders. Dig Dis. 2017, 35 Suppl 1: 25-29
2. Allescher H-D, Burgell R, Malfertheiner P, Mearin F. Multi-target Treatment for Irritable Bowel Syndrome with STW 5: Pharmacological Modes of Action. Gastrointest Liver Dis. 2020;29: 227-233

Disclosure

OK and HA-K are empolyees of Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany. MTK has been obtaining travel support and speakers fees from Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany.

Introduction

Aims & Methods

Results

Conclusion