Introduction

This study investigates the pharmacological activity of Amara-Drops, a traditional herbal remedy used for gastrointestinal dysmotility, and its nine individual herbal extracts on fundus accommodation, a characteristic aspect of functional dyspepsia. Impaired fundus accommodation after food intake can lead to symptoms such as epigastric pain and vomiting, yet its etiology remains poorly understood. Previous studies have demonstrated that the extract of Amara-Drops relaxes guinea-pig fundus stomach, potentially mediated by M2 muscarinic receptor inhibition, though the exact mechanism and responsible individual extracts were not investigated.

Aims & Methods

Our study aimed to explore the mechanisms of action of Amara whole extract and its constituent extracts (Artemisia absinthium Herba, Centaurium erythraea Herba, Cichorium intybus Planta tota, Gentiana lutea Rhizoma, Juniperus communis Summitates, Achillea millefolium Herba, Peucedanum ostruthium Rhizoma, Salvia officinalis Folium and Taraxacum Planta tota) on fundus accommodation, both ex vivo and in vitro. Dry extracts were obtained from the commercial product Amara-Drops or from the individual ethanolic tinctures. Guinea-pig fundus muscle strips were prepared and set up in organ baths in a circular orientation to study the relaxation effect of the whole extract (94.4–1,000 μg/mL) or vehicle, with or without Carbachol-induced contraction. To elucidate whether M2 or M3 muscarinic receptors were involved in the relaxation effect, guinea-pig fundus was pretreated with J-014129, an antagonist of M3, followed by addition of whole extract or three selected individual extracts. Furthermore, binding and antagonist activities on muscarinic M3 and M2, and opioid μ (OP1) receptors expressed in CHO-K1 cell line were assessed for the whole extract and/or individual extracts.

Results

Exposure of the whole extract to guinea-pig fundus muscle strips induced significant relaxation at the highest concentrations tested (p<0.001). Significant relaxation was observed in Carbachol-contracted muscle strips (p<0.05), regardless of J-014129 pretreatment, suggesting potential modulation of the M2 receptor. In vitro studies revealed the whole extract bound to M3, M2 and OP1 receptors (IC₅₀: 380, 294 and 55 μg/mL, respectively), with selective M2 and OP1 receptor activity impairment (IC₅₀: 219 and 304 μg/mL, respectively) via inhibition of their respective reference agonist activity. M3 receptor activity was not affected. Juniperus communis, Salvia officinalis, and Peucedanum ostruthium extracts showed M2 receptor inhibition (IC₅₀: 32, 20, and 21 μg/mL, respectively), with only Peucedanum ostruthium extract binding to M2 receptor (IC₅₀: 137 μg/mL) and significantly relaxing Carbachol-contracted muscle strips, irrespective of J-014129 pretreatment (p<0.001). However, Juniperus communis and Salvia officinalis did not show M2 receptor binding nor relaxation effects. Furthermore, Gentiana lutea, Juniperus communis, Artemisia absinthium, and Centaurium erythraea extracts inhibited OP1 receptor activity (IC₅₀: 42, 25, 22 and 104 μg/mL, respectively).

Conclusion

These data highlight the potential of the medicinal product Amara-Drops, particularly its Peucedanum ostruthium extract, in modulating fundus accommodation by inhibiting M2 receptor activity. Further investigations are needed to elucidate relaxation mechanisms through OP1 receptor inhibition. Nevertheless, this study provides a promising molecular basis for the efficacy of Amara-Drops in improving impaired fundus accommodation in functional dyspepsia.

Disclosure

All authors are employees of Weleda AG.

Introduction

Functional dyspepsia (FD) is a prevalent disorder that effects the proper function of the gastrointestinal (GI) system. One of the hallmarks of FD is the impaired ability of the stomach to accommodate after food intake, leading to epigastric pain, heartburn, bloating and nausea. However, the exact cause of this disorder is poorly understood. Studies have shown that combinations of herbal extracts known as phytotherapeutic preparations have demonstrated efficacy in improving dyspeptic symptoms in FD. Amara oral drops is traditionally used for the treatment of GI dysmotility and contains an herbal mixture of nine hydroethanolic herbal extracts (Artemisia abstinthium, Erythraea centaurium, Cichorium intybus, Gentiana lutea, Juniperus communis, Millefolium, Imperatoria ostruthium, Salvia officinalis and Taraxacum).

Aims & Methods

The study aim was to investigate the mechanisms of the Amara whole extract and its individual extracts on gastric motility ex vivo and in vitro. The whole extract and the individual extracts were prepared from the commercial medicinal product Amara oral drops or from the ethanolic tinctures, respectively. Muscle strips from guinea-pig (GP) gastric fundus were set up in organ baths in circular orientation and exposed to the whole extract or vehicle in a concentration-dependent manner (3.5 – 1,000 μg/mL). To assess the relaxation mechanism of the whole extract and its individual extracts on the stomach muscle strips, we studied different G-protein-coupled receptors known to play a central role in GI disorders: muscarinic M₃ and M₂, opioid μ (OP1) and several serotonin receptors (5-HT1B, 5-HT1D, 5-HT3, 5-HT7 and 5-HT1A). The whole and individual extracts were studied in vitro for antagonist activity on those motility receptors. All assays were performed in CHO-K1 cell line. To investigate M₂ antagonist activity ex vivo, muscle strips from GP gastric fundus were exposed to Carbachol (Cch), a well-known muscarinic agonist. Once the contraction was stabilized, vehicle or whole extract were added in increasing concentrations (94 – 1,000 μg/mL) to study their relaxation effect on the muscle contraction.

Results

Addition of the ethanol-free whole extract caused relaxation of guinea-pig fundus circular muscle strips which was found to be significantly different compared to the vehicle group at the highest concentrations tested (p-value < 0.001). In vitro studies revealed that the whole extract impaired the activity of OP1 and M₂ receptors, shown by inhibition of intracellular cAMP release (IC₅₀: 304 & 219 μg/mL, respectively). Furthermore, Juniperus, Salvia and Imperatoria extracts impaired M₂ receptors’ activity (IC₅₀: 32, 20 & 21 μg/mL, respectively), whereas Gentiana, Artemisia, Cichorium and Juniperus inhibited OP1 receptors’ activity (IC₅₀: 42, 22, 104 & 25 μg/mL, respectively). However, serotonin and M₃ receptors’ activities were not affected. After Cch-induced contraction, the whole extract showed a clear tendency on producing a concentration-dependent relaxation of the contracted muscle strips. Ongoing research is being conducted to strengthen the latter mentioned data.

Conclusion

This data demonstrates that the whole extract is capable of altering gastric motility by relaxing the fundus part of the stomach, most likely through the modulation of motility-related M₂ and OP1 receptors. Additionally, all individual extracts’ properties may act together, resulting in an increase of the overall preparation’s efficacy. These findings suggest that Amara oral drops could be an efficient treatment for FD patients suffering from impaired gastric accommodation.

Disclosure

All authors are employees of Weleda AG.

Introduction

Functional dyspepsia (FD) is a common yet complex gastrointestinal disorder, characterised by postprandial fullness, early satiety, epigastric pain, and burning. With growing evidence linking diet to inflammation and symptoms, our objective was to review the evidence for the impact of dietary factors on FD symptomatology.

Aims & Methods

A systematic review was conducted to identify dietary components influencing FD symptoms in adults. Databases searched included MEDLINE, EMBASE, PsycINFO, Scopus, and Cochrane, covering January 2000 to December 2024. A total of 14 studies met eligibility criteria, with findings synthesised through narrative analysis.

Results

The search strategy yielded 18,424 articles, of which 14 met the inclusion criteria. Analysis identified seven key dietary components associated with FD: (1) a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet significantly improved symptoms (p = 0.04), while gluten intake was linked to early satiety (p = 0.03); (2) probiotics or prebiotics provided symptom relief (RR 1.15, p = 0.52), with probiotics alone showing a trend toward improved FD scores (RR 1.35, p = 0.061); (3) capsaicin significantly exacerbated symptoms (p < 0.001), and spicy foods were associated with increased gastric fullness (p = 0.001); (4) both peppermint-caraway oil (p < 0.00001) and cinnamon oil (p < 0.001) demonstrated significant symptom relief; (5) ginseng-based herbal porridge led to a higher rate of epigastric symptom remission by day 90 compared to placebo (45.71% vs. 20.69%, p = 0.036), while the STW 5-II formulation (a nine-herb extract) also yielded significant improvement (p = 0.008); (6) prokinetic agents reduced symptom severity (RR 0.81, p < 0.0001), while amitriptyline outperformed both placebo (40%) and escitalopram (38%), relieving symptoms in 53% of patients—particularly those with ulcer-like FD; and (7) ginger/artichoke capsules improved symptoms within 14 days (p = 0.017), while ginger/perilla tablets offered progressive relief over one to two weeks (p < 0.05 and p < 0.01, respectively). Study quality was assessed using ROBIS, RoB 2.0, and ROBINS-I tools. Of the included studies, three were rated as low risk of bias, eight as moderate, and three as serious. Despite adherence to a standardised PRISMA-based search strategy, variability in outcome reporting limited direct comparability across studies.

Table 1

Conclusion

This review highlights dietary interventions as a promising strategy for managing FD. Our findings show that specific dietary components can be implicated in inducing inflammation and symptoms in FD. Since the symptoms are related to inflammation, we propose using “inflammatory dyspepsia” to represent the true presentation of this form of dyspepsia. Large-scale randomised trials are needed to confirm findings and refine dietary guidelines.

Introduction

The bitterness of medicinal products used for functional dyspepsia and irritable bowel syndrome containing herbal extracts is well known, although the underlying mechanisms are poorly understood. In previous works of our group, bitter tasting phenolic plant compounds were shown to elicit (1) an anti-inflammatory activity in immune competent cells, and (2) stimulate proton secretion in parietal cells as key mechanism of gastric acid secretion.^1-3 Both effects were mediated through bitter taste receptors (TAS2Rs), and were demonstrated to correlate with the compound’s bitter taste in their effect size.^1-4

Aims & Methods

In this work, a commercially available liquid herb formulation used to aid digestive discomfort was tested in a concentration range of 5 – 500 µg/ml for its TAS2R-mediated effects on the mechanisms of proton secretion by means of a pH-sensitive fluorescent dye in the well-established human parietal HGT-1 cell model.⁴ This native cell line expresses all 25 TAS2Rs and all the elements necessary for signal transduction of functional gastric acid secretion. Individual plant extracts of the more effective formulation, namely extracts from Artemisia absinthium, Cichorium, Erythraea centaurium, Gentiana lutea, Imperatoria ostruthium, Juniperus communis, Millefolium, Salvia officinalis, and Taraxacum, were studied for their effects on proton secretion and TAS2R gene regulation by means of RT-qPCR. Moreover, total phenolic content, expressed as gallic acid equivalents (GAE), were analyzed by using the colorimetric Folin-Ciocalteu method.

Results

Treatment of the HGT-1 cells with the ethanolic plant extracts (cytotoxic effects were excluded; cell viability ≥ 95%) revealed a concentration-dependent (1 – 300 µg/mL herbal extract) stimulation of proton secretion by seven of nine extracts, of which those from Imperatoria ostruthium and Juniperus communis demonstrated the strongest effects. Gene expression experiments resulted a regulation of 16 out of 25 TAS2Rs after exposure of the HGT-1 cells to the herbal product. Without exception, these regulations were reproduced by treatment of the cells with the individual plant extracts. For example, exposure of HGT-1 cells to the liquid formulation led to a regulation of TAS2R4 and TAS2R5, which are known to be activated by polyphenolic compounds.^2,5 These regulations were also found for the ethanolic extracts from Juniperus communis and Imperatoria ostruthium (TAS2R4 and TAS2R5) and Gentiana lutea (TAS2R4). Quantitation of the total polyphenol content showed a high polyphenol concentration (> 1500 µg/mL GAE) for four out of the nine extracts, including that from Imperatoria ostruthium (2063.7 ± 31.6 µg/mL GAE) and Juniperus communis (2859.5 ± 13.6 µg/mL GAE), which also had a strong effect on proton secretion. In contrast, extracts with lower polyphenol concentrations (< 1500 µg/mL GAE) demonstrated a less pronounced effect on or no effects on proton secretion.

Conclusion

In summary, exposure of parietal HGT-1 cells to herbal plant extracts with a high polyphenol content lead to a stronger stimulation of proton secretion compared to extracts with low polyphenol contents (R² = 0.77; p < 0.0001). For the most active extracts from Imperatoria ostruthium and Juniperus communis, a gene regulation of TAS2R4 and TAS2R5 was demonstrated. Next experimental steps will include (1) a functional involvement of TAS2R4 and TAS2R5 by means of knock-out (CRISPR-Cas9) or knock-down (by means of specific siRNA) approaches, and (2) identification of key active phenolic compounds by mass-spectrometry.

References

1 Tiroch, J. et al. & Somoza, V. (2023). Human Gingival Fibroblasts as a Novel Cell Model Describing the Association between Bitter Taste Thresholds and Interleukin-6 Release. Journal of Agricultural and Food Chemistry (Vol. 71, Issue 13, pp. 5314–5325). https://doi.org/10.1021/acs.jafc.2c06979
2 Sterneder, S. et al. & Somoza, V. (2021). Astringent Gallic Acid in Red Wine Regulates Mechanisms of Gastric Acid Secretion via Activation of Bitter Taste Sensing Receptor TAS2R4. Journal of Agricultural and Food Chemistry (Vol. 69, Issue 36, pp. 10550–10561). https://doi.org/10.1021/acs.jafc.1c03061
3 Tiroch, J. et al. & Somoza, V. (2021). Bitter Sensing TAS2R50 Mediates the trans-Resveratrol-Induced Anti-inflammatory Effect on Interleukin 6 Release in HGF-1 Cells in Culture. Journal of Agricultural and Food Chemistry (Vol. 69, Issue 45, pp. 13339–13349). https://doi.org/10.1021/acs.jafc.0c07058
4 Liszt, K. I. et al. & Somoza, V. (2017). Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells. Proceedings of the National Academy of Sciences (Vol. 114, Issue 30). Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1703728114
5 Soares, S. et al. & De Freitas, V. (2013). Different Phenolic Compounds Activate Distinct Human Bitter Taste Receptors. Journal of Agricultural and Food Chemistry (Vol. 61, Issue 7, pp. 1525–1533). https://doi.org/10.1021/jf304198k

Disclosure

M-R. Piqué-Borràs and G. Künstle are employees of Weleda AG, Arlesheim, Basel-Country, Switzerland.

Introduction

Functional Dyspepsia (FD), a common disorder of gut-brain interaction [1], is associated with alterations in gastric accommodation, gastric emptying, gastric sensitivity, gastroduodenal permeability, and the gut microbiome. Resilience, the ability to maintain function under personal or physical stress, may play a role in the development of FD, although no studies have evaluated this theory. We hypothesize that FD patients have lower resilience than the general population, which may lead to a new therapeutic target.

Aims & Methods

This prospective questionnaire study compared patients with FD (Rome IV criteria) with internal medicine clinic patients without dyspepsia at a tertiary referral center. Participants completed the FD symptom severity score [2], Brief Resilience Scale (BRS) [3], Connor-Davidson Resilience Scale (CDRS) [4], hospital anxiety and depression scale (HADS) [5], early childhood adverse life event questionnaire [6], and perceived stress score [7]. Questionnaires were distributed to clinic patients meeting inclusion/exclusion criteria.

Results

38 FD (mean age 43 years old, 87% female) and 31 control (mean age 57 years old, 39% female) patients completed the survey. FD patients exhibited lower resilience on the CDRS (96.83 vs. 90.26, P<0.04, CI -12.93 to -0.21) but not on the BRS (3.018 vs. 3.022, P<0.96, CI -0.15 to 0.13). FD patients and controls scored no different on the HADS anxiety index (17.05 vs. 18.38, P<0.064, CI -2.74 to 0.08) and depression scores (P<0.14, CI -0.21 to 1.5). The FD group reported "high" perceived psychological stress while the control group reported a “moderate” level (P<0.004, CI 2.002 to 9.827). In childhood, FD patients had significantly more adverse childhood events (29.3% vs. 15%, P<0.004, CI 0.05 to 0.25). FD patients were more likely to have been exposed to a household member suffering from a psychiatric illness compared to control patients (47% vs. 20%, P<0.049, CI 0.001 to 0.5). FD patients were also more likely to report psychological abuse in childhood (53% vs. 17%, P<0.03, CI 0.034 to 0.67). No other significant differences were found in types of early childhood trauma including physical abuse, familial substance abuse, witnessed maternal violence, or criminal behavior by a household member.

Conclusion

This novel, prospective questionnaire pilot study shows that FD patients have lower resilience compared to the general outpatient population on the CDRS. The long-term symptoms of FD may further decrease resilience. While anxiety and psychological stress are not strongly associated with FD, the significant exposure to childhood household members with a psychiatric diagnosis and significantly higher prevalence of self reported psychological abuse may explain the higher prevalence of antidepressant use in this population, especially considering the significantly higher level of self perceived psychological stress [8]. Otherwise, early childhood trauma appears similar between FD patients and patients without FD and is thus not likely to influence resilience markers. Understanding the contribution of resilience to development of FD may lead to therapies enhancing resilience, improving symptoms, and patient well-being.

References

1. El-Serag HB, Talley NJ. Systemic review: The prevalence and clinical course of functional dyspepsia. Aliment Pharmacol Ther. 2004;19:643-654.
2. Taylor F, Higgins S, Carson RT, et al. Development of a symptom-focused patient-reported outcome measure for functional dyspepsia: the functional dyspepsia symptom diary (FDSD). Am J Gastroenterol. 2018 Jan,113(1):39-48.
3. Smith BW, Dalen J, Wiggins K, et al. The brief resilience scale: assessing the ability to bounce back. Int J Behav Med. 2008;15(3):194-200
4. Connor KM & Davidson JR. 2003. Development of a new resilience scale: The Connor-Davidson Resilience Scale (CD-RISC). Depress. Anxiety, 18; 76-82
5. Zigmond AS & Snaith RP. 1983. The hospital anxiety and depression scale. Acta Psychiatrica Scandinavica, 67: 361-370
6. Felitti VJ, Andra RF, Nordenburg D, et al. Relationship of childhood abuse and household dysfunction to many of the causes of death in adults. The adverse childhood experiences (ACE) study. Am J Prev Med. 1998 May;14(4):245-58
7. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav. 1983 Dec;24(4):385-96.
8. Esterita T, Dewi S, Suryatenggara FG, Glenardi G, et al. Association of Functional Dyspepsia with Depression and Anxiety: A Systematic Review. J Gastrointestin Liver Dis. 2021 Jun 18;30(2):259-266.

Introduction

STW5-II is a medicinal product composed by 6 herbal extracts that has been shown to relieve clinical symptoms in patients with dyspepsia. The mechanisms of action include selective effects on gastric tone, antro-pyloric activity
and visceral sensitivity. Patients with functional dyspepsia (FD) have a poor tolerance to gastric gas that has been related to a combination of several factors, including delayed gas transit and evacuation, visceral hypersensitivity and altered viscero-visceral reflexes.

Aims & Methods

The aim of the present study was to determine the effect of STW5-II on transit and tolerance of gastric gas in patients with FD. In 27 patients (26 female and 1 male, age range 22-70 years old) with FD and bloating (17 postprandial distress syndrome, 4 epigastric pain syndrome and 6 mixed type dyspepsia), a gas challenge test was performed after two weeks on STW5-II 20 drops t.i.d. or placebo, in a parallel, double blinded, controlled trial. The gas challenge test consisted in infusion of a mixture of gases into stomach through a nasogastric tube at 100 mL/min for 15 minutes (total volume infused 1500 mL) with concomitant gastric nutrient perfusion (Nutridrink 1.5 Kcal/ml, total 315 Kcal), mimicking a normal meal. Rectal gas evacuation, via a rectal tube connected to a barostat, and belching, by an esophageal multilumen impedance catheter, were continuously measured for 90 min from infusion start. Abdominal symptoms, using a 0-6 perception scale, and abdominal distension, using a tape measure, were quantified at 10-min intervals.

Results

Gastric gas infusion was followed by a progressive gas evacuation from the rectum, that was accelerated when patients were on STW5-II, compared to placebo. After 20 min from infusion start (when gas and nutrient perfusion was already finished) only 80±39 mL of gas had been expelled in studies on placebo, whereas 319±81 mL of gas were collected on STW5-II group (p=0.015). Thereafter, both groups continued to expel gas at similar rates, without differences between groups at the end of the study (837±180 mL and 1030±160 mL, saline and STW5-II, respectively; p=0.432). Gastric belches were exceptional in both groups (0.8±1.0 and 1.1±1.6 gastric belches in 90 min, saline and STW5, respectively; p=0.318).
Gastric gas infusion gas associated to a rapid rise in perception of abdominal symptoms, that was significantly lower in patients treated with STW5-II than those treated with placebo (score increment 3.0±0.4 vs 1.9±0.6, placebo and STW5-II, respectively; p=0.036). Following continuous rectal gas evacuation, perception decreased in both groups, however perception remained significantly greater at the end of the 90-min study period in patients on saline (score increment 1.4±0.6; p=0.018 vs infusion start), whereas it had returned to basal levels in patients treated with STW5-II (score increment -0.2±0.4; p=0.324 vs infusion start). There were no significant differences in abdominal girth increment between groups (max increment 16±2 mm and 13±2 mm placebo and STW5-II, respectively; p=0.224).

Conclusion

STW5-II is a medicinal product that improves tolerance to gastric gas in patients with functional dyspepsia, by acceleration of transit and rectal evacuation of gas, and reduction of the intensity of symptoms elicited by gas. Hence, this medicinal product could be beneficial for management of gas-related abdominal symptoms like bloating in patients with functional dyspepsia.
EudraCT: 2019-003976-38