Introduction

Introduction: KeishI-ka-shakuyaku-to (TJ-60), a traditional Japanese herbal medicine, has been reported to relieve abdominal pain in patients with irritable bowel syndrome (IBS) and has been used to IBS patients in Japan. However, its precise mechanisms of action are not well understood.

Aims & Methods

Aims: The aim of this present study was to investigate the effects of TJ-60 on visceral pain induced colorectal distension (CRD) in mice. Knockout (KO) studies were employed to determine the involvement of transient receptor potential vanilloid1 (TRPV1) in mediating the effects of TJ-60. TRPV1 is a nonselective cation channel known to play an important role in visceral hypersensitivity and inflammation.
Methods: CRD was induced to assess visceral perception thresholds in the gut. The behavioral responses to CRD were evaluated by measuring the score of abdominal withdrawal reflex (AWR) in mice. The AWR score (AWR 0 to AWR 4) was measured by two blinded observers while inflating the plastic balloon inserted intrarectally into the distal colon, with air pressures of 10, 15, 20, 25, 30, 35, 40, 45, 50, and 55 mmHg for 30 seconds in C57BL wild mice (control) and TRPV1 KO mice. In order to let the mice recover from the previous distension, 3-minute rest was allowed between each distension. After 1g/kg TJ-60 was administrated for 7 days, CRD was induced to investigate the efficacy of TJ-60 in both control and TRPV1 KO mice.

Results

Results: CRD caused an increase in AWR scores in control (n=7) and TRPV1 KO mice (n=6), that was depended on the distension pressure. The higher the pressure of distension, the higher the score of AWR. TRPV1 KO mice exhibited reduced behavioral response scores to CRD at distension pressures of 15 and 20 mmHg when compared to control mice (p<0.01). AWR scores significantly decreased at distension pressures of 20, 25, and 30 mmHg following the administration of TJ-60 in control mice, while a distension pressure of more than 40 mmHg produced decreases in pain response after TJ-60 administration in TRPV1 KO mice (p<0.05).
Table 1 Mean changes in AWR score induced by CRD

Conclusion

Conclusions: TJ-60 inhibited the visceral pain responses. These results suggest that TJ-60 exerts an antinociceptive effect, which in part mediated by TRPV1 signal transduction.

Introduction

Managing patients with severe irritable bowel syndrome (IBS) has significant challenges for practicing physicians due to the condition's refractoriness to standard therapy and the lack of clinical remission. The prevalence of IBS reaches 9–21% among the adult working population and is associated with a low quality of life. According to various sources, visceral hypersensitivity (VHS) plays a key role in the pathogenesis of IBS.

Aims & Methods

The aim is to show the relationship between clinical symptoms, the visceral sensitivity index, and the visceral sensitivity threshold in patients with severe IBS-D.
A total of 84 patients with severe IBS-D, according to the Rome IV criteria, were examined. The median (Me) patient age was 32 (25; 37.2) years, with a disease duration of 5 (4; 6) years. Pain syndrome was assessed using the VAS scale in points (pts.), the level of visceral sensitivity index (VSI) using the J. Labus questionnaire reflecting gastrointestinal anxiety (pts.), and the visceral sensitivity threshold (VST) was studied via balloon dilatation test (BDT) (ml). Statistical analysis was conducted using non-parametric methods (Statistica 12). Quantitative data were described using Me and interquartile ranges (Q1 – Q3). Differences were considered statistically significant at p < 0.05.

Results

Before treatment, all patients showed a high level of pain syndrome - 9 (8; 9) pts. on VAS, and level of gastrointestinal anxiety at 71.00 (63; 75) according to the J. Labus questionnaire. BDT data revealed a low VST (first threshold—urge to defecate): 34.00 (27; 43.5) mm Hg. After examination, patients were randomly divided into two equal groups. The first group received the SNRI antidepressant (duloxetine) 60 mg/day, while the second group received trimebutine maleate 600 mg/day for 8 weeks, followed by assessment of therapy effectiveness. In the first group, SNRI therapy showed positive dynamics: a decrease of pain levels (from 9 (9 - 10) to 2 (1.75 - 3), p < 0.01*), an increase in VST (from 34.0 (29.75, 45.0) to 92.0 (86.0, 123.0), p < 0.01*), and a reduction in gastrointestinal anxiety (from 56.50 (47.50 – 68.00) to 12.00 (10.00 – 19.25), p < 0.01*). No significant positive changes were achieved in the second group. After the treatment, the overall group showed an inverse correlation between abdominal pain (VAS) and VST (BDT data) (ρ = -0.772; p < 0.01), and between gastrointestinal anxiety (VSI by J. Labus) and VST (BDT data) (ρ = -0.782; p < 0.001).

Conclusion

The effectiveness of therapy in the first group of patients was associated with the severe course of IBS, characterized by high gastrointestinal anxiety, abdominal pain, and low VST. In the overall group, post-treatment correlation analysis revealed a connection between the severity of clinical presentation and VST levels (BDT). Balloon dilatation test allows an objective assessment of IBS severity and therapeutic effectiveness. The treatment of choice for severe IBS-D is the SNRI duloxetine, which acts on the pain center and patients' emotional status.

Introduction

Agonists and antagonists of G protein-coupled receptors (GPCRs) are widely used medications that serve in the therapy of constipation, diarrhea, and pain. However, little is known about how the effect of those drugs is modulated by Regulator of G Protein Signaling (RGS) proteins which promote timely silencing of the GPCR responses. RGS proteins have been documented to regulate the magnitude and duration of signals initiated by several types of GPCRs occurring in the GI tract, including opioid and cannabinoid receptors. Serving as a central control point in GPCR signaling cascades, RGS proteins hold great promises as targets for the drug development however their expression profile and function in the gut constitute a major gap in the knowledge.

Aims & Methods

The major emphasis of this study is on elucidating the expression and function of RGS proteins in physiology and pathophysiology of the GI tract. We hypothesize that identification of RGS proteins and GPCR signaling pathways that they control will reveal novel molecular targets combating GI disorders. METHODS: We used total RNA sequencing to evaluate the expression profile of RGS proteins in the mouse ileum and colon. Then we confirmed the expression of the most abundant transcripts with the qPCR and measured the expression of proteins with Western blot. Then in the in vivo conditions we used an RGS6 knockout (RGS-/-) mouse model to evaluate the effect of this protein on intestinal motility, pain and inflammation in naïve mice as well in the presence of the cannabinoid agonist WIN 55,212-2.

Results

RNA sequencing showed similar profile of expression of RGS proteins in the ileum and colon. qPCR analyses showed that Rgs2, 5 and 6 are the most abundant transcripts in the colon. At the level of protein we observed that RGS6 exhibits the highest expression in the ileum colon as well as intestinal intraepithelial lymphocytes. Moreover we observed a significant increase in RGS6 expression in the mouse colon samples during intestinal inflammation. In vivo experiments showed that RGS6-/- animals exhibit increased intestinal motility in physiological conditions and resistance to stress-induced diarrhea. Moreover RGS6-/- animals exhibit anti-nociceptive phenotype and are more susceptible to the analgesic effect of WIN 55,212-2. We did not observe the impact of RGS6 on the severity of colitis in the DSS-induced model.

Conclusion

Here we present RGS6 protein as a novel candidate for drug targeting in the GI tract. Our study suggests that loss and perhaps also pharmacological blockade of RGS6 might be used as standalone or an adjunct treatment to increase the potency of cannabinoids in the gut. The project is ongoing and further experiments are pending.

Introduction

Irritable bowel syndrome with diarrhea (IBS-D) is a common gastrointestinal disorder that presents chronic abdominal pain and altered bowel habits. Although treatments like loperamide exist, many patients have challenges with symptom relief. Eluxadoline, a mixed opioid receptor agonist and antagonist, has shown promise to reduce abdominal pain and diarrhea in Phase 3 trials.

Aims & Methods

The aim of the study appears to be to evaluate the efficacy and safety of Eluxadoline 100 mg versus placebo for the treatment of irritable bowel syndrome (IBS), with a focus on assessing both clinical outcomes (e.g., abdominal pain, stool consistency) and adverse events.
We conducted a comprehensive search of PubMed, Scopus, Web of Science, Embase, and Cochrane from their inception to April 2025, focusing on randomized controlled trials (RCTs) and observational studies evaluating Eluxadoline 100 mg versus placebo for the treatment of irritable bowel syndrome. Meta-analyses were performed using a random-effects model, with adverse events reported as the number of events and total patients. This approach was critical for calculating odds ratios (ORs) and mean differences (MDs), along with their 95% confidence intervals (CIs).

Results

Out of 1220 studies initially screened, 5 studies met the inclusion criteria for our meta-analysis, comprising 7,198 adult patients. , Eluxadoline 100 mg exhibited mixed efficacy outcomes compared to placebo. While the worst abdominal pain (WAP) responder rate was non-significantly trending in favor of Eluxadoline (RR 1.20, 95% CI 0.95–1.51; P = 0.13), the composite responder rate (simultaneous improvement in pain and stool consistency) was numerically better but not statistically significant (RR 1.68, 95% CI 0.98–2.87). Interestingly, Eluxadoline improved stool .
Safety analysis revealed expected gastrointestinal side effects, with significantly higher proportions of constipation (RR 3.36, 95% CI 2.19–5.15; P < 0.01) and nausea (RR 1.46, 95% CI 1.05–2.04; P = 0.03) among the Eluxadoline treatment group.

Conclusion

Eluxadoline 100 mg improved stool consistency but was not significantly helpful in lowering abdominal pain as a single endpoint. Composite responder analysis showed a clinically meaningful but not statistically meaningful benefit. The safety profile was consistent with anticipated μ-opioid agonist effects, making patient selection of particular importance, particularly in those prioritizing diarrhea control over pain reduction. Prediction of response predictors should be ascertained in future studies to optimize eluxadoline use in IBS-D.

References

1. Lembo AJ, Covington PS, Dove LS, Andrae DA. Effects of treatment with eluxadoline on abdominal pain in patients with IBS-D: Additional post hoc analyses of Phase 3 trials. Neurogastroenterol Motil. 2020 Apr;32(4):e13774. doi: 10.1111/nmo.13774. Epub 2020 Jan 27. PMID: 31984655; PMCID: PMC7154635.
2. Brenner DM, Sayuk GS, Gutman CR, Jo E, Elmes SJR, Liu LWC, Cash BD. Efficacy and Safety of Eluxadoline in Patients With Irritable Bowel Syndrome With Diarrhea Who Report Inadequate Symptom Control With Loperamide: RELIEF Phase 4 Study. Am J Gastroenterol. 2019 Sep;114(9):1502-1511. doi: 10.14309/ajg.0000000000000327. PMID: 31356229; PMCID: PMC6738625
3. Lacy BE, Chey WD, Cash BD, Lembo AJ, Dove LS, Covington PS. Eluxadoline Efficacy in IBS-D Patients Who Report Prior Loperamide Use. Am J Gastroenterol. 2017 Jun;112(6):924-932. doi: 10.1038/ajg.2017.72. Epub 2017 Apr 18. Erratum in: Am J Gastroenterol. 2017 Jul;112(7):1210. doi: 10.1038/ajg.2017.152. PMID: 28417992; PMCID: PMC5465428.
4. Chey WD, Dove LS, Andrae DA, Covington PS. Early response predicts a sustained response to eluxadoline in patients with irritable bowel syndrome with diarrhoea in two Phase 3 studies. Aliment Pharmacol Ther. 2017 May;45(10):1319-1328. doi: 10.1111/apt.14031IF: 6.6 Q1 . Epub 2017 Mar 22. PMID: 28326568; PMCID: PMC5413805.

Introduction

Functional abdominal pain is a common disorder for which pharmacological strategies are still inadequate. Melatonin has many direct and indirect effects on the gastrointestinal tract and seems to have an important influence on the brain-gut axis.

Aims & Methods

We aimed to assess the efficacy of melatonin versus placebo for treating patients with functional abdominal pain, performing subgroup analyses by age range, dosage of melatonin, and follow-up time. We systematically searched PubMed, Embase, and Cochrane Library databases until March 31, 2024. The primary outcome was the improvement of abdominal pain severity. The secondary outcomes were reduction in abdominal pain frequency and improvement in quality of life. We analyzed continuous outcomes using the standardized mean difference (SMD) with 95% confidence interval (CI). We used random-effects model, and statistical significance was regarded at p-value <0.05. Between-study heterogeneity was assessed using Cochran’s Q test and I² statistics. Statistical analyses were performed using R statistical software. We assessed the certainty of evidence for each outcome using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool.

Results

Five randomized controlled trials (including 236 patients) were included. The summary of findings for the primary and secondary outcomes is shown in Table 1. Melatonin was associated with greater improvements in abdominal pain severity (SMD 1.18; 95% CI 0.75, 1.61), abdominal pain frequency (SMD 1.19; 95% CI 0.62, 1.75), and quality of life (SMD 0.47; 95% CI 0.05, 0.88) compared to placebo. The subgroup analysis of adult patients showed that melatonin had a significantly greater decline in pain severity (SMD 1.13; 95% CI 0.57,1.69) and pain frequency than placebo (SMD 1.30; 95% CI 0.51,2.09). In the subgroup analysis based on the lowest dosage of melatonin (3 mg), the intervention showed a greater decline in pain severity scores compared to placebo (SMD 1.14; 95% CI 0.58,1.69). When analyzing only studies with longer follow-up (≥8 weeks), melatonin improved pain severity (SMD 0.56; 95% CI 0.04,1.07), pain frequency (SMD 0.89; 95% CI 0.04,1.76), and quality of life (SMD 0.56; 95% CI 0.003,1.11) compared to placebo.

Table 1. Results from the pooled analyses

Conclusion

In patients with gastrointestinal functional disorders, melatonin was associated with a statistically significant decline in abdominal pain severity and frequency when compared to placebo, as well as greater improvement in quality of life. The subgroup analyses suggest that the improved outcome can be achieved even with low melatonin dosage, may be sustained over a longer follow-up time, and is effective in adult patients.

References

1. Dipasquale V, Palermo L, Barbalace A, et al. Randomised controlled trial of melatonin for paediatric functional abdominal pain disorders. J Paediatr Child Health 2023; 59: 458–463.
2. Lu WZ, Gwee KA, Moochhalla S, et al. Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Aliment Pharmacol Ther 2005; 22: 927–934.
3. Saha L, Malhotra S, Rana S, et al. A preliminary study of melatonin in irritable bowel syndrome. J Clin Gastroenterol 2007; 41: 29–32.
4. Song GH, Leng PH, Gwee KA, et al. Melatonin improves abdominal pain in irritable bowel syndrome patients who have sleep disturbances: a randomised, double blind, placebo controlled study. Gut 2005; 54: 1402–1407.
5. Faghih Dinevari M, Jafarzadeh F, Jabbaripour Sarmadian A, et al. The effect of melatonin on irritable bowel syndrome patients with and without sleep disorders: a randomized double-blinded placebo-controlled trial study. BMC Gastroenterol 2023; 23: 135.