Introduction

Real-time symptom assessment provides a detailed understanding of the dynamic interplay between gastrointestinal symptoms in irritable bowel syndrome (IBS) and potential triggers, including affect and environmental factors. This study evaluates the association between abdominal pain and potential triggers over time in IBS patients with and without comorbidities, using the Experience Sampling Method (ESM) as a real-time, ecologically valid measurement method.

Aims & Methods

In this prospective, observational multicenter study, as part of the DISCOvERIE project, we included 215 Rome IV IBS patients (80% female; mean age 42.1) from six European countries, categorized into 103 IBS-alone, 67 IBS-mental (anxiety/depression), 16 IBS-somatic (fibromyalgia/chronic fatigue syndrome), and 29 IBS-multicomorbid patient subgroups. Participants scored abdominal pain and affect using an 11-point Numeric Rating Scale and environmental factors using ESM at up to ten random moments each day over seven consecutive days. Linear mixed-effects models analyzed the associations between abdominal pain and these potential triggers, both concurrently and predictively (trigger scores lagged by one time point, maximum of 90 minutes), in each subgroup.

Results

ESM assessment completion rate was 63%. Regarding affect triggers, abdominal pain was significantly correlated with concurrent positive and negative affect in all IBS groups (p<0.02), while significant lagged associations were only found within IBS-mental for positive affect (p=0.02) and within IBS-alone and IBS-multicomorbid for negative affect (p<0.001). Regarding environmental triggers, abdominal pain was significantly associated with concurrent ‘feeling comfortable in situation’ within IBS-alone, IBS-mental and IBS-multicomorbid (p<0.001), concurrent ‘feeling of pleasantness of company’ (p=0.01) and being alone (versus with somebody, p=0.01) within IBS-alone, and eating since the last ESM-assessment within IBS-alone (p=0.04) and IBS-multicomorbid (p=0.002). No significant lagged associations or correlations with location, activity, alcohol consumption, and nicotine use were found.

Conclusion

Our results demonstrate that in IBS patients, real-time abdominal pain is significantly associated with environmental and affect triggers, with both positive and negative affect correlating with abdominal pain irrespective of mental comorbidities. Moreover, fewer triggers predict abdominal pain over time, underscoring the importance of in-the-moment assessments. This study highlights the value of ESM in accurately identifying symptom triggers, thereby enhancing personalized healthcare in IBS.

Disclosure

MB, LV, MH, IM, SM, MRB, and DD declare no conflicts of interests. DJ has received research funding from public-private partnership grants of Top Knowledge Institute (TKI) Agri&Food and Health Holland, by the Carbokinetics program as part of the NWO-CCC Partnership Program, and by Organic A2BV/Mothersfinest BV. DK has received research funding from ZonMw, MLDS, UEG, Rome Foundation, Horizon Europe, Horizon 2020, Grunenthal, Allergan and speaker’s fee from Dr Falk (paid to host institute).

Introduction

Non-celiac gluten/wheat sensitivity (NCGWS) is characterized by gastrointestinal and extra-intestinal symptoms triggered by gluten/wheat ingestion. Symptoms of NCGWS overlap with those of irritable bowel syndrome (IBS) or functional dyspepsia (FD). Due to diagnostic challenges and symptom overlap, data on the prevalence and predictors of NCGWS among patients with IBS or FD, especially those with refractory symptoms, are limited.

Aims & Methods

This was a prospective, multicentric, double-blind, placebo-controlled, crossover trial conducted from October 2021 to March 2023 in India.This was prospectivly registered with the clinical trials Registry, INDIA (CTRI/2021/10/037323). Adults aged 18–65 years with Rome IV-defined irritable bowel syndrome (IBS) or functional dyspepsia (FD) refractory to standard treatment were enrolled after excluding celiac disease, wheat allergy, and alarm features. Participants underwent a two-step diagnostic protocol. In Step I, patients adhered to a 6-week strict gluten-free diet (GFD) under dietitian supervision. Weekly assessments of gastrointestinal and extra-intestinal symptoms, health-related quality of life (HRQoL), and psychological scores were performed using validated instruments. Gluten responders—defined by ≥30% reduction in one to three primary symptoms—were advanced to Step II: a randomized, double-blind, placebo-controlled gluten challenge with crossover. Subjects received indistinguishable gluten or placebo cookies (8 g/day) for one week, followed by a one-week washout and crossover. A ≥30% symptom difference between gluten and placebo phases confirmed non-celiac gluten/wheat sensitivity (NCGWS). Primary outcome was NCGWS prevalence; secondary outcomes included symptom and HRQoL changes post-GFD and predictors of NCGWS. Statistical analyses included intention-to-treat principles and multivariable regression to identify baseline predictors.

Results

Of the 252 patients screened, 177 were enrolled for 6-week GFD (step I), and 154 patients completed this phase (mean age 41.9±14.2 years, 53.2% males). Eighty two (52.3%) patients responded to GFD, of whom 77 entered step 2 (DBPCGC). Thirty one (20.1%) patients had significant symptom worsening on blinded gluten ingestion, suggesting the presence of NCGWS. Independent predictors of NCGWS were female gender, FD-IBS overlap, headache, fatigue, and anxiety. Significant improvements in gastrointestinal symptoms, health-related quality of life, and psychological scores were observed after GFD in responders. No significant impact of diet sequence was noted.

Conclusion

Introduction

Human transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis, spurring development of the oral TG2 inhibitor ZED1227. In the phase 2a CEC-003/CEL study in CeD patients on a gluten-free diet (GFD), once-daily treatment with ZED1227 with gluten challenge (3 g/day) for 6 weeks led to significant improvement in the ratio of intestinal villous height to crypt depth (VH:CrD) versus placebo.¹ Despite adherence to a gluten-free diet, up to half of CeD patients report persistent symptoms often combined with varying degrees of small intestinal injury. Hence, potential treatments for CeD should ideally address these symptoms and improve mucosal injury.

Aims & Methods

The aim of the present study was a dose-ranging trial of ZED1227 in CeD patients with residual symptoms and villous atrophy despite a GFD. This was a double-blind, randomized, placebo-controlled phase 2b study. It enrolled adult CeD patients who had followed a GFD for at least one year and who experienced at least one moderate or severe gastrointestinal (GI) symptom in the month prior to baseline. All patients underwent an initial 5-week placebo run-in phase, followed by endoscopy and 1:1:1:1 randomization of patients with VH:CrD ≤2.5. Treatment was placebo thrice-daily (TID) or ZED1227 at doses of 10 mg TID, 25 mg TID, or 50 mg once-daily (QD) for 12 weeks. No gluten challenge was carried out. The primary endpoint was the rate of patients with both improvement by ≥ 0.4 in VH:CrD and improvement by ≥ 15% in either of two symptom scores (non-stool GI or diarrhea severity) on the celiac disease symptom diary (CDSD) from the end of the run-in phase to week 12. Key secondary endpoints included the change in VH:CrD, change in CDSD GI total severity score, and safety.

Results

A total of 397 patients were randomized to the 4 arms, of whom 92.7% completed treatment. The primary endpoint was achieved by 27.1% of patients receiving 10 mg ZED1227 TID, 16.9% for 25 mg TID, 25.3% for 50 mg QD, and 19.3% for placebo, with no significant differences between any treatment arm and placebo. The mean change in VH:CrD ratio from baseline was 0.21 for 10 mg ZED1227 TID, 0.17 for 25 mg TID, and 0.26 for 50 mg QD versus 0.12 for placebo. Within-group changes from baseline to week 12 were statistically significant within each arm, while the between-group difference in changes was significant only for 50 mg ZED1227 QD versus placebo (p<0.05). Similarly, mean changes in the CDSD GI total severity score were -0.96 with 10 mg ZED1227 TID, -0.95 with 25 mg TID, -1.20 with 50 mg QD, and -1.05 with placebo. Improvements within each arm were again statistically significant, with no significant differences between any treatment arm and placebo. There were no notable differences in the rates of adverse events or serious adverse events (SAEs) between the study arms, and no SAEs related to the study drug were reported.

Conclusion

The CEC-004/CEL study did not meet its primary endpoint of combined improvement in histology and symptoms. However, changes in the VH:CrD ratio achieved with 50 mg ZED1227 QD were statistically superior to placebo, consistent with the results of the prior CEC-003/CEL study. Significant within-group improvement from baseline to week 12 in both histologic and symptom outcomes within the placebo group underscored the challenges of clinical trials without deliberate gluten exposure in patients with the heterogeneous symptom and histology typical of partially treated CeD. The favorable safety profile of ZED1227 was confirmed, and no new safety concerns were identified.

References

1. Schuppan D, Maki M, Lundin KEA, Isola J, Friesing-Sosnik T, Taavela J, et al. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. N Engl J Med. 2021;385(1):35-45.

Disclosure

Sponsor of the trial: Dr. Falk Pharma GmbH
Acknowledgement: This research was supported by Takeda.

Introduction

Spasmolytic polypeptide expressing metaplasia (SPEM) is a cell repair lineage and is a very important phenotype of gastric mucosal injury and precancerous lesion.
Previously, parietal cells loss is considered as the first step and followed with chief cells transdiffernation to induce SPEM. But whether chief cells initial loss cause SPEM
needs to be further investigation. Acidic mammalian chitinase (CHIA) belongs to the 18 glycosidase family and is highly expressed in the chief cells. Our previous study showed that CHIA deficiency in the chief cells is the key event to induce SPME to progress to gastric cancer (Liu et al., DDW 2023 and 2024). However, the molecular role of CHIA in the development of SPEM is need further investigated.

Aims & Methods

Electron microscopy, qRT-PCR and single-cell sequencing (scRNA-seq) technology, as well as histopathological and immunofluorescence (IF) stainning with specific markers were performed in chief cells specific CHIA knockout mouse model (CHIA^rox/rox-GIF-Dre) and wild-type mice(CHIA^rox/rox), and in CHIA over - expression mice (CHIA ^rox/rox - GIF - Dre + rAAv - CHIA) and the control group (CHIA ^rox/rox - GIF - Dre + rAAv - control).

Results

Compared with CHIA^rox/rox mice, histological analysis and scRNA-seq technology data showed that loss of chief cells with increased M2 macrophage infiltration and final SPEM formation, but remaining of parietal cells in CHIA^rox/rox-GIF-Dre mice. Electron microscopy showed CHIA deficiency in mice resulted in endoplasmic reticulum was dilated and swollen, as well as the mitochondrial membrane was discontinuous of chief cells, followed with the accumulation of endoplasmic reticulum stress marker, including PERK, XBP-1, eIF2α/P-eIF2α, and GRP78, together with upregulation of pyroptosis-related marker, including NLRP3, ACS, GSDMD, NEK7, Caspase1, Caspase11, IL-1β, and IL-18, which was detected by qRT-PCR. These data indicating that target CHIA deletion caused chief cells pyroptosis. Furthermore, qRT-PCR analysis showed that CHIA deficiency caused the activation of IL33/IL-13 circuit in the mucosa of mice. Moreover, double immunofluorescence staining confirmed that upregulation and colocalization of IL-33 induced M2 macrophage polarization markers, including F4/80 and CD163⁺ with NLRP3 in the base of gastric mucosal of CHIA^rox/rox-GIF-Dre mice when compared with CHIA^rox/rox mice.Notably, CHIA ^rox/rox - GIF - Dre + rAvv - CHIA mice reversed the above process compared with controls.

Conclusion

Chief cells specific CHIA deficiency resulted in endoplasmic reticulum stress mediate NLRP3 inflammasome activation to induce chief cells proptosis.
Chief cells initial loss is sufficient and the key step to activate IL-33/ST2-M2 macrophage polarization axis to induce SPEM, which is independent of parietal cells loss.