Introduction

Irritable bowel syndrome (IBS) and functional dyspepsia (FD) are common disorders of gut-brain interaction (DGBI), and bloating and visible abdominal distension are common symptoms among individuals with IBS and/or FD. Bloating refers to a subjective sensation of tension or pressure in the abdomen, which may or may not be reported together with visible abdominal distension. The underlying pathophysiological mechanisms may differ, with bloating suggested to be more related to hypersensitivity and visible abdominal distension to altered motility. The prevalence of these two symptoms in IBS and FD, especially as distinct symptoms, is not well known.

Aims & Methods

The aim was to investigate the link between bloating and distension with IBS and FD. Therefore, we performed a population-based internet survey of adults in the US, UK, and Mexico, including Rome IV IBS and FD diagnostic questions, somatization (PHQ-12), and psychological distress (PHQ-4). Four groups were created: those meeting the Rome IV criteria for IBS only, FD only, both IBS+FD, and a reference group including individuals without IBS, FD and organic diagnoses that could result in IBS- or FD-like symptoms. Within each group, we identified individuals who reported ≥weekly bloating alone (B), ≥weekly visible abdominal distension alone (D), ≥weekly combined B+D, or neither of both. The relationship between B, D and B+D in those with IBS and/or FD vs. the reference group was investigated using logistic regression models.

Results

The analysis included 5,448 participants (49.7% female; mean age 46.5 years, range 18-99), with 131 meeting criteria for IBS only, 360 for FD only, 217 for IBS+FD and 4,740 for the reference group. A larger proportion of individuals with IBS only (64.9%), FD only (50.6%), and especially those with IBS+FD (88.5%) reported bloating and/or visible abdominal distension compared to the reference group (13.7%). In the IBS only group, 16.0% reported bloating alone, 8.4% visible abdominal distension alone, and 40.5% combined bloating and visible abdominal distension. In the FD only group this was 12.8% (B), 8.9% (D), and 28.9% (B+D), and in the IBS+FD group 18.9% (B), 8.3% (D), and 61.3% (B+D), respectively. Reporting bloating alone or combined bloating and visible abdominal distension was strongly linked to fulfilling criteria for IBS only, FD only, and concomitant IBS+FD vs. the reference group, with weaker links for visible abdominal distension in the absence of bloating (Table). After adjusting for age, sex, BMI, psychological distress and somatization, the links persisted. The strongest association was observed between combined bloating and visible abdominal distension (vs. neither) and concomitant IBS+FD (vs. the reference group); adjusted odds ratio 28.6 [95%CI 17.6-46.6].

Conclusion

Bloating and visible abdominal distension as distinct and overlapping symptoms are strongly linked to IBS, FD, and concomitant IBS+FD in the general population. Assessing bloating and visible abdominal distension as separate symptoms may be important to enable individualized treatment for individuals with IBS and FD.

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

Avoidant/restrictive food intake disorder (ARFID) is characterized by reduced dietary intake leading to medical and/or psychosocial impairment, independent of body image concerns. Its prevalence in gastrointestinal (GI) disorders remains unclear despite frequent symptom-induced restrictive eating behaviors.

Aims & Methods

We aim to assess the prevalence and characteristics of ARFID in patients with various GI disorders compared to healthy volunteers (HV), and its associations with symptom severity, extraintestinal somatic symptoms and depression.
Data from 92 HV and 467 GI patients across seven tertiary care diagnostic categories —including irritable bowel syndrome (IBS, n=88), functional dyspepsia (FD, n=83), (refractory slow transit) constipation (n=59), reflux (n=107), globus (n=45), (non-obstructive) dysphagia (n=37), and achalasia (n=48)—were analyzed. Questionnaires included Rome IV criteria, ARFID screening, extraintestinal symptoms and depression scores (PHQ-12/9). Positive NIAS screening (NIAS+) was defined as meeting any subscale cutoff (≥10 for Picky Eating, ≥9 for Appetite, and ≥10 for Fear). Medical and/or psychosocial impairment in NIAS+ individuals was evaluated using the ARFID DSM-5 checklist. ARFID+ was defined as NIAS+ plus DSM-5 impairment. Odds ratios were calculated using a multiple logistic regression model with three-level hierarchical approach. Odds of fulfilling ARFID or NIAS criteria between DGBI diagnoses (step 1) were adjusted for z-scores of symptom severity (step 2) and extra-intestinal somatic symptoms and depression (step 3). Esophageal and non-esophageal disorders were analyzed separately.

Results

Table 1 shows demographics and characteristics of patients. Compared to HV, ARFID+ was significantly associated with IBS (OR: 15.00, p < 0.001), FD (OR: 10.59, p = 0.002), constipation (OR: 18.21, p < 0.001), dysphagia (OR: 7.03, p = 0.024) and reflux (OR: 5.16, p = 0.036), but not with achalasia and globus. Within disease categories, there were no differences in the odds of ARFID+ after adjusting for symptom severity (step 2) and for comorbid extraintestinal symptoms and depression (step 3). Increase in PHQ9, contributed independently to the presence of ARFID in non-esophageal disorders (OR: 1.11, p = 0.009).

Conclusion

ARFID symptoms are prevalent across various GI disorders. While mechanical factors may drive ARFID in esophageal conditions, psychological factors (e.g., depression) may play a role in ARFID in non-esophageal disorders. Further research is needed to establish the contribution of mechanical factors to ARFID in esophageal conditions. Routine ARFID screening is crucial to address psychosocial and nutritional impacts in GI patients.