Introduction

The synthetic peptide p31–43, derived from α-gliadin, is known to elicit innate immune responses and epithelial stress in the small intestine. In murine models, intragastric administration of p31–43 reproduces some of the key features of celiac disease (CeD), including reduced villus-to-crypt (V/C) ratio, intraepithelial lymphocyte (IEL) infiltration, production of proinflammatory mediators, inflammasome activation, and epithelial cell death. Previously, we reported that Saccharomyces boulardii CNCM I-745 (S.b.) pre-treated mice effectively prevented histological alterations and inflammation in the proximal small intestine triggered by a single intragastric administration of p31-43 peptide. To better replicate the chronic and progressive nature of small intestinal inflammation observed in human pathology, such as in CeD, we developed a more stringent and sustained model through repeated p31–43 exposure.

Aims & Methods

To evaluate whether the histological and inflammatory changes induced by a three-week intragastric administration of the gliadin peptide p31-43, could be alleviated by concomitant treatment with S.b.
Seven-week-old C57BL/6 mice received daily oral gavage of either S.b. (3 g/kg/day) or vehicle for three weeks. Concurrently, animals were challenged five times per week with 40 µg of the p31-43 gliadin peptide (LGQQQPFPPQQPY) via intragastric administration, either alone or in combination with S.b. (p31-43+S.b.). Sixteen hours after the final challenge, mice were euthanized, and the small intestine was collected for histological and molecular analyses. Histological assessments included V/C ratio, IEL, and Goblet cell count. Caspase-1 activation was evaluated by Western blot (WB) to assess inflammasome activation. Expression of genes related to inflammation and tissue repair was assessed by RT-qPCR. Statistical significance was determined using ANOVA.

Results

Histological analysis revealed that S.b. significantly prevented mucosal alterations induced by p31–43, restoring V/C ratio (p = 0.025) and reducing IEL infiltration (p = 0.08). No significant changes were observed in Goblet cell numbers; however, MUC2 mRNA expression was significantly upregulated after three weeks of p31-43 exposure independently of S.b. intervention (p=0.01). Markers related to epithelial cell proliferation and differentiation (ATOH1/HES1) suggested a trend toward enhanced differentiation of secretory epithelial cells in mice treated with S.b., either alone or in combination with p31-43.
RT-qPCR analysis of genes associated with barrier protection, including AREG, REG3g, and RELMB did not reveal significant changes. However, exposure to p31-43 led to upregulation of proinflammatory genes such as MX1, IFNβ, and CXCL10. Notably, S.b. treatment effectively blocked the p31-43-induced upregulation of CXCL10 (p=0.09). WB further demonstrated that S.b. attenuated caspase-1 activation, indicating suppression of p31-43-induced inflammasome activation (p=0.09).

Conclusion

This study demonstrates that treatment with S.b. effectively impedes the mucosal damage and inflammation induced by gliadin peptide p31-43. Although Goblet cell numbers remained unchanged, the upregulation of MUC2 expression suggests an enhanced mucosal defense response. S.b. also suppressed key inflammatory markers, including CXCL10 and caspase-1 activation. Collectively, these findings support the therapeutic potential of Saccharomyces boulardii CNCM I-745 in managing gliadin-induced intestinal damage and highlight its promise for preventing or alleviating intestinal pathology caused by sterile inflammation.

Disclosure

Biocodex (France) funded this study, but did not play a role in the experiment design or the results analysis

Introduction

Hypermobile Ehlers-Danlos syndrome (hEDS) is a hereditary non-inflammatory disorder of connective tissue laxity characterized by joint hyperextensibility in association with musculoskeletal symptoms. The prevalence of gastrointestinal (GI) symptoms, such as abdominal pain, nausea, and constipation is high in hEDS. Research on the relationship between EDS and GI symptoms has mostly been restricted to disorders of the gut-brain axis, whereas the relationship between hEDS and GI dysmotility remains to be clarified.

Aims & Methods

This study aimed to explore antro-duodenal manometry (ADM) patterns in patients with hEDS presenting with GI symptoms.

In a prospective open-label study, patients with hEDS and GI symptoms presumed to be the results of GI dysmotility underwent a 6-hour high resolution ADM. The manometry tracings were analyzed by two investigators (KS and JC) independently. Antral contraction frequency (contractions per minute) < 1.0 was considered as antral hypomotility. Pylorospasm was defined as isolated pyloric pressure waves within 60 minutes postprandial. The following neuropathic enteric patterns were scored: presence of retrograde peristalsis, bursts, clustered contractions, and absence of phase III contractions. Abnormal ADM was defined as having antral hypomotility and/ or pylorospasm and/ or neuropathic enteric patterns.

Results

Fifty patients (48 women, mean age 30.4 ± 11.1 yrs.) were included. At baseline, 74% of patients were dependent on enteral feeding and the mean BMI was 20.4 ± 4.4 kg/m².
Overall, ADM tracings with one or more abnormal patterns were identified in 53% of patients. Antral hypomotility and pylorospasm were detected in 29% and 15% of patients, respectively. Neuropathic enteric patterns were only seen in 17% of patients. In all cases, no more than one neuropathic pattern was identified. Among the observed neuropathic enteric patterns, 15% of patients showed retrograde peristalsis, 13% absence of phase III contractions, and 2% bursts. Clustered contractions were not identified in this cohort.

Conclusion

Hypermobile Ehlers-Danlos patients presenting with gastrointestinal symptoms showed low numbers of abnormal ADM patterns. In particular, enteric dysmotility was observed in only a small minority of cases. Antroduodenal dysmotility therefore does not appear to be a principle pathomechanism in the majority of hEDS cases studied. Further research is needed to understand the mechanisms that underlie GI symptom generation in this population.

Introduction

Current evidence suggests that joint complaints without any underlying rheumatic condition are common in patients with celiac disease. This important clinical aspect of non-rheumatic joint complaints has not systematically been investigated and the prevalence of joint complaints is not known.

Aims & Methods

The aim of this study was to estimate the prevalence of joint complaints in patients with celiac disease through a systematic review and meta-analysis of existing literature. We searched Medline, Embase, Cochrane, and Web of Science databases for studies reporting joint complaints in patients with celiac disease between January 1, 1990 and November 26, 2024. Search results were screened by two independent reviewers. The quality of included studies was appraised and meta-regression analysis performed. A study protocol was pre-registered in the PROSPERO database and results were reported according to the PRISMA guidelines.

Results

A total of 7,414 publications were identified in the search. Of these, 226 were reviewed in full-text and 27 included in the meta-analysis. Among 6,901 patients with celiac disease, 530 had joint complaints, yielding a weighted pooled prevalence of 10.7% (95 % CI 6.9-15.1). Stratified by adults (n=17 studies) vs. children (n=13 studies), the pooled prevalence was 16.8% (95% CI 9.0-26.3) in adults compared with 6.4% (95% CI 3.4-10.1) in children. In comparison by region, studies in South and North America (n=5) showed the highest weighted pooled estimate (12.9%; 95% CI 8.7-17.8). Europe (n=15) had the second highest (12.4%; 95% CI 6.8-19.4, and Asia (n=3) the lowest prevalence (5.2%; 95% CI 0.0-18.3). In meta-regression analysis, no association between the prevalence of joint complaints and study characteristics or demographics was found.

Conclusion

One in 10 patients with celiac disease suffers from joint complaints that are not directly associated with any specific rheumatic comorbidity. This indicates that joint complaints are extraintestinal manifestations in patients with celiac disease, occurring more frequently than commonly thought. Increased awareness of joint complaints is warranted to improve the clinical care of patients with celiac disease.

Disclosure

Drs. Poddighe, Galiyeva, Zhubanova and Mussina declare no conflicts of interest. Dr. Forss has served as a speaker and an advisory board member for Janssen Cilag AB and Tillotts Pharma.

Introduction

Qualitative exit interviews provide key insights into patient experience and treatment expectations, which are particularly important in celiac disease (CeD) for which there are no current medications. Data relating to patients’ experiences are critical to understand what is considered a ‘meaningful change’ to patients when they participate in clinical trials. The objective of this study was to understand the clinical trial participants’ experience of CeD, their treatment expectations, and how they define meaningful changes in their symptoms as they exited from a phase 2 clinical trial.

Aims & Methods

Semi-structured telephone interviews of 60 minutes were conducted with eligible patients following a phase 2 double-blind, randomized, placebo-controlled trial in patients with moderate-to-severe CeD who maintained a gluten-free diet (GFD) for ≥ 12 months (NCT05353985).¹ Patients could provide more than one response to some questions. Interviews were blinded to treatment assignment and were audio recorded, transcribed and coded guided by an a priori coding dictionary and a qualitative analysis plan. Transcript analysis was facilitated by ATLAS.ti 9 software. This study was approved by the relevant Institutional Review Boards as part of the phase 2 trial.

Results

Overall, 29 English-speaking patients from 15 clinical sites in the USA were interviewed. Three patients exited the trial early. Most participants were female (23/29, 79.3%), the mean age was 50.6 years, and the mean duration of disease before study enrollment was 6.9 years. These characteristics were similar to the full clinical trial population in which most patients were female (115/153, 75.2%), the mean age was 46 years, and the average time to CeD diagnosis was 9 years. The most commonly reported symptoms were abdominal pain (27/29, 93.1%), bloating (26/29, 89.7%), and diarrhea (24/29, 82.8%). The most bothersome symptom reported was diarrhea (12/29, 41.4%).
Participants most often stated that they were hoping for an improvement in their CeD (25/29, 86.2%) providing descriptions that included the desire to be able to eat without the worry of potential gluten contamination.
Participants were asked if a ‘symptom-free day’ (SFD) (defined as a day with no diarrhea, abdominal pain, bloating, or nausea) would be meaningful. All participants agreed that the concept of SFD is important, with the majority stating that an increase of 1–2 SFDs per week would be meaningful (20/28, 71.4%).
Participants were also asked what improvements on the PGIS (Patient Global Impression of Severity) and PGIC (Patient Global Impression of Change) scales would be meaningful to them (participants could provide multiple responses). The majority (31 responses) reported that a 2-point decrease in severity would represent a meaningful improvement, followed by 21 responses for a 1-point decrease in PGIS. Regarding PGIC, most patients (15/25, 60.0%) stated that ‘much improved’ would indicate a meaningful change, followed by ‘a little improved’ (6/25, 24.0%).

Conclusion

Despite adhering to a GFD, patients experienced frequent and bothersome symptoms, particularly abdominal pain, bloating, and diarrhea, prior to enrolling in the study. This study identified potential thresholds for meaningful improvement in weekly SFDs and PGIS and PGIC scales. These data are important to inform the design and interpretation of future CeD clinical trials.

References

1. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/study/NCT05353985 (Accessed April 1, 2025).

Disclosure

SG, MA, and DAL are employees of Takeda Development Center Americas, Inc. and receive stock or stock options. NH and SM are employees of RTI Health Solutions which received funding from Takeda for participation in this study.

Introduction

Nanoparticles containing gliadin (TAK-101) are under development to induce gliadin tolerance in patients with celiac disease (CeD). We assessed the immunomodulatory signature induced by TAK-101 treatment in a mouse model of CeD.

Aims & Methods

Human leukocyte antigen (HLA)-DQ8 transgenic mice were intravenously pretreated on Days −11 and −3 with 2.5 mg TAK-101 or were not pretreated (‘gliadin immunization-only’). Animals were then immunized with gliadin on Day 0 and boosted on Day 14. Mice from both groups were sacrificed after 1month. After sacrifice, spleen cells were cultured for 3 days with gliadin, and supernatant cytokine and antigliadin IgG2c antibody levels assessed. Single cell RNA-Seq was performed on cultured spleen cell samples from both groups (n=4).

Results

Production of complement-fixing anti-gliadin IgG2c and pro-inflammatory cytokines, including interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor α (TNFα), IL-17, IL-6 and IL-22 was reduced in splenic cells of TAK-101-treated relative to gliadin immunization-only mice. Differential expression of 1380 genes was demonstrated in B cells following TAK-101 treatment relative to gliadin immunization-only, confirming earlier results from bulk RNA-Seq, including of fractionated B cells. Transcriptomic changes in B cell activation, signaling, proliferation and apoptosis pathways (Gene Ontology) were significantly associated with TAK-101 treatment, while manually curated pathways for B cell anergy and regulatory B cells also matched the identified gene signature.

Conclusion

B cells appear to be important for the immunomodulation of the adaptive gliadin immune response by TAK-101.