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

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

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

Disease-specific knowledge plays a central role in chronic disease management. In patients with inflammatory bowel disease (IBD), limited knowledge is linked to poorer perceived health and increased discomfort (1).

Aims & Methods

This study assessed disease-specific knowledge among adult patients with IBD at a tertiary center and defined existing knowledge gaps. Factors associated with higher or lower levels of knowledge were explored.
The retrospective cohort study included 392 IBD patients who completed a comprehensive questionnaire between March 2020 and April 2021 (2). Questionnaire responses were analyzed alongside clinical records to quantify disease-specific knowledge. A scoring system was developed to quantify disease-specific knowledge (0–8 points), based on correct diagnosis, Montreal classification, complications, and current therapies. Scores were categorized as low (0–5) or high (6–8) knowledge levels. Associations between knowledge levels and disease-related, sociodemographic, and psychosocial factors were analyzed using logistic regression analysis.

Results

While most patients correctly identified their diagnosis (kappa: 0.863, CI: 0.816–0.905, p < 0.001) and advanced treatment (e.g. infliximab: kappa: 0.959, CI: 0.925–0.983, p < 0.001), knowledge gaps were observed regarding disease location (e.g. isolated proctitis in ulcerative colitis: kappa: 0.101, CI: –0.051–0.341, p = 0.128), complications, comorbidities, and certain other medications. In the univariate analysis a higher knowledge level was found in patients with Crohn’s disease, younger age at diagnosis, in patients with no disease activity, and treatment with biologics, in those receiving disability pension and in patients with a high Perceived Stress Questionnaire (PSQ) score for worries (table). A younger age at diagnosis (p = 0.028) and having Crohn’s disease (p < 0.001) were independently associated with higher knowledge levels whereas active disease was associated with lower disease-specific knowledge.
Table:
Univariate logistic regression analysis for items significantly associated with higher knowledge levels

Conclusion

Significant disease-specific knowledge gaps were identified, particularly concerning disease location, complications, and comorbidities. Targeted patient education should focus on addressing these specific deficits in susceptible groups.

References

1. Tormey LK, Reich J, Chen YS, Singh A, Lipkin-Moore Z, Yu A, et al. Limited Health Literacy Is Associated With Worse Patient-Reported Outcomes in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2019;25:204–12.
2. Koletzko L, Klucker E, Le Thi TG, Breiteneicher S, Rubio-Acero R, Neuhaus L, et al. Following Pediatric and Adult IBD Patients through the COVID-19 Pandemic: Changes in Psychosocial Burden and Perception of Infection Risk and Harm over Time. J Clin Med. 2021;10:4124.

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.

Introduction

Coeliac disease (CD) affects 1% of the population in the United Kingdom (U.K.) but is often underdiagnosed¹. Complications of CD include detrimental effects on bone health and increased fracture risk². Currently, evidence supporting routine serological testing for CD in adults with fractures is limited.

Aims & Methods

The aims of this study were to:
1. Determine whether the prevalence of CD among adult fracture patients exceeds the expected 1% in the general population.
2. Characterise demographic and fracture‑site patterns to identify high‑risk subgroups.
This cross-sectional observational study was conducted at a single U.K. fracture clinic with 1000 adults (≥16 years) with a fracture recruited between April 2023 and April 2025. Patients under 16 or unable to provide consent were excluded. Patients with known CD were included. Demographic data (age, gender, ethnicity) and fracture sites were recorded. Anti-tissue transglutaminase antibody (tTG-IgA) tests were performed unless known to have CD. Equivocal tTG-IgA results were reviewed by a gastroenterologist, and repeat testing was conducted if needed. Seropositive participants were invited for duodenal biopsy. Laboratory processing issues were treated as negative results. Statistical analyses included descriptive demographic analyses and prevalence calculations.

Results

Baseline characteristics are summarised in Table 1. Of 1000 participants, 978 participants underwent tTG-IgA testing, of which 5 participants tested positive, yielding a seroprevalence of 5/1000 (0.5%). Duodenal biopsy confirmed CD in 2 participants 2/1000 (0.2%), while 1 seropositive participant did not attend biopsy, 1 is awaiting biopsy, and 1 had a negative biopsy. 28 participants were classified as having negative results. This group included untested samples (n=15), equivocal results (n=6), and known CD (n=7). The overall prevalence of CD in our study population was 9/1000 (0.9%): 7 known and 2 newly confirmed CD. The CD population were predominantly white, and upper limb fractures were most common, aligning with prior studies^3,4.

Table 1

Conclusion

This represents one of the largest evaluations of CD prevalence in fracture patients. The observed prevalence of CD 9/1000 (0.9%) closely aligns to the expected UK prevalence for CD. However, given only 5/1000 (0.5%) tested positive serologically and 2/1000 (0.2%) confirmed through biopsy, these findings suggest that routine screening in fracture clinics is unlikely to be efficient. Instead, we should explore targeted screening in fracture clinics, reserving testing for patients with iron‑deficiency anaemia, chronic GI symptoms, or a first‑degree family history of coeliac disease.

References

1. West J, Logan RF, Hill PG, Lloyd A, Lewis S, Hubbard R, Reader R, Holmes GK, Khaw KT. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut. 2003 Jul;52(7):960-5. doi: 10.1136/gut.52.7.960. PMID: 12801951; PMCID: PMC1773707.
2. Heikkilä K, Pearce J, Mäki M, Kaukinen K. Celiac disease and bone fractures: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015 Jan;100(1):25-34. doi: 10.1210/jc.2014-1858. PMID: 25279497.
3. Thomason, K., West, J., Logan, R. F., Coupland, C., & Holmes, G. K. (2003). Fracture experience of patients with coeliac disease: a population based survey. Gut, 52(4), 518–522. https://doi.org/10.1136/gut.52.4.518
4. Mardini, H. E., Westgate, P., & Grigorian, A. Y. (2015). Racial Differences in the Prevalence of Celiac Disease in the US Population: National Health and Nutrition Examination Survey (NHANES) 2009-2012. Digestive diseases and sciences, 60(6), 1738–1742. https://doi.org/10.1007/s10620-014-3514-7