Introduction

The cause of Crohn’s Disease (CD) remains unclear; however evidence suggests that dietary factors play a key role. With a rising incidence and no definitive cure, identifying modifiable risk factors is critical in preventing CD development. We aimed to study the association between fermentable dietary fibre intake and the future development of CD in an at-risk population.

Aims & Methods

Participants were recruited as part of the Crohn’s and Colitis Canada GEM study, a prospective cohort study of healthy first-degree relatives of patients with CD. At enrolment, a validated food frequency questionnaire was administered. Pectin, β-glucan, inulin, fructooligosaccharides (FOS), and arabinoxylan intake were quantified, and values energy-adjusted. Survival analysis was used to test the association between intake of fibre subtypes and risk of CD development. Generalized estimating equation tested the association between fibre intake and baseline impaired intestinal permeability (fractional urinary excretion of lactulose to mannitol ratio (LMR) >0.025); subclinical gut inflammation (faecal calprotectin (FCP) >250 μg/g); and faecal microbiome composition via 16s rRNA sequencing.

Results

76 of the 2,659 participants developed CD with a median follow-up of 8.9 years (IQR=5.7-12.3). Median age at recruitment was 17 years (IQR=12-25). 47% were male. Higher intake of inulin (HR = 0.78; 95% CI=0.61–0.99; p=0.04) and β-glucan (HR = 0.78; 95% CI=0.61–0.99; p=0.04) were associated with a reduced risk of CD development. No fibre subtype was associated with a higher risk of CD development. Lower intake of pectin, inulin, FOS and β-glucan was associated with impaired intestinal permeability (0.005<p<0.04). Lower inulin intake was associated with high FCP levels (p = 0.046). Higher pectin intake was associated with increased alpha diversity of faecal microbiome (p = 0.028). Higher inulin, FOS and pectin intake was associated with a shift in microbial taxa previously shown to be protective against CD onset in the GEM cohort; a reduction in Ruminococcus torques and an increase in NK4A214 group (phylum Firmicutes) presence (3.25×10⁻¹⁰<q<0.04).

Conclusion

This study demonstrates that dietary intake of fermentable fibre subtypes is associated with a reduced risk of CD development as well as with pleiotropic changes in CD risk biomarkers including microbiome, intestinal permeability, and subclinical inflammation. This suggests that the potential benefit of fermentable fibres on CD risk may involve changes in barrier function, and microbiome composition and function. Targeted interventions based on these findings could prove effective in preventing the onset of CD.

Introduction

Gastroesophageal reflux disease (GERD) is a common disorder characterized by the backward flow of stomach contents into the esophagus, impacting millions globally and significantly reducing quality of life. Typical symptoms include heartburn and acid reflux, while atypical presentations may involve noncardiac chest pain, chronic cough, and laryngitis(1).Over the past decade (2010–2021), GERD incidence and prevalence have risen sharply in Europe compared to global trends, leading to increased disability-adjusted life years (DALYs). Its multifactorial pathogenesis—driven by chemical, mechanical, psychological, and neurological mechanisms—affects symptom severity, diagnosis, and therapeutic outcomes(2).

Aims & Methods

This study aims to investigate the escalating burden of Gastroesophageal Reflux Disease (GERD) in Europe from 2010 to 2021, comparing its incidence, prevalence, and disability-adjusted life years (DALYs) with global trends to evaluate current healthcare policies and highlight the need for streamlined, evidence-based interventions that address regional disparities in disease burden. The findings will support policy refinement, ensuring healthcare systems are equipped with effective prevention strategies, optimized treatment protocols, and equitable resource allocation to reduce GERD’s long-term impact on patient health and healthcare infrastructure.
Incidence, Prevalence and disability-adjusted life years (DALYs) were calculated using the Global Burden of Disease (GBD) Database 2021. Joinpoint regression was used to calculate annual percentage changes (APCs) in ASDR, DALYs, and YLL with 95% uncertainty intervals, and significant trends over time were identified. Statistical significance was set at a p-value of <0.05

Results

Globally, GERD-related DALYs increased from 72.24 per 100,000 (95% CI: 36.45–128.77) in 2010 to 75.56 per 100,000 (95% CI: 38.05–133.87) in 2021. Prevalence rose from 9,398.70 per 100,000 (95% CI: 8,342.02–10,517.59) in 2010 to 9,838.60 per 100,000 (95% CI: 8,732.46–11,056.05) in 2021, while incidence climbed from 3,717.75 per 100,000 (95% CI: 3,298.17–4,113.24) in 2010 to 3,881.86 per 100,000 (95% CI: 3,445.56–4,299.95) in 2021.
Europe saw GERD-related DALYs rise from 75.38 per 100,000 (95% CI: 37.98–133.77) in 2010 to 77.57 per 100,000 (95% CI: 39.13–137.23) in 2021. Prevalence increased to 10,091.72 per 100,000 (95% CI: 8,938.24–11,206.79), and incidence reached 3,978.62 per 100,000 (95% CI: 3,521.81–4,418.93) in 2021.
Eastern Europe consistently showed the highest GERD burden, followed by Central Europe, while Western Europe had the lowest figures.

• Eastern Europe: 88.73 DALYs per 100,000 (95% CI: 44.67–156.85) in 2021
• Central Europe: 86.05 per 100,000 (95% CI: 43.45–152.64)
• Western Europe: 63.30 per 100,000 (95% CI: 31.76–112.67)

Conclusion

The increasing burden of Gastroesophageal Reflux Disease (GERD) in Europe from 2010 to 2021, particularly in Eastern Europe, highlights the need for targeted healthcare interventions. With rising incidence, prevalence, and disability-adjusted life years (DALYs), addressing lifestyle, environmental, and healthcare access disparities is essential. Streamlined policies, optimized treatment strategies, and preventive measures can help mitigate GERD’s impact, improve patient outcomes, and reduce the strain on healthcare systems.

References

1-Mahajan R, Kulkarni R, Stoopler ET. Gastroesophageal reflux disease and oral health: A narrative review. Spec Care Dentist. 2022;42(6):555-564. doi:10.1111/scd.12726
2-Sharma P, Yadlapati R. Pathophysiology and treatment options for gastroesophageal reflux disease: looking beyond acid. Ann N Y Acad Sci. 2021;1486(1):3-14. doi:10.1111/nyas.14501

Disclosure

No conflict of interest.

Introduction

The phenotype and behavior of immune cells have been linked to cellular energy metabolisms, leading to the emergence of a new field of immunometabolism. The crucial role of the gut microbiota in immune system maturation and functions and the relatedness of mitochondria and bacteria suggest a role for the gut microbiota in intestinal epithelial and immune cell energy metabolism. The gut microbiota and its metabolites have a critical role in establishing and maintaining health and in the pathogenesis of diseases, including inflammatory bowel disease (IBD). Following an in vitro screening, we showed that indole-3-propionic acid (IPA) stimulates mitochondrial respiration of CD4+ T cells. IPA is a microbiota-derived tryptophan metabolite shown to be decreased in the feces of patients with IBD and which plays a crucial part in regulating intestinal immune tolerance, improving mucus barrier function and suppressing intestinal inflammation.

Aims & Methods

We aim at exploring the mechanisms involved in the anti-inflammatory effects of IPA. SCENITH technology (Single-cell energetic metabolism by profiling translation inhibition) was used to screen and identify the effect of metabolites on energy metabolism of specific subpopulations in mixed immune cell systems in both in vitro and in vivo. Seahorse, Mitotracker, metabolomics, proteomics experiments were used to explore the role of identified metabolites on energy metabolism in purified cells in vitro. Antibiotic-depleted gut microbiota, dextran sodium sulphate-induced colitis and adoptive reinfusion experiments in mice were used to evaluate the effects of metabolites on cellular energy metabolism and their anti-inflammation function in vivo.

Results

Using SCENITH technology on human blood mononuclear cells (PBMCs), we showed that IPA stimulates mitochondrial respiration of CD4+ T cells, by promoting fatty acid/amino acid oxidation rather than traditional glucose metabolism in the CD3/CD28 activation setting. Similar results were observed in mouse CD4+ T cells. In parallel with cellular energy reprogramming, IPA impacts CD4+ T cell behavior by favoring Treg over the Th17 phenotype in vitro. Blocking mitochondrial respiration with oligomycin or long-chain fatty acid metabolism with etomoxir inhibit IPA effects on T cells phenotype. IPA is a relatively weak Aryl hydrocarbon receptor (AhR) agonist. Using an AhR inhibitor (CH-223191) or AhR KO T cells, we showed that the effect of IPA on CD4+ T cell energy metabolism was not dependent on AhR. In microbiota-depleted mice, the alteration in mitochondrial respiration of small intestine and colon CD4+ T cells was rescued by IPA administration. In DSS-induced colitis, IPA administration increases mitochondrial respiration of CD4+ T cells by enhancing the oxidation of fatty acids and amino acids in the colon. Adoptive reinfusion of CD4+ T cells from IPA-treated mice into Rag2 KO mice induced protection against intestinal inflammation, confirming that IPA protective effects are mediated by CD4+ T cells.

Conclusion

Collectively, our study reveals from a whole new perspective that the anti-inflammatory effects of IPA are mediated by metabolic reprogramming of CD4+ T cells toward the enhancement of mitochondrial respiration, thereby leading to an anti-inflammatory phenotype and eventually protection in colitis context in mice. This study paves the way for the development of new therapeutic strategies in IBD.

Disclosure

Competing interests: HS report lecture fee, board membership, or consultancy from Carenity, AbbVie, Astellas, Danone, Ferring, Mayoly Spindler, MSD, Novartis, Roche, Tillots, Enterome, BiomX, Biose, Novartis,Takeda, Biocodex and is cofounder of Exeliom Biosciences.

Introduction

Eosinophilic esophagitis (EoE) is an increasingly prevalent esophageal disease resulting in dysphagia and food impaction. ESO-101 targets the esophageal mucosa by significantly increasing topical medication contact time through the slow release of mometasone furoate. This innovative application technology consists of a drug-loaded thin-film rolled up in a capsule that unravels and sticks to the esophageal mucosa when swallowed. The current proof-of-concept phase 2 study evaluated the efficacy and safety of ESO-101.

Aims & Methods

This randomized, double-blind, placebo-controlled trial (NCT04849390) investigated the safety and efficacy of ESO-101 in adult patients with EoE and dysphagia. Patients were randomized 2:1 to once-daily treatment with ESO-101 800 µg or placebo and treated for 4-weeks. The primary endpoint was the absolute change in peak eosinophil count (eos/hpf) from baseline. Secondary endpoints were the change in EoE Endoscopic Reference Score (EREFS) and dysphagia symptoms measured by the 11-point numeric rating scale (NRS). Safety was also assessed.

Results

59 patients were screened at 13 European study sites, 43 patients were randomized, and 40 (27 to ESO-101 and 13 to placebo) completed the trial. For all histological and endoscopic endpoints, ESO-101 led to a statistical improvement compared to placebo. The mean decrease in peak eosinophil count was 49.1 (±88.4) eos/hpf with ESO-101, while counts increased by a mean of 6.6 (±65.1) eos/hpf in the placebo group (p=0.0318). Mean EREFS decreased by 3.9 (±2.6) with ESO-101 and there was no change with placebo (-0.1 [2.3]) (p=0.0001). A higher proportion of patients showed a histological response (<15 eos/hpf) with ESO-101 versus placebo (48% vs 0%; p=0.0028). There was also numerical improvement in the dysphagia severity score in the ESO-101 group (median improvement in the dysphagia severity of 4 scores [relative change: -71%]) compared to placebo (improvement in 3 scores [relative change: -57%]). No cases of oropharyngeal or esophageal candidiasis were observed (Table 1).

Conclusion

ESO-101 resulted in statistically significant histologic and endoscopic improvements compared with placebo, even with the 4-week treatment duration. ESO-101 was well tolerated. The ACESO study underscores the promise of topical drug delivery to the esophagus using the ESO-101 drug delivery system and provides a robust foundation for future ESO-101 development for EoE therapy.

Disclosure

• Lucendo AJ: Principal Investigator of the ACESO Study sponsored by EsoCap Biotech AG
  
• Dellon ES: Consultant to EsoCap Biotech AG
  
• Bredenoord AJ: Investigator of the ACESO study sponsored by EsoCap Biotech AG
  
• Straumann A: Consultant to EsoCap Biotech AG
  
• Racamier I: CEO of EsoCap Biotech AG
  
• Ghazaleh Gouya-Lechner: Medical ​Advisor of EsoCap Biotech AG