Introduction

Anti-TNF are the first biologic treatment option in inflammatory bowel diseases (IBD). Few data is available on the long term risk of relapse after anti-TNF withdrawal in paediatric-onset IBD, especially at the population level.

Aims & Methods

All paediatric-onset (<17 years) IBD diagnosed between 1988 and 2011 were included in a prospective population-based study and were retrospectively followed until 2013. Among patients treated with first-line anti-TNF, the cumulative probability of relapse after anti-TNF withdrawal was evaluated using a composite outcome (intestinal resection, and/or flare-related hospitalization, and/or IBD treatment initiation, and/or active disease). Factors associated with relapse were investigated with a Cox model.

Results

Among a total of 1,344 patients (Crohn’s disease (CD): n=1,007; Ulcerative colitis (UC): n=337), 562 were treated with anti-TNF. Anti-TNF was stopped in 73 patients (CD: n=66; UC: n=7) during remission defined by Harvey-Bradshaw score < 4 in CD and Mayo score ≤ 2 in UC. Among them, median time to anti-TNF initiation was 1.6 years (IQR, 0.7-4.0) and median duration of treatment was 1.0 year (0.3-1.7). The first line anti-TNF therapy was infliximab in 68 (93%) patients. At anti-TNF withdrawal, 47 (64%) patients received immunosuppressant. The cumulative probability of relapse after anti-TNF withdrawal at 1, 3 and 5 years was respectively 62%, 85% and 93%. Median delay of relapse was 9.5 months (7.5-12.0). The cumulative probability of flare-related hospitalization at 1, 3 and 5 years was respectively 7%, 7% and 8%. No patient required intestinal resection after a median follow-up of 8.7 (5.8-13.8) years. In multivariate analysis, median time to anti-TNF initiation >1 year was the only factor associated with the risk of relapse (HR 0.58, CI95% [0.35-0.97], p=0.036). Among relapsers, 46 (63%) were retreated with anti-TNF. Retreatment with anti-TNF was effective in 45 (98%) patients after a median delay of 3.9 months (3.5-10.0). Infusion reaction occurred in only 2 patients.

Conclusion

In a population-based cohort of paediatric-onset IBD, the risk of relapse after anti-TNF withdrawal was high, but was not associated with major complication. Retreatment with anti-TNF was effective and well tolerated.

Disclosure

Consultant fees from Sandoz and AbbVie

Introduction

Celiac disease, a chronic autoimmune enteropathy caused by exposure to gluten in genetically predisposed individuals, is characterized by a broad clinical spectrum often with multisystem involvement. Symptoms related to the reproductive system include delayed menarche, early menopause, fertility disorders, miscarriages, and prematurity.

Aims & Methods

To study the impact of celiac disease on fertility in a female Greek population. A retrospective review of all patient records from the celiac disease outpatient clinic at our hospital.

Results

Medical histories of 231 female patients were reviewed (69% of the total patient population) with a mean age of 44.3 years and a mean age at diagnosis of 35.3 years. The mean age of menarche was 12.7 years. Menstrual irregularities were reported in 27% (20% instability, 7% dysmenorrhea). A total of 28% (65/231) were in menopause, with an average age of menopause onset at 50.7 years. A history of miscarriages was recorded in 15% of all women (35/231), but in 29% of women in menopause (19/65). 82% (53/65) of women in menopause had children, with 98% (52/53) having been pregnant before the diagnosis of the disease. Among all women who gave birth, only 12/113 (11%) had been diagnosed before pregnancy. 56% (63/113) and 44% (50/113) had a vaginal delivery and cesarean section, respectively. Pregnancy complications were recorded in 24 women (18 preterm births, 15 low birth weight infants, 1 intrauterine death).

Conclusion

Women with celiac disease tend to have relatively late menarche and an increased rate of miscarriages. However, the disease does not seem to significantly affect fertility.

References

1.Ehud Galron MD, Rayna Boyarsky MD,Ido Sold MD, Chen Ben David MD,and Eyal Gal MD,Interactions between celiac disease and pregnancy:A literature review, Isr Med Assoc J.2023 Dec;25(12):830-835
2.Giovanni Casella et. Al. Celiac disease and obstetrical-gynecological contribution, Gastroenterol Hepatol Bed Bench. 2016 Autumn; 9(4): 241–249.
3.Stephanie M. Moleski et. Al., Increased rates of pregnancy complications in women with celiac disease, Annals of Gastroenterology (2015) 28, 236-240
4.Nafeesa N. Dhalwani et Al., Women With Celiac Disease Present With Fertility ProblemsNo More Often Than Women in the General Population, Gastroenterology 2014;147:1267–1274

Introduction

Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten ingestion in genetically predisposed individuals, characterized by small intestinal inflammation and villous atrophy. Microbial agents such as Helicobacter pylori (H. pylori) may influence autoimmune disorders, including CD, through immune modulation. However, the relationship remains controversial.This study aimed to assess the association between CD and H. pylori infection by comparing the prevalence of H. pylori in patients with and without CD.

Aims & Methods

We conducted a retrospective study from January 2019 to December 2024. Two groups were analyzed: patients with biopsy-confirmed CD and controls without CD who underwent upper endoscopy for dyspeptic or non-specific gastrointestinal symptoms. Exclusion criteria included prior H. pylori eradication, recent use of PPIs, antibiotics, or bismuth compounds, other autoimmune disorders, and incomplete data.

Results

A total of 231 patients were included: 103 with CD (19.4% male, mean age 28.8 ± 12.6 years) and 128 controls (28.1% male, mean age 33.9 ± 11.9 years).
No significant differences were observed in age (p = 0.73) or sex distribution (p = 0.167) between groups.
H. pylori was detected in 67% of CD patients and 50% of controls, with a significantly higher prevalence in the CD group (p = 0.014).

Conclusion

Contrary to some previous reports suggesting a protective effect, this study found a significantly higher prevalence of H. pylori in patients with CD compared to controls.
These findings highlight the need for further investigations into the potential impact of H. pylori on the clinical presentation and management of celiac disease.

Introduction

Irritable bowel syndrome (IBS) imposes a substantial burden on patients and healthcare systems globally, with diverse gut symptoms. Its pathophysiology involves disorders in gut-brain interaction and gut barrier dysfunction related to diet and stress. Confocal laser endomicroscopy (CLE) can detect barrier dysfunctions in vivo. Multimodal integrative mind-body medicine-based (MBM) therapy, including stress management, exercise, relaxation, and nutrition, may enhance gut barrier function, symptoms and patient well-being.

Aims & Methods

This study aims to screen IBS patients for prevalent and food-induced gut barrier dysfunction via CLE and explore the impact of a multimodal integrative therapy on barrier integrity, IBS-symptom severity, -quality of life and psychological well-being.
Methods: IBS patients (N=119) admitted between 1 February 2021 and 1 July 2023 at a Clinic for Internal and Integrative Medicine for a two-week inpatient stay underwent esophagogastroduodenoscopy with confocal laser endomicroscopy (CLE) and local food challenge (standardized protocol for egg white, soy, milk, yeast or wheat) to test for a primary prevalent (1°CLE+) or secondary food-induced (2°CLE+) duodenal barrier dysfunction – after exclusion of IgE-mediated food allergy and coeliac disease. All IBS patients received a multimodal MBM therapy. Patients with barrier dysfunction were recommended to adhere to an adjuvant preclinically-tested barrier-stabilising therapy with myrrh, chamomile and coffee charcoal (MYRRHINIL INTEST® 3x4 dragées/ day), and exclusion of CLE-identified barrier-disrupting foods until a voluntary follow-up CLE (2^nd CLE). Pre (=1^st CLE) and Post (=2^nd CLE) intervention, IBS-symptom severity (IBS-SSS), IBS-quality of life (IBS-QoL) and psychological well-being via clinically validated questionnaires were additionally assessed.

Results

Of the 119 IBS patients included in the study, 62% (n=74) showed duodenal barrier dysfunction [1°CLE+: n=27 (23%); 2°CLE+: n=47 (39%)]. Of those, N=35 IBS patients (47%) with barrier dysfunction at 1^st CLE returned for a voluntary 2^nd CLE after 6.3 ± 3.0 months [at 1^st CLE: 1°CLE+: n=15 (43%), 2°CLE+: n=20 (57%); n=25 (71%) female; age 42.9 ± 15.4 yrs, diagnosis age 32.1 ± 15.0 yrs; disease duration 11.1 ± 11.2 yrs]. Of returned IBS patients, n=25 (71%) showed an improved gut barrier integrity, of whom 16 (46%) achieved complete stabilisation of the gut barrier (CLE-).
Pre-intervention, IBS patients were clinically characterized by severe IBS symptom severity (IBS-SSS 304.8 ± 83.4), severely impaired IBS-related quality of life (IBS-QoL 42.7 ± 16.6) and concomitant severe level of anxiety and depression (HADS 19.2 ± 7.7), fatigue (MFI-20 66.8 ± 13.1) and perceived stress (PSS-10 31.3 ± 7.7). Post-intervention, patients exhibited significant and clinically relevant (MCID) improvement in all of these clinical outcomes (IBS-SSS p=<.001, IBS-QoL p=<.001, HADS p=<.001, MFI-20 p=<.001, PSS-10 p=0.004), even allowing the severity score level to be reduced from severe to moderate. Patients reported particular improvement in abdominal pain, change in stool frequency and consistency, abdominal cramps and nausea assessed via 5-point Likert scale.

Conclusion

IBS patients have a high prevalence of existing and food-induced duodenal barrier dysfunction (62%). A multimodal integrative therapy showed a stabilisation of the gut barrier in 71% of IBS patients in a 2^nd CLE as well as significant and clinically relevant improvement in IBS-related symptom severity, quality of life and psychological well-being.

References

1) Sperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology. 2021;160(1):99-114.e3. doi:10.1053/j.gastro.2020.04.014
2) Martin CR, Osadchiy V, Kalani A, Mayer EA. The Brain-Gut-Microbiome Axis. Cell Mol Gastroenterol Hepatol. 2018 Apr 12;6(2):133-148. doi: 10.1016/j.jcmgh.2018.04.003.
4) Hanning N, Edwinson AL, Ceuleers H, Peters SA, De Man JG, Hassett LC, De Winter BY, Grover M. Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review. Therap Adv Gastroenterol. 2021 Feb 24;14:1756284821993586. doi: 10.1177/1756284821993586.
5) Fritscher-Ravens A, Pflaum T, Mösinger M, Ruchay Z, Röcken C, Milla PJ, Das M, Böttner M, Wedel T, Schuppan D. Many Patients With Irritable Bowel Syndrome Have Atypical Food Allergies Not Associated With Immunoglobulin E. Gastroenterology. 2019 Jul;157(1):109-118.e5. doi: 10.1053/j.gastro.2019.03.046. Epub 2019 May 15.
6) Fritscher-Ravens A, Schuppan D, Ellrichmann M, Schoch S, Röcken C, Brasch J, Bethge J, Böttner M, Klose J, Milla PJ. Confocal endomicroscopy shows food-associated changes in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology. 2014 Nov;147(5):1012-20.e4. doi: 10.1053/j.gastro.2014.07.046. Epub 2014 Jul 30.
7) Rosenthal R. et al. Myrrh exerts barrier-stabilising and –protective effects in HT-29/B6 and Caco-2 intestinal epithelial cells. Int J Colorectal Dis (2016)

Disclosure

Jost Langhorst
Fees and lecturing: Falk Foundation; Repha GmbH biological medicines; Dr. Willmar Schwabe; Medice Arzneimittel, Galapagos Pharma, Takeda Pharmaceutical, Janssen Cilag, Dr. Pfleger Arzneimittel
Research funding: Steigerwald Arzneimittelwerke GmbH, Falk Foundation, TechLab, Inc., Dr. Willmar Schwabe, Repha GmbH biological medicines,
Other financial or non-financial benefits: none
Consulting and expert activities: Medical Publishers Stuttgart; Steigerwald Arzneimittelwerke GmbH; Repha GmbH; Ferring Arzneimittel GmbH; Dr. Willmar Schwabe
Corporate investments: none
Other conflicts of interest: None

Miriam Bittel
Fees and lecturing: Falk Foundation; Weber & Weber GmbH
Research funding: Deutsche Morbus Crohn/Colitis ulcerosa Vereinigung (DCCV)
Other financial or non-financial benefits: none
Consulting and expert activities: Weber & Weber GmbH
Corporate investments: none
Other conflicts of interest: None

The other co-authors: no conflicts of interest

Introduction

Barrett’s esophagus (BE), the major precursor of esophageal adenocarcinoma (EAC), is a condition where the normal stratified squamous esophageal epithelium undergoes transdifferentiation into the specialized, intestinal-like epithelium. This reprogramming, also termed ‘paligenosis’, is predominantly caused by gastroesophageal reflux disease (GERD)¹. On the other hand, hydrogen sulfide (H₂S) next to carbon monixide (CO) is an important endogenous gaseous mediator. H₂S is biosynthesized by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). Both, H₂S and CO have been shown to maintain gastrointestinal (GI) integrity^2,3,4. However, the contribution of gaseous mediators signaling to esophageal transdifferentiation process is overlooked.

Aims & Methods

Thus, in this study we aimed to explore the role of H₂S bioavailability in mTOR-dependent paligenosis induced by chronic epithelial injury. Furthermore, we evaluated the relationship between GERD, the barrier function of cultured cells, and the pattern of selected components involved in the formation of the tight junctions (TJs) and responsible for epithelial barrier integrity.
We implemented an animal model of GERD, based on Male Wistar rats with esophagogastroduodenal anastomosis (EGDA) treated i.g. for 8 weeks with vehicle or with H₂S- releasing chemicals: GYY4137 (5.0 mg/kg)/NaHS (1.0 mg/kg) or CTH/CBS inhibitors: PAG (15 mg/kg)/AOAA (11 mg/kg). In parallel, we employed optimized in-vitro GERD model based on human-derived esophageal epithelial (EPC2) cells +/- CRISPR-Cas9-induced knockout of H₂S-producing enzymes that were treated with acidified bile mixture (BM) or with GYY4137/NaHS (100 µM). We evaluated activation of AKT/mTOR pathway by multiplex microbeads fluorescent assay and an expression of TJ-associated protein (ZO-1) and occludin by capillary immunoblotting. The barrier function of cultured cells was evaluated by measurement of transepithelial electrical resistance (TER).

Results

We observed that either chronic reflux in EGDA-rats and/or treatment of human esophageal cells with BM led to a slight or a significant activation of AKT/mTOR signaling pathway and its down-stream effector - p70S6K. Additionally, we observed that pharmacologically-derived H₂S reversed this effect, while inhibition of endogenous H₂S biosynthesis (pharmacological or induced by knockout of H₂S-producing enzymes) had either no effect or increased GERD-induced phosphorylation of AKT/mTOR pathway components. Moreover, we showed that ZO-1 is highly expressed in BM treated EPC2 cells and this was reflected by the increase in TER measurment. Level of occludin remained unchanged. We did not observe any changes in expression of ZO-1 and occludin after GYY4137 treatment; however, TER measurment decreased in comparison to BM treated cells. Selective knockout of H₂S-producing enzymes led to a decrease in ZO-1 protein content in comparison to wild-type cells.

Conclusion

We conclude that interventional enhancing or decreasing of H₂S bioavailability in esophageal epithelium respectively delay or accelerate the GERD-induced paligenosis process via regulation of the mTOR pathway. H₂S-prodrugs may provide a protective effect on the esophageal epithelium by substituting the phisiological defensive response of the tissue against GERD, which is reflected by an increase in the expression of ZO-1 and tightening of the cellular barrier.

References

1. Souza RF, Spechler SJ. Mechanisms and pathophysiology of Barrett oesophagus. Nat Rev Gastroenterol Hepatol 2022.
2. Fiorucci S, Distrutti E, Cirino G, Wallace JL. The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver. Gastroenterology 2006.
3. Magierowska K, Korbut E, Wójcik-Grzybek D, Bakalarz D, Sliwowski Z, Cieszkowski J, Szetela M, Torregrossa R, Whiteman M, Magierowski M. Mitochondria-targeted hydrogen sulfide donors versus acute oxidative gastric mucosal injury. J Control Release 2022.
4. Magierowska K, Brzozowski T , Magierowski M. Emerging role of carbon monoxide in regulation of cellular pathways and in the maintenance of gastric mucosal integrity. Pharmacol Res 2018.

[Funding: National Science Centre, Poland (UMO-2016/23/D/NZ4/01913, UMO-2019/33/B/NZ4/00616) and Statutory Grant (N41/DBS/000874), Jagiellonian University Medical College].

Introduction

Large language models, such as ChatGPT-4, have significantly enhanced access to Artificial Intelligence (AI) tools. However, their role in clinical practice of gastroenterology remains uncertain¹. Accurate classification of esophageal varices is pivotal in managing patients with portal hypertension as it directly influences prognosis and treatment².

Aims & Methods

This study aimed to assess the potential of ChatGPT-4 as a diagnostic tool to accurately classify esophageal varices, and to compare its diagnostic accuracy and reliability to experienced and trainee endoscopists.
We collected photos taken during esophagogastroduodenoscopy performed at the Endoscopic Units of six tertiary Italian centers. The images were input into blank sheets of ChatGPT-4, which was asked to classify the varices by size, indicate the presence of red markings, and evaluate image quality in terms of insufflation, clarity and lightning. The same set of images and evaluation criteria was shown to six experienced endoscopists (E1, E2, E3, E4, E5, E6), to four junior endoscopists (J1, J2, J3, J4) and to five trainee endoscopists (T1, T2, T3, T4, T5). The evaluations from the experienced endoscopists were used as a Ground Truth. ChatGPT-4 had not undergone any prior task‐specific training for esophageal varices detection and classification.

Results

We collected 327 photos, of which 279 were considered to be of good quality by the experienced endoscopists. In detecting esophageal varices, ChatGPT-4 showed a lower AUC (0.77, 95% CI 0.66-0.88, Se 86.2%, Sp 68.4%) compared to one of the junior endoscopists (J2 AUC 0.92, 95% CI 0.87-0.98, Se 90.4%, Sp 94.4%; p<0.05) and comparable to other endoscopists (p>0.05). ChatGPT-4 showed a lower AUC (0.75, 95% CI 0.70-0.80, Se 67.6%, Sp 81.7%) than 3/4 junior endoscopist and 3/5 trainee endoscopists in distinguishing small (F1) from large (F2-F3) varices (p<0.05). For the classification of F3 varices, ChatGPT-4 achieved a higher AUC (0.71, 95% CI 0.63-0.80, Se 52.8%, Sp 89.7%) compared to one of the trainee endoscopists (T5 AUC 0.58, 95% CI 0.51-0.65; p<0.05) and comparable to that of all endoscopists (p>0.05). In identifying red signs, ChatGPT-4 (AUC 0.58, 95% CI 0.52-0.65, Se 20.5%, Sp 96.2%) performed less effectively than the endoscopists (p<0.05).

Conclusion

ChatGPT-4 achieved diagnostic accuracy comparable to junior and trainee endoscopists in detecting esophageal varices and classifying F3 varices, but it was overperformed in differentiating small (F1) from large varices (F2–F3) and in identifying red signs. While it cannot replace the clinical judgment of an experienced operator, the model shows potential as a supportive tool for training and preliminary triage of endoscopic images. Further refinement and dedicated training on endoscopic sign interpretation are needed to enhance its reliability and applicability in routine clinical practice.

References

1) Klang E, Sourosh A, Nadkarni GN, Sharif K, Lahat A. Evaluating the role of ChatGPT in gastroenterology: a comprehensive systematic review of applications, benefits, and limitations. Therap Adv Gastroenterol. 2023 Dec 25
2) Nguyen GC, Correia AJ, Thuluvath PJ. The impact of cirrhosis and portal hypertension on mortality following colorectal surgery: a nationwide, population- based study. Dis Colon Rectum. 2009 Aug