Introduction

Vasoactive intestinal peptide (VIP) is a neuropeptide that plays a crucial role in the regulation of intestinal physiology. However, while previous studies hint at its role in the regulation of intestinal proliferation and differentiation, its detailed effect on intestinal stem cells (ISC) in homeostasis and regeneration remains poorly understood. Hence, we here aimed to investigate the effects of VIP on ISC proliferation, differentiation and intracellular signaling in intestinal homeostasis and in a radiation-induced injury model.

Aims & Methods

To study the role of VIP on ISC homeostasis and regeneration, we employed an in vitro 3D organoid model. Intestinal crypts were isolated from the murine proximal small intestine and cultured in vitro with or without VIP treatment. Its effect on ISC differentiation was analyzed by RT-PCR and immunocytochemical analysis. Flow cytometry analysis of organoids derived from Lgr5‐EGFP‐CreERT2 and induced Lgr5-IRES-CreERT2/R26R-TdTomato mice, respectively, allowed for the analysis of the effect of VIP on Lgr5+ ISC and their progeny. Further experiments included EdU and CTG assays as well as bulk RNA sequencing analysis.

Results

Administration of VIP promoted secretory cell differentiation in treated organoids as evidenced by expansion of Lysozyme 1- and Mucin 2-positive cells and increased expression of secretory cell transcripts. The promotion of secretory cell differentiation, interestingly, appeared to be mediated mainly by p38 MAPK and MEK1 signaling. Further, VIP treatment induced an expansion of Lgr5+ ISC, while it prominently reduced overall Edu+ cell proliferation in homeostatic conditions. This coincided with upregulated hallmark gene sets associated with cell cycle such as HALLMARK_MITOTIC_SPINDLE or HALLMARK_G2M_CHECKPOINT in sorted, VIP-treated Lgr5+ ISC. Importantly, in the context of radiation-induced acute injury, we could observe the promotion of organoid viability as well as a marked increase in overall Edu+ cell proliferation with concurrent VIP treatment. This was accompanied by the prominent expansion of Lgr5+ ISC as well as upregulated Lgr5+ ISC activity.

Conclusion

Our findings provide evidence that VIP prominently modulates ISC activity and differentiation in homeostasis. Moreover, VIP may have potential in mitigating radiation-induced damage to the intestinal epithelium and promoting tissue regeneration after injury.

Clinical Case Summary

We present the case of a 50-year-old man diagnosed with anti-EJ positive anti-synthetase syndrome in 2020. Two years after the diagnosis, he began experiencing subacute episodes of postprandial abdominal pain, distension, and vomiting. On physical examination, the abdomen was distended, non-tender, and tympanic. Abdominal CT revealed dilatation of small bowel loops without evidence of mechanical obstruction. Endoscopic studies ruled out endoluminal lesions. Given the suspicion of a severe gastrointestinal (GI) motility disorder, a comprehensive motility evaluation was performed. Esophageal manometry revealed absent contractility, gastric emptying scintigraphy was consistent with gastroparesis, and small bowel manometry demonstrated absence of normal migrating motor complexes during fasting and a weak postprandial motor response, findings compatible with a myopathic pattern. A diagnosis of chronic intestinal pseudo-obstruction (CIPO) secondary to autoimmune disease activity was established. The patient’s immunosuppressive therapy was escalated to tofacitinib and supportive treatment with prokinetics (prucalopride), non- absorbable antibiotics for small intestinal bacterial overgrowth and nutritional supplementation, was initiated. The patient showed symptomatic improvement during follow-up, although small bowel dilation persisted on imaging studies. CIPO is the most severe form of GI motility disorder, representing the end stage of various conditions affecting the neuromuscular system of the GI tract (1). Autoimmune diseases are recognized causes of CIPO, with connective tissue disorders being the most frequently documented. The treatment of CIPO involves two main approaches: addressing the underlying disease, in this particular case, through immunosuppression, and providing supportive care to maintain adequate nutrition. A high index of suspicion for severe GI motility disorders is essential to avoid delays in diagnosis and to initiate effective treatment promptly.

References

1. Malagelada C and Alcalá-González LG. Mistakes in chronic intestinal pseudoobstruction and how to avoid them. UEG Education 2024; 24: 12-17.
Pictures from abdominal distention crisis, radiological CT images and manometric tracings, including high-resolution jejunal manometry (small bowel) will be presented.

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