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THE EFFECT OF VASOACTIVE INTESTINAL PEPTIDE ON INTESTINAL STEM CELL DIFFERENTIATION AND ACTIVITY

Tatiana Agibalova 1, Anastasia Ermolova 1, Jessica Wieland 1, Ihsan Ekin Demir 2, Dieter Saur 1, Birgit Kohnke-Ertel 1, Michael Quante 3,1, Roland M. Schmid 1, Moritz Middelhoff 1

Affiliations

1 Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany

2 Klinikum Rechts Der Isar, Technical University of Munich, Munich, Germany

3 The University Medical Center Freiburg, University of Freiburg, Freiburg, Germany

Summary

AI Generated

In vitro organoid study demonstrates that vasoactive intestinal peptide modulates intestinal stem cell activity and secretory differentiation in homeostasis and enhances stem cell expansion and proliferation following radiation-induced injury.

VIP treatment promoted secretory cell differentiation in murine intestinal organoids, with expansion of Lysozyme 1-positive and Mucin 2-positive cells mediated mainly by p38 MAPK and MEK1 signaling.
Under homeostatic conditions, VIP induced expansion of Lgr5-positive intestinal stem cells while reducing overall EdU-positive cell proliferation, with upregulated cell cycle gene sets in sorted stem cells.
In a radiation-induced acute injury model, VIP treatment promoted organoid viability, markedly increased EdU-positive cell proliferation, and caused prominent expansion and upregulated activity of Lgr5-positive stem cells.
The authors suggest VIP may have potential in mitigating radiation-induced intestinal epithelial damage and promoting tissue regeneration after injury.

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Abstract

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.

Conference

UEG Week Copenhagen 2023

Topics

Small Intestine & Nutrition

Submission format

Abstract

Session

The small intestine: A hidden treasure! (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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Marcin Magierowski

UEG Presentation

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Autoimmune gastritis: Solving controversies

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Autoimmune gastritis: Solving controversies

Marino Venerito 1

Affiliations

1 Otto-von-Guericke University, Magdeburg, Germany

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Abstract

Event

UEG Week Barcelona 2026

Topics

Immunology Stomach & H. Pylori Oesophagus Digestive Oncology

Session

Management of upper GI: Precancerous conditions and early neoplasia

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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Marcin Magierowski

UEG Presentation

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IMPACT OF THE ORDER OF THE FIRST TWO BIOLOGIC THERAPIES IN INFLAMMATORY BOWEL DISEASE: THE SECUTEM STUDY FROM THE ENEIDA REGISTRY

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IMPACT OF THE ORDER OF THE FIRST TWO BIOLOGIC THERAPIES IN INFLAMMATORY BOWEL DISEASE: THE SECUTEM STUDY FROM THE ENEIDA REGISTRY

Diego Casas Deza 1, Carmen Yagüe Caballero 1, ANA ROYO ESTEBAN 1, Laura Figueras Panillo 1, Pilar Nos Mateu 2, Elena Ricart 3, María Dolores Martín-Arranz 4, Laura Ramos Lopez 5, Eva Iglesias-Flores 6, Maria Luisa De Castro Parga 7, Manuel Barreiro de Acosta 8, PILAR VARELA TRASTOY 9, Carla Jerusalén Gargallo-Puyuelo 10, Isabel Pascual-Moreno 11, Montserrat Rivero 12, Jesús Barrio 13, Francisco Mesonero Gismero 14, Daniel Sebastian Ceballos Santos 15, Cristina Martinez Pascual 16, Esther García-Planella 17, Beatriz Sicilia Aladrén 18, Cristina Rodríguez Gutiérrez 19, Ana Gutiérrez 20, Jordi Guardiola 21, Isabel Pérez-Martínez 22, MERCEDES NAVARRO LLAVAT 23, Fernando Bermejo 24, David Rafael de la Cruz 25, Carmen Bulnes Labrador 26, Javier P. Gisbert 27, Maria Isabel Vera Mendoza 28, Xavier Calvet Calvo 29, Iago Rodríguez-Lago 30, Monica Sierra 31, Marta Piqueras Cano 32, Ángel Ponferrada-Díaz 33, Mariana Fe García Sepulcre 34, Eva Sesé 35, José Lázaro Pérez-Calle 36, Miriam Mañosa Ciria 37, Pilar Robledo 38, Rufo Lorente Poyatos 39, Jose Maria Huguet 40, Lucia Márquez Mosquera 41, Yamile Zabana 42, Olga Merino 43, Pablo Vega 44, Elena Betoré 45, Ana María Fuentes Coronel 46, María Teresa Diz-Lois Palomares 47, David Busquets Casals 48, Gloria Esther Rodríguez González 49, Luis Fernández-Salazar 50, Carmen Orenga Sánchez 51, Ramón Pajares 52, Raquel Camargo Camero 53, Empar Sainz Arnau 54, Ana Maria Trapero-Martínez 55, Eugeni Domenech Morral 56, Santiago García-López 1

Affiliations

1 Hospital Universitario Miguel Servet, Zaragoza, Spain

2 Hospital La Fe, Valencia, Spain

3 Hospital Clinic, Barcelona, Spain

4 Hospital La Paz, Madrid, Spain

5 Hospital Universitario de Canarias, Tenerife, Spain

6 Hospital Universitario Reina Sofía, Córdoba, Spain

7 Hospital Álvaro Cunqueiro, Vigo, Spain

8 University Hospital of Santiago, Santiago de Compostela, Spain

9 Hospital Universitario de Cabueñes, Cabueñes, Spain

10 Hospital Lozano Blesa, Zaragoza, Spain

11 Hospital Clinic Universitari de Valencia, Valencia, Spain

12 Marqués de Valdecilla Universitary Hospital, Madrid, Spain

13 Hospital Universitario Río Hortega, Valladolid, Spain

14 Hospital Ramon y Cajal, Madrid, Spain

15 Hospital Universitario de Gran Canaria Dr. Negrín ., Las Palmas de Gran Canaria, Spain

16 Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain

17 Hospital del la Santa Creu i Sant Pau, Barcelona, Spain

18 H Universitario de Burgos, Burgos, Spain

19 Complejo Hospitalario de Navarra, Pamplona, Spain

20 Hospital General Universitario de Alicante (HGUA) in Alicante, Alicante, Spain

21 Hospital Universitario de Bellvitge, L'Hospitalert de LLobregat (Barcelona), Spain

22 Hospital Universitario Central de Asturias, Oviedo, Spain

23 H.SANT JOAN DESPI-MOISES BROGGI, Barcelona, Spain

24 Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain

25 Hospital Universitario Doce de Octubre, Madrid, Spain

26 Complejo Asistencial Universitario de Palencia, Palencia, Spain

27 Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa and CIBEREHD, Madrid, Spain

28 Hospital Universitario Puerta de Hierro, Madrid, Spain

29 Hospital de Sabadell, Institut Universitari Parc Tauli, UAB, Sabadell, Spain

30 Hospital Universitario de Galdakao, Bilbao, Spain

31 Complejo Asistencial Universitario de León, León, Spain

32 Hospital Consorci Terrassa, Terrassa, Spain

33 Hospital Infanta Leonor, Madrid, Spain

34 Hospital General Universitario de Elche, Elche, Spain

35 Hospital Universitario Arnau de Vilanova de Lleida, Lleida, Spain

36 Hospital Universitario Fundación de Alcorcón, Alcorcon, Spain

37 Hospital Universitari Germans Trias i Pujol, Badalona, Spain

38 Hospital Universitario de Cáceres, Cáceres, Spain

39 Hospital General Universitario de Ciudad Real, Ciudad real, Spain

40 Consorcio Hospital General Universitario de Valencia, Valencia, Spain

41 Hospital del Mar, Barcelona, Spain

42 Hospital Universitari Mútua Terrassa, Terrassa, Spain

43 Hospital Universitario de Cruces, Bilbao, Spain

44 COMPLEXO HOSPITALARIO UNIVERSITARIO DE OURENSE, Ourense, Spain

45 Hospital General San Jorge, Huesca, Spain

46 Hospital Virgen de la Concha, Zamora, Spain

47 Hospital A Coruña, A Coruña, Spain

48 Hospital Universitari de Girona Doctor Josep Trueta, Girona, Spain

49 Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain

50 Hospital Clínico de Valladolid, Valladolid, Spain

51 Hospital General de Granollers, Granollers, Spain

52 Hospital Universitario Infanta Sofía, Madrid, Spain

53 Hospital Universitario Virgen de la Victoria, Málaga, Spain

54 Althaia Xarxa Assistencial Universitària de Manresa, Manresa, Spain

55 Complejo Hospitalario de Jaén, Jaén, Spain

56 Hospital Germans Trias i pujol, Badalona, Barcelona, Spain

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Abstract

Introduction

The increasing availability of targeted therapies has transformed the treatment paradigm of inflammatory bowel disease (IBD), yet their optimal positioning remains unclear. This study aimed to evaluate whether the order of the first two biologic agents influences treatment persistence.

Aims & Methods

Observational study based on the ENEIDA registry. All patients ≥18 years who received at least two biologic therapies for luminal activity between January 2015 and January 2025 were included. Patients who switched to a biosimilar during follow-up and those with more than three months between discontinuation of the first biologic and initiation of the second were excluded. Only sequences with patients in both complementary orders were analyzed. The primary outcome was treatment durability from initiation of the first biologic, with discontinuation of the second as the event of interest. Adjusted hazard ratios (aHR) were calculated for each pair of complementary sequences according to initial drug exposure, adjusting for perianal disease, extraintestinal manifestations, immunomodulator use, prior surgery, smoking status, disease duration, and disease type.

Results

A total of 5,528 patients were included, grouped into eight sequence pairs. Baseline characteristics were similar across groups, except for a higher rate of extraintestinal manifestations in patients starting with anti-TNF agents.
In the anti-TNF–ustekinumab sequence, initiating therapy with ustekinumab was associated with lower durability (aHR 2.51, 95% CI 1.85–3.41), both for infliximab (aHR 3.23, 95% CI 2.12–4.93) and adalimumab (aHR 1.83, 95% CI 1.14–2.93).
In the anti-TNF–vedolizumab sequence, starting with vedolizumab was associated with lower durability (aHR 1.62, 95% CI 1.32–2.00), both with infliximab (aHR 1.56, 95% CI 1.23–1.97) and adalimumab (aHR 1.67, 95% CI 0.96–2.90), although the latter did not reach statistical significance.
In anti-TNF–anti-TNF sequences, starting with infliximab in the adalimumab–infliximab sequence was associated with a lower risk of discontinuation (aHR 0.79, 95% CI 0.70–0.89), both in Crohn’s disease (aHR 0.78, 95% CI 0.68–0.90) and ulcerative colitis (aHR 0.78, 95% CI 0.63–0.97).
In the vedolizumab–ustekinumab sequence, initiating treatment with vedolizumab was associated with a lower risk of discontinuation (aHR 0.41, 95% CI 0.24–0.69).

Conclusion

The order of the first two biologic therapies in patients with IBD significantly impacts the durability of the overall treatment sequence. Initial use of an anti-TNF agent, particularly infliximab, is associated with greater treatment durability compared with starting with vedolizumab, ustekinumab, or adalimumab.

Event

UEG Week Barcelona 2026

Topics

Surgery IBD

Submission format

Abstract

Session

Real-world observations in IBD: Things we don't see in clinical trials

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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Santiago García-López

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Marcin Magierowski

UEG Presentation

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EFFICACY AND SAFETY OF TEGOPRAZAN IN FUNCTIONAL DYSPEPSIA: A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL STUDY

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EFFICACY AND SAFETY OF TEGOPRAZAN IN FUNCTIONAL DYSPEPSIA: A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL STUDY

Tian He 1, Jianhua Zhang 1, Rui Feng 2, Lichun Zhong 3, Maoxing Lin 4, Qian Xiang 5, XIA CHEN 5, Hongbing Chen 2, LING LIU 1

Affiliations

1 Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China

2 The First Veterans Hospital of Sichuan Province, Chengdu, China

3 Sichuan Tianfu New Area People's Hospital, Chegndu, China

4 West China (Airport) hospital Sichuan University, Chengdu, China

5 The Sixth People's Hospital of Chengdu, Chengdu, China

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Abstract

Introduction

Functional dyspepsia (FD) is one of the most common diseases of the digestive system, which comprises two subtypes, postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Acid suppression therapy has been recognized as the first-line treatment for H.pylori-negative FD patients. Potassium-competitive acid blocker (PCAB), a novel acid suppressant, has the characteristics of faster onset of effect and more stable acid suppression compared with traditional proton pump inhibitor (PPI). However, there has been no prospective study of PCAB for FD treatment.

Aims & Methods

This study was therefore conducted to investigate the efficacy and safety of PCAB in FD patients, and initially explore the effects of PCAB on gut microbiota. Patients diagnosed with FD were included prospectively. Eligible subjects were randomly assigned to the trial group and placebo group by 2:1, respectively, to receive Tegoprazan or placebo treatment with 50mg once a day for 2 weeks. 7-point global overall symptom scale (GOSS) was used to evaluate the relief of dyspepsia symptoms (primary endpoint) before the trial and at 1 and 2 weeks after randomization. Quality of life was assessed using the short form Nepean dyspepsia index (SFNDI). The generalized anxiety disorder-7 (GAD-7) and patient health questionnaire -9 (PHQ-9) were used to evaluate anxiety and depression, respectively. Stool samples were collected for 16SrRNA sequencing to evaluate gut microbiota alterations. Blood samples were collected to detect blood routine and blood biochemistry, and drug-related adverse events reported by subjects were collected to evaluate the safety of Tegoprazan.

Results

A total of 84 subjects were randomized, including 55 in the trial group and 29 in the placebo group. Among the subjects, 58.3% (49/84) were females, the median age was 51.00 (38.75, 55.00) years, and the mean BMI was 21.21 ± 3.06kg/m². For FD subtypes, EPS accounted for 44.0% (37/84), and no significant difference between the two groups was evident. In addition, there were no significant differences in the GOSS score, GAD-7 score and PHQ-9 score between the two groups at baseline. In the ITT analysis, the overall response rate was 25.5% (14/55) in the trial group and 17.2% (5/29) in the placebo group at 1 week, with no significant difference between the two groups (P =0.392). The 2-week response rate was 38.2% (21/55) in the trial group and 27.6% (8/29) in the placebo group, with no significant difference between the two groups (P =0.331). The results of PP analysis were consistent with ITT analysis. In the analysis of FD subtype, the response rate of EPS receiving Tegoprazan for 1 week was 45.8% (11/24), and that of the placebo group was 7.7% (1/13), with significant difference between the two groups (P =0.027).The response rate at 2 weeks of treatment with Tegoprazan was 50.0% (12/24), and the response rate after 2 weeks of placebo treatment was 15.4% (2/13), with no significant difference between the two groups (P =0.074). No significant difference was found between Tegoprazan and placebo on PDS (P > 0.05). In terms of gut microbiota, after 2 weeks of Tegoprazan treatment, the abundance of fecal genus streptococcus increased significantly (P < 0.001), especially streptococcus salivarius. There were no significant differences in the incidence of adverse events between the trial group and the placebo group (P > 0.05). No severe adverse events occurred in this study.

Conclusion

Tegoprazan is suitable for short course treatment of EPS. For patients requiring long-term treatment with Tegoprazan, the benefits of acid suppression should be weighed against the risk of intestinal microbiota dysbiosis. Tegoprazan had a similar safety profile to placebo.

Event

UEG Week Vienna 2024

Topics

Neurogastroenterology & Motility Stomach & H. Pylori Oesophagus

Submission format

Abstract

Session

Dyspepsia and H.pylori

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Marcin Magierowski

UEG Presentation

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The gut microbiome in MASLD

Debbie Shawcross 1

Affiliations

1 Kings College London, NHS Foundation Trust, London, United Kingdom

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Abstract

Event

UEG Week Barcelona 2026

Topics

IBD Gut Microbiota

Session

Gut microbiome in non-communicable disorders

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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Autoimmune gastritis: Solving controversies

Marino Venerito

IMPACT OF THE ORDER OF THE FIRST TWO BIOLOGIC THERAPIES IN INFLAMMATORY BOWEL DISEASE: THE SECUTEM STUDY FROM THE ENEIDA REGISTRY

Santiago García-López

EFFICACY AND SAFETY OF TEGOPRAZAN IN FUNCTIONAL DYSPEPSIA: A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL STUDY

XIA CHEN

The gut microbiome in MASLD

Debbie Shawcross

ENRICHMENT OF POLYSTYRENE-DEGRADING MICROBES IN THE UPPER GASTROINTESTINAL TRACT OF FUNCTIONAL DYSPEPSIA PATIENTS

Simon Keely

CYTOPROTECTIVE CARBON MONOXIDE SIGNALING IS MITOCHONDRIA-ORIENTED AND ENHANCES GASTRIC MUCOSAL ABILITY TO COUNTERACT PATHOLOGY-DRIVEN DISINTEGRATION EVOKED BY NON-STEROIDAL ANTI-INFLAMMATORY DRUG

Marcin Magierowski

UEG Poster

Standard Poster

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ENRICHMENT OF POLYSTYRENE-DEGRADING MICROBES IN THE UPPER GASTROINTESTINAL TRACT OF FUNCTIONAL DYSPEPSIA PATIENTS

Emily Hoedt 1,2, Jennifer Pryor 1,2, Ayesha Shah 3,4, Gerald J. Holtmann 3,4, Nicholas J. Talley 1,2, Simon Keely 1,2

Affiliations

1 University of Newcastle, Newcastle, Australia

2 Hunter Medical Research Institute, Newcastle, Australia

3 Princess Alexandra Hospital, Brisbane, Australia

4 University of Queensland, Brisbane, Australia

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Abstract

Introduction

Microplastics are unavoidable in our current environment and can enter the human body through ingestion, inhalation, and skin contact. Gut microbes play a role in plastic degradation, breaking down polymers into smaller molecules through enzymatic processes like depolymerization and oxidation, which can then be used as a carbon source (1). However, there is mounting alarming evidence that implicates microplastics in causing oxidative stress, DNA damage, and chronic inflammation, potentially leading to various health issues, including gastrointestinal disorders (2-4). In individuals with digestive disorders such as DGBI (disorders of gut-brain interaction), microplastics may exacerbate symptoms by disrupting gut microbiome and immune responses. Previously, within a functional dyspepsia (FD) cohort we identified a strong positive correlation between plastic degrading Exiguobacterium genus (5) within the duodenal mucosa and mucosa Th2 immune cells (6).

Aims & Methods

We aimed to investigate the differential abundance of microbes and metabolic pathways known to degrade plastics in patients with FD. Previously, we have published the 16S duodenal mucosa associated microbiome sequence data for FD (n=17) and asymptomatic control (n=11) groups (6), in addition we conducted a systematic review and retrieved 1 raw duodenal mucosa-associated microbiome 16S sequence dataset (FD n=61, controls n=38) for re-analysis with a consistent bioinformatic pipeline. This included quality assessment, demultiplexing and denoising with QIIME2 and taxonomic assignment with SILVA database. Functional differences in the microbiome were predicted with PICRUSt2. Differentially abundant plastic utilising genes were assessed in R, after CLR-transformation.

Results

As the two 16S upper gastrointestinal mucosa microbiome FD studies were sequenced separately, and the batch effect are pronounced we could not combine them for pooled analysis. When we examined the first study for predicted metabolic pathways for differential polyethylene terephthalate (PET) utilization when comparing FD patients to controls in the duodenum mucosa-associated microbiome, we did not identify any significant differences. An increase in the "partial TCA cycle (obligate autotrophs)" was observed in the gastric mucosa-associated microbiome of FD patients vs controls; PET by-products have been linked to the TCA cycle (7).
The study retrieved through our systematic review identified several significantly increased predicted functional polyethylene-associated genes, primarily from later stages of degradation. The findings revealed that the gene 3-oxoadipate enol-lactonase [EC:3.1.1.24] was significantly increased in FD patients. Furthermore, the genes 5-carboxymethyl-2-hydroxymuconic-semialdehyde dehydrogenase [EC:1.2.1.60] and 5-oxopent-3-ene-1,2,5-tricarboxylate decarboxylase/2-hydroxyhepta-2,4-diene-1,7-dioate isome were significantly increased in controls. Finally, 5-carboxymethyl-2-hydroxymuconate isomerase [EC:5.3.3.10] was also increased in controls though not significantly.

Conclusion

Our recent microbiome analysis reveals a significant enrichment of PET-degrading microbes colonising the upper gastrointestinal tract of patients with FD compared to controls. These findings provide new insights into the microbial and immune landscape of FD patients, highlighting potential microbial biomarkers and immune associations that warrant further investigation.

References

1. Yang X-G, Wen P-P, Yang Y-F, Jia P-P, Li W-G, Pei D-S. 2023. Plastic biodegradation by in vitro environmental microorganisms and in vivo gut microorganisms of insects. Frontiers in Microbiology
2. Jayavel S, Govindaraju B, Michael JR, Viswanathan B. 2024. Impacts of micro and nanoplastics on human health. Bulletin of the National Research Centre
3. Cheng Y, Yang Y, Bai L, Cui J. 2024. Microplastics: an often-overlooked issue in the transition from chronic inflammation to cancer. J Transl Med
4. Han Q, Gao X, Wang S, Wei Z, Wang Y, Xu K, Chen M. 2023. Co-exposure to polystyrene microplastics and di-(2-ethylhexyl) phthalate aggravates allergic asthma through the TRPA1-p38 MAPK pathway. Toxicology Letters
5. Parthasarathy A, Miranda RR, Eddingsaas NC, Chu J, Freezman IM, Tyler AC, Hudson AO. 2022. Polystyrene Degradation by Exiguobacterium sp. RIT 594: Preliminary Evidence for a Pathway Containing an Atypical Oxygenase. Microorganisms
6. Hoedt EC, Burns GL, Kang S, Bruce J, Morrison M, Keely S, Talley NJ. 2025. Altered Duodenal Mucosa-Associated Microbiota and Immune Profiles in Functional Dyspepsia: A Study of Host-Microbiome Homeostasis. bioRxiv doi:10.1101/2025.04.10.648308:2025.04.10.648308.
7. Carr CM, Clarke DJ, Dobson ADW. 2020. Microbial Polyethylene Terephthalate Hydrolases: Current and Future Perspectives. Front Microbiology

Disclosure

Keely reports consultancy and positions held on advisory boards for: Gossamer Bio (Scientific Advisory Board), Anatara Lifescience (Scientific Advisory Board), Microba Life Science (Consultancy) and Immuron Ltd. (Consultancy).
Talley reports personal fees from Biocodex (FD) (2024), Brown University (fiber and laxation), Microba (microbiome), outside the submitted work. NJT has a patent Licensing Questionnaires Talley Bowel Disease Questionnaire licensed to Mayo/Talley and Nepean Dyspepsia Index (NDI) 1998, patent “Diagnostic marker for functional gastrointestinal disorders” Australian Provisional Patent Application 2021901692, “Methods and compositions for treating age-related neurodegenerative disease associated with dysbiosis” US Application No. 63/537,725.

Conference

UEG Week Berlin 2025

Topics

Oesophagus

Submission format

Abstract

Session

Dyspepsia (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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CYTOPROTECTIVE CARBON MONOXIDE SIGNALING IS MITOCHONDRIA-ORIENTED AND ENHANCES GASTRIC MUCOSAL ABILITY TO COUNTERACT PATHOLOGY-DRIVEN DISINTEGRATION EVOKED BY NON-STEROIDAL ANTI-INFLAMMATORY DRUG

Marcin Magierowski

UEG Presentation

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CYTOPROTECTIVE CARBON MONOXIDE SIGNALING IS MITOCHONDRIA-ORIENTED AND ENHANCES GASTRIC MUCOSAL ABILITY TO COUNTERACT PATHOLOGY-DRIVEN DISINTEGRATION EVOKED BY NON-STEROIDAL ANTI-INFLAMMATORY DRUG

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CYTOPROTECTIVE CARBON MONOXIDE SIGNALING IS MITOCHONDRIA-ORIENTED AND ENHANCES GASTRIC MUCOSAL ABILITY TO COUNTERACT PATHOLOGY-DRIVEN DISINTEGRATION EVOKED BY NON-STEROIDAL ANTI-INFLAMMATORY DRUG

Aleksandra Danielak 1, Urszula Glowacka 1, Malgorzata Szetela 1, Monika Pinkas 1, Kinga Krukowska 1, Maciej Suski 1, Beata Gryzło 1, Monika Marcinkowska 1, Marcin Magierowski 1

Affiliations

1 Jagiellonian University Medical College, Cracow, Poland

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Abstract

Introduction

Carbon monoxide (CO) is an endogenous gaseous messenger produced by the enzymatic activity of heme oxygenase with anti-inflammatory and anti-oxidative properties [1]. Pharmacological CO donors with ability to release small amounts of CO exerted gastroprotective effects against injuries induced by ethanol, ischemia/reperfusion or non-steroidal anti-inflammatory drugs (NSAIDs) [2,3]. Interestingly, further studies revealed that low concentrations of CO influence mitochondrial bioenergetics and respiration by binding to heme proteins in electron transport chain (ETC), resulting in cytoprotective action [4]. Therefore, novel and unique startegy based on „click chemistry” has been invented by the Binghe Wang Lab (Georgia State University, USA) to deliver CO directly to the mitochondria [5]. However, this approach is yet to be implemented in GI pharmacology. Moreover, mitochondria as a fundamental target of endogenous CO-signaling in pathogenesis and prevention of GI pathologies has been ignored.

Aims & Methods

Therefore, we aimed to prove for the first time that mitochondrial rather than stochastic CO-signaling contributes in gastric mucosal integrity maintenance under pathogenic conditions. We also evaluated if targeted mitochondrial delivery of novel CO-prodrug described by Zheng et al. (Nature Chemistry 2018) [5] (working name: BW-mito-CO) protects gastric mucosa against acute injury evoked by NSAIDs representative, acetylsalicylic acid (ASA). Thus, male Wistar rats were pretreated intragastrically (i.g.) with 1) DMSO/H2O as vehicle, 2) BW-mito-CO (0.2, 1, 5 mg/kg) and CO-release activating „click”-moiety, 3) selected, the most effective dose of BW-mito-CO (5 mg/kg) + rotenone, a mitochondrial complex I inhibitor (5 mg/kg). Subsequently, gastric mucosal injury was induced by i.g. administration of ASA (125 mg/kg). Gastric mucosal damage and gastric mucosal blood flow (GBF) have been assessed by planimetry and laser flowmetry, respectively. Proteome profiling and molecular targets screening in gastric mucosal biopsies was performed using mass spectrometry-based proteomics. BW-mito-CO platform was synthesized in house according to Zheng et al. (Nature Chemistry 2018) [5].

Results

BW-mito-CO dose-dependently reduced the area of ASA-induced gastric mucosal damage, with the most notable effect observed at the dose of 5 mg/kg, while GBF remained without significant changes. Rotenone did not alter the protective effect of BW-mito-CO. Proteomic analysis revealed that BW-mito-CO (5 mg/kg) significantly upregulated proteins related to the tricarboxylic acid cycle and cytoprotective agents associated with gastric mucosal defense, including calpaines and treofil factor that were mostly altered in opposite manner by ASA. Pretreatment with BW-mito-CO upregulated mitochondrial complex I hemoproteins that were not affected by ASA.

Conclusion

We conclude that gastric mucosal CO-signaling mostly relies on its impact on mitochondrial compartments. Increased mitochondrial bioavailability of CO counteracts pathology-driven proteomic shifts in gastric mucosa. Implementation of mito-targeted CO delivery platforms appeared here as a novel and promising approach to GI pharmacology vs NSAIDs-induced gastric mucosal injuries. Mitochondrial CO signaling seems to mechanistically depend on its capacity to activate mitochondrial complex I and to enhance gastric mucosal ability to maintain its integrity under pathological conditions [Founding source: National Science Centre (Poland): 2019/33/B/NZ4/00616; Ministry of Science and Higher Education (Poland): Perły Nauki PN/01/0279/2022].

References

1. Yang X, Mao Q, Wang B. On the Question of CO’s Ability to Induce HO-1 Expression in Cell Culture: A Comparative Study Using Different CO Sources. ACS Chem Biol. 2024 Mar 15; 19(3): 725–735. doi:10.1021/acschembio.3c00750.
2. Danielak A, Wallace JL, Brzozowski T, et al. Gaseous Mediators as a Key Molecular Targets for the Development of Gastrointestinal-Safe Anti-Inflammatory Pharmacology. Front Pharmacol. 2021;12: 657457. doi:10.3389/fphar.2021.657457.
3. Bakalarz D, Surmiak M, Yang X, et al. Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage. Acta Pharm Sin B. 2021;11(2). doi:10.1016/j.apsb.2020.08.005.
4. Iacono LL, Boczkowski J, Zini R, et al. A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species. Free Radic Biol Med. 2011; 1;50(11):1556-64. doi: 10.1016/j.freeradbiomed.2011.02.033.
5. Zheng Y, Ji X, Yu B, et al. Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide. Nat Chem. 2018;10(7). doi:10.1038/s41557-018-0055-2.

Event

UEG Week Vienna 2024

Topics

Digestive Oncology Mechanisms & Personalised Medicine Oesophagus Stomach & H. Pylori

Submission format

Abstract

Session

Upper GI basic: Reflux, gastritis and cancer

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

More Like This:

Autoimmune gastritis: Solving controversies

Marino Venerito

IMPACT OF THE ORDER OF THE FIRST TWO BIOLOGIC THERAPIES IN INFLAMMATORY BOWEL DISEASE: THE SECUTEM STUDY FROM THE ENEIDA REGISTRY

Santiago García-López

EFFICACY AND SAFETY OF TEGOPRAZAN IN FUNCTIONAL DYSPEPSIA: A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL STUDY

XIA CHEN

The gut microbiome in MASLD

Debbie Shawcross

ENRICHMENT OF POLYSTYRENE-DEGRADING MICROBES IN THE UPPER GASTROINTESTINAL TRACT OF FUNCTIONAL DYSPEPSIA PATIENTS

Simon Keely

CYTOPROTECTIVE CARBON MONOXIDE SIGNALING IS MITOCHONDRIA-ORIENTED AND ENHANCES GASTRIC MUCOSAL ABILITY TO COUNTERACT PATHOLOGY-DRIVEN DISINTEGRATION EVOKED BY NON-STEROIDAL ANTI-INFLAMMATORY DRUG

Marcin Magierowski