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FOOD-INDUCED ALTERATIONS IDENTIFIED USING CONFOCAL LASER ENDOMICROSCOPY ARE NOT ASSOCIATED WITH DIET OUTCOMES IN PATIENTS WITH IRRITABLE BOWEL SYNDROME: A RANDOMISED DOUBLE BLIND CROSSOVER DIET INTERVENTION STUDY

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FOOD-INDUCED ALTERATIONS IDENTIFIED USING CONFOCAL LASER ENDOMICROSCOPY ARE NOT ASSOCIATED WITH DIET OUTCOMES IN PATIENTS WITH IRRITABLE BOWEL SYNDROME: A RANDOMISED DOUBLE BLIND CROSSOVER DIET INTERVENTION STUDY

Lukas Balsiger 1, Jolien Schol 2, Karlien Raymenants 2, Cedric Van de Bruaene 2, Joran Toth 1, Karen Routhiaux 1, Matthias Ceulemans 3, Julie Vanderstappen 4, Astrid Verbiest 1, Michael P. Jones 5, Ricard Farré 1, Tim Vanuytsel 6, Jan Tack 2

Affiliations

1 TARGID KU Leuven, Leuven, Belgium

2 TARGID KU Leuven, Leuven, Belgium|||University Hospitals Leuven, Leuven, Belgium

3 Icahn School of Medicine at Mount Sinai, New York, United States

4 University Hospitals Leuven, Leuven, Belgium

5 Macquarie University, North Ryde, Australia

6 University Hospitals Leuven, Leuven, Belgium|||TARGID KU Leuven, Leuven, Belgium

Summary

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A double-blind controlled cross-over trial found that confocal laser endomicroscopy-guided exclusion diets did not improve IBS symptoms more than sham diets, and mucosal alterations observed were not specific to IBS.

In 31 IBS patients who completed both diet phases, clinical response rate was 42% for CLE-guided real diet versus 36% for sham diet (odds ratio 1.33, 95% CI 0.46-3.84), with no difference in IBS-SSS change (median -30 points vs -20 points, p=0.7).
The trial was terminated prematurely for futility after interim analysis showed the odds ratio fell below the predetermined futility threshold of 1.5.
Mucosal alterations were observed in 100% of CLE exams in IBS patients (54/54 exams), either at baseline (11%) or after food administration, most commonly after milk, fish, and eggs.
Identical mucosal alterations were observed in all 15 healthy control exams (100%), with similar distribution among foods, suggesting the alterations are not disease-specific for IBS.
Acute mucosal alterations were not associated with altered permeability (25.6 vs 24.6 Ωxcm², p=0.6) or tryptase release (1.1 vs 0.62 µg/mg tissue, p=0.15).
No differences were observed between real and sham diets in pain duration, pain severity, bloating severity, or flatulence severity on visual analogue scales.

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Abstract

Introduction

Food-induced mucosal reactions have been visualised in the duodenum of patients with irritable bowel syndrome (IBS) using confocal laser endomicroscopy (CLE). The mechanisms underlying these alterations remain elusive but uncontrolled studies have reported symptomatic improvement in patients on a diet excluding foods that triggered acute alterations.

Aims & Methods

Aim: 1/ elucidate mechanisms underlying food-induced, acute mucosal alterations and 2/ assess whether a diet based on CLE results improves symptoms in patients with IBS.
Methods: Randomised, double-blind, controlled, cross-over study. Patients with ROME IV IBS (non-C), underwent CLE with sequential administration of foods (wheat, soy, milk, egg white, fish mix, and nut mix) in a randomised order ≥2 weeks after index gastroscopy. CLE was terminated after acute reactions or after administration of all foods. In case less than three foods were administered, a second exam was scheduled. Biological measures were compared between index endoscopy and CLE with food administration. Patients excluded food(s) that did (=real diet) and food(s) that did not (=sham diet) cause alterations for 4 weeks each in a blinded, cross-over diet intervention. Clinical response rate (=improvement of ≥50 points IBS-SSS) between real and sham diet was compared. Missing data was replaced using an extreme case approach (missing data on the primary endpoint was considered non-response). Healthy controls underwent CLE to assess disease specificity of observed alterations.

Results

Thirty-three patients were included, of which 21 underwent a second CLE. Alterations were observed in all 54 exams (100%) either at baseline (6/54, 11%) or after administration of food. Acute alterations were not associated with altered permeability (transepithelial electrical resistance 25.6 Ωxcm² after CLE vs 24.6 Ωxcm²at baseline; p = 0.6) nor with tryptase release from duodenal biopsies (1.1 µg/mg tissue vs 0.62 µg/mg tissue; p =0.15) . Two patients dropped out during the diet phase (one due to maladherence to study protocol, one due to acute increase of IBS symptoms during washout). Thirty-one patients completed the diet phase: 13 were clinical responders to the real diet (42%) versus 11 responders to sham (36%). The odds ratio (OR) for clinical response to the real diet was 1.33 (95% confidence interval: 0.46-3.84). The trial was terminated prematurely for futility (predetermined futility threshold OR <1.5). There was no difference in symptom evolution between real and sham diet (median change in IBS-SSS real diet: -30 points, median change sham diet: -20 points ; p = 0.7). No differences were observed between real and sham diet regarding change in pain duration (-0.1 vs +0.1, p =0.5) , in pain severity (-0.1 vs -0.1, p = 0.9), in bloating severity (-0.1 vs -0.4, p=0.6) or in flatulence severity (± 0.0 vs -0.2 p=0.5) based on 10cm VAS scales in symptom diaries. Fifteen healthy volunteers underwent CLE with alterations in all 15 (100%) exams at baseline (2/15, 13%) or after food administration. Distribution of alterations among different foods was similar to that in patients.

Conclusion

In this double-blind controlled cross-over trial, trigger foods identified based on CLE responses were not associated with superior clinical improvement following a targeted exclusion diet compared to a sham diet. Acute alterations in healthy controls suggest these alterations are not specific for IBS. The underling physiological or pathophysiological mechanism requires further studies.

Event

UEG Week Berlin 2025

Topics

Gut Microbiota Neurogastroenterology & Motility Small Intestine & Nutrition Colorectal

Submission format

Abstract

Session

Lower GI motility II

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Transglutaminase inhibition in CeD

Detlef Schuppan

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Kevin Whelan

COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) PEPTIDE MEDIATES INTRACELLULAR CA2+ RELEASE IN SENSORY NEURONS AND INDUCES FIRING OF THE COLON-INNERVATING LUMBAR SPLANCHNIC NERVE

David Bulmer

GP perspective: How to diagnose, review lifestyle and diet

Jelena Rakic Matic

ATOPY AND OTHER (FOOD) HYPERSENSITIVITIES IN NON-CELIAC WHEAT SENSITIVITY: SHOULD WE RECLASSIFY THESE PATIENTS AS ‘ALLERGIC’? A RETROSPECTIVE CASE-CONTROL STUDY

Antonio Carroccio

WESTERNIZED DIETS EXACERBATE TUMORIGENESIS BY EXPANDING H2S-PRODUCING DESULFOVIBRIO IN MURINE MODELS OF ATF6-DRIVEN COLON CANCER

Miriam von Stern-Gwiazdowski

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Transglutaminase inhibition in CeD

Detlef Schuppan 1

Affiliations

1 Medical University Mainz - Institute of Translational Immunology, Medical University Mainz ; Mainz/D, Mainz, Germany

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Abstract

Event

UEG Week Berlin 2025

Topics

Immunology Nurses Small Intestine & Nutrition

Session

What's new in coeliac disease in 2025?

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Transglutaminase inhibition in CeD

Detlef Schuppan

Challenges of research and practice in diet and DGBI

Kevin Whelan

COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) PEPTIDE MEDIATES INTRACELLULAR CA2+ RELEASE IN SENSORY NEURONS AND INDUCES FIRING OF THE COLON-INNERVATING LUMBAR SPLANCHNIC NERVE

David Bulmer

GP perspective: How to diagnose, review lifestyle and diet

Jelena Rakic Matic

ATOPY AND OTHER (FOOD) HYPERSENSITIVITIES IN NON-CELIAC WHEAT SENSITIVITY: SHOULD WE RECLASSIFY THESE PATIENTS AS ‘ALLERGIC’? A RETROSPECTIVE CASE-CONTROL STUDY

Antonio Carroccio

WESTERNIZED DIETS EXACERBATE TUMORIGENESIS BY EXPANDING H2S-PRODUCING DESULFOVIBRIO IN MURINE MODELS OF ATF6-DRIVEN COLON CANCER

Miriam von Stern-Gwiazdowski

UEG Presentation

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Challenges of research and practice in diet and DGBI

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Challenges of research and practice in diet and DGBI

Kevin Whelan 1

Affiliations

1 King's College London - Diabetes & Nutritional Sciences Division, King's College London; London/GB, London, United Kingdom

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Abstract

Event

UEG Week Berlin 2025

Topics

IBD Neurogastroenterology & Motility Primary Care

Session

Diet and disorders of gut-brain interaction: From IBS to IBD

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Transglutaminase inhibition in CeD

Detlef Schuppan

Challenges of research and practice in diet and DGBI

Kevin Whelan

COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) PEPTIDE MEDIATES INTRACELLULAR CA2+ RELEASE IN SENSORY NEURONS AND INDUCES FIRING OF THE COLON-INNERVATING LUMBAR SPLANCHNIC NERVE

David Bulmer

GP perspective: How to diagnose, review lifestyle and diet

Jelena Rakic Matic

ATOPY AND OTHER (FOOD) HYPERSENSITIVITIES IN NON-CELIAC WHEAT SENSITIVITY: SHOULD WE RECLASSIFY THESE PATIENTS AS ‘ALLERGIC’? A RETROSPECTIVE CASE-CONTROL STUDY

Antonio Carroccio

WESTERNIZED DIETS EXACERBATE TUMORIGENESIS BY EXPANDING H2S-PRODUCING DESULFOVIBRIO IN MURINE MODELS OF ATF6-DRIVEN COLON CANCER

Miriam von Stern-Gwiazdowski

UEG Presentation

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COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) PEPTIDE MEDIATES INTRACELLULAR CA2+ RELEASE IN SENSORY NEURONS AND INDUCES FIRING OF THE COLON-INNERVATING LUMBAR SPLANCHNIC NERVE

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COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) PEPTIDE MEDIATES INTRACELLULAR CA2+ RELEASE IN SENSORY NEURONS AND INDUCES FIRING OF THE COLON-INNERVATING LUMBAR SPLANCHNIC NERVE

Nicole Rudi 1, Remigijus Lape 2, Edward Stevens 2, David Bulmer 1

Affiliations

1 University of Cambridge, Cambridge, United Kingdom

2 Metrion Biosciences, Cambridge, United Kingdom

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Abstract

Introduction

Inflammatory bowel disease (IBD) is characterised by inflammatory flares with excruciating pain, for which effective analgesics are lacking. Cocaine- and amphetamine-regulated transcript (CART) peptide regulates peripheral pain in mice.¹ However, its role in visceral nociception as well as the underlying molecular signalling mechanism in primary sensory neurons remains elusive. CART is highly expressed in TRPV1-positive colon-projecting sensory neurons.² In addition, the enzyme prohormone convertase 1/3, which is involved in processing CART into its bioactive fragment 55-102, is upregulated in colonic biopsies of IBD patients (internal data), suggesting a potential role for the peptide in colonic pain.

Aims & Methods

Here, we aimed to test if CART would affect firing of the colon-innervating lumbar splanchnic nerve (LSN) as model of visceral nociception and characterise its effect and signalling pathway in sensory neurons innervating the colon. Studies were performed using tissue from male and female C57BL/6J mice euthanised by cervical dislocation and exsanguination in accordance with Schedule 1 of the Animals (Scientific Procedures) Act 1986. Thoracolumbar dorsal root ganglia (DRG) neurons were dissociated and cultured overnight for Ca²⁺ imaging using Fluo-4 AM as previously described.³ Cells were perfused with extracellular solution (ECS) alone or supplemented with either rat CART 55-102, (20-300nM, ECS), thapsigargin (10mM, DMSO), xestospongin C (1mM, ECS), edelfosine (10mM, ECS), capsaicin (10mM, ethanol) or KCl solution (60mM, ddH₂O) for respective challenge or pre-treatment. All conditions were blinded and randomised. Colorectum with attached lumbar splanchnic nerve was carefully removed and mounted on a tissue bath superfused with Krebs buffer as previously described.³ Rat CART 55-102 was superfused at 5ml/min, resulting in a final concentration of 200nM. Statistical analysis was performed using Student´s t test or ANOVA and Dunnett´s multiple comparisons test. Data is displayed as mean ± SEM.

Results

CART elicited a concentration-dependent increase in intracellular Ca²⁺ in DRG neurons, which at the highest concentration tested (300nM) induced a significant increase in intracellular Ca²⁺ in 29.2 ± 2.98% of DRG neurons relative to 8.35 ± 1.25% of vehicle responders (p < 0.0001). 55.05% of CART-responsive neurons were putative nociceptors due to co-sensitivity to capsaicin. Further investigation revealed a statistically significant reduction in the proportion of CART-sensitive neurons compared to CART (300nM) alone following pre-treatment with edelfosine, a phospholipase C inhibitor (10.5 ± 3.88%, p = 0.006), thapsigargin, a SERCA pump inhibitor (7.25 ± 1.78%, p = 0.001), or xestospongin C, an inositol triphosphate receptor inhibitor (6.74± 1.87%, p = 0.006). Furthermore, tissue bath application of CART (200nM) elicited a marked transient increase in ongoing LSN discharge, which increased from a baseline of 12.8 ± 3.9 (spikes/s) to a peak firing of 19.7 ± 6.1 spikes/s (p = 0.0385).

Conclusion

CART stimulates intracellular Ca²⁺ release in capsaicin-sensitive neurons consistent with a role in pain processing. This response was mediated by the release of Ca²⁺ from intracellular stores such as the endoplasmic reticulum and attenuated by inhibitors of the G_q pathway, suggesting activation of a G_q-coupled GPCR. The pronociceptive activity of CART on nerve firing suggests a potential role in colonic pain. Further research is necessary to identify the role of CART in IBD.

References

1. Ohsawa M, Dun SL, Tseng LF, Chang J, Dun NJ. Decrease of hindpaw withdrawal latency by cocaine- and amphetamine-regulated transcript peptide to the mouse spinal cord. Eur J Pharmacol. Jul 7 2000;399(2-3):165-9. doi:10.1016/s0014-2999(00)00374-5
2. McGuire C, Boundouki G, Hockley JRF, et al. Ex vivo study of human visceral nociceptors. Gut. Jan 2018;67(1):86-96. doi:10.1136/gutjnl-2016-311629
3. Higham JP, Bhebhe CN, Gupta RA, et al. Transcriptomic profiling reveals a pronociceptive role for angiotensin II in inflammatory bowel disease. Pain. Jan 29 2024;doi:10.1097/j.pain.0000000000003159

Disclosure

The PhD research is partially funded by Metrion Biosciences.

Event

UEG Week Berlin 2025

Topics

Gut Microbiota Neurogastroenterology & Motility Small Intestine & Nutrition IBD

Submission format

Abstract

Session

Lower GI motility II

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Transglutaminase inhibition in CeD

Detlef Schuppan

Challenges of research and practice in diet and DGBI

Kevin Whelan

COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) PEPTIDE MEDIATES INTRACELLULAR CA2+ RELEASE IN SENSORY NEURONS AND INDUCES FIRING OF THE COLON-INNERVATING LUMBAR SPLANCHNIC NERVE

David Bulmer

GP perspective: How to diagnose, review lifestyle and diet

Jelena Rakic Matic

ATOPY AND OTHER (FOOD) HYPERSENSITIVITIES IN NON-CELIAC WHEAT SENSITIVITY: SHOULD WE RECLASSIFY THESE PATIENTS AS ‘ALLERGIC’? A RETROSPECTIVE CASE-CONTROL STUDY

Antonio Carroccio

WESTERNIZED DIETS EXACERBATE TUMORIGENESIS BY EXPANDING H2S-PRODUCING DESULFOVIBRIO IN MURINE MODELS OF ATF6-DRIVEN COLON CANCER

Miriam von Stern-Gwiazdowski

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

GP perspective: How to diagnose, review lifestyle and diet

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GP perspective: How to diagnose, review lifestyle and diet

Jelena Rakic Matic 1

Affiliations

1 Health Care Center Zagreb West, ZAGREB, Croatia

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Abstract

Event

UEG Week Berlin 2025

Topics

Primary Care

Session

Bloating

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Transglutaminase inhibition in CeD

Detlef Schuppan

Challenges of research and practice in diet and DGBI

Kevin Whelan

COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) PEPTIDE MEDIATES INTRACELLULAR CA2+ RELEASE IN SENSORY NEURONS AND INDUCES FIRING OF THE COLON-INNERVATING LUMBAR SPLANCHNIC NERVE

David Bulmer

GP perspective: How to diagnose, review lifestyle and diet

Jelena Rakic Matic

ATOPY AND OTHER (FOOD) HYPERSENSITIVITIES IN NON-CELIAC WHEAT SENSITIVITY: SHOULD WE RECLASSIFY THESE PATIENTS AS ‘ALLERGIC’? A RETROSPECTIVE CASE-CONTROL STUDY

Antonio Carroccio

WESTERNIZED DIETS EXACERBATE TUMORIGENESIS BY EXPANDING H2S-PRODUCING DESULFOVIBRIO IN MURINE MODELS OF ATF6-DRIVEN COLON CANCER

Miriam von Stern-Gwiazdowski

UEG Poster

Standard Poster

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ATOPY AND OTHER (FOOD) HYPERSENSITIVITIES IN NON-CELIAC WHEAT SENSITIVITY: SHOULD WE RECLASSIFY THESE PATIENTS AS ‘ALLERGIC’? A RETROSPECTIVE CASE-CONTROL STUDY

Aurelio Seidita 1, Pasquale Mansueto 2, Maurizio Soresi 2, Diana Di Liberto 2, Marianna Lauricella 2, Giovanni Pratelli 2, Lydia Giannitrapani 2, Giorgia Cavallo 1, Francesco Faraci 1, Oriana Taibi 1, Laura Verona 1, Mirco Pistone 1, Giuseppe Mazzarella 3, Alessandra Camarca 3, Francesco Maurano 3, Antonio Carroccio 1

Affiliations

1 University of Palermo, Palermo, Italy|||“V. Cervello” Hospital, Ospedali Riuniti “Villa Sofia-Cervello”, Palermo, Italy

2 University of Palermo, Palermo, Italy

3 Institute of Food Sciences-CNR, Avellino, Italy

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Abstract

Introduction

Advances in non-celiac wheat sensitivity (NCWS) have proved that it should be considered a protean condition in which several potential triggers [e.g. gluten, wheat amylase-trypsin inhibitors, etc.] might determine an intestinal mucosal damage with increased permeability and exposure of foods/microbial peptides to immune cells (1,2), resulting in both a local and systemic inflammatory activation responsible for its gastrointestinal and extraintestinal manifestations (3,4). Up to 75% of NCWS subjects complain of multiple foods hypersensitivities (MFH) (5). These patients usually have clinical, immunological and histological features similar to wheat allergy patients, although without positive gluten/wheat IgE assays, allowing to hypothesize the existence of a non-IgE mediated hypersensitivity. In addition, several studies have reported an association between atopic diseases and NCWS.

Aims & Methods

This study aimed to define the presence and features of atopic diseases and other hypersensitivities (primarily food allergies/intolerances) in NCWS compared with celiac disease (CD) and irritable bowel syndrome/functional dyspepsia (IBS/FD) and to analyze a possible correlation between these diseases and NCWS clinical manifestations. This retrospective, multicenter study included NCWS patients diagnosed by double-blind placebo-controlled challenge with wheat. Their clinical, laboratory and histology data at diagnosis (i.e. before the start of a wheat-free diet) were analyzed and compared to control subjects with CD and IBS/FD. Specific allergology data, other than clinical/laboratory features typical of NCWS, were collected and analyzed: family and personal history of atopic diseases, type of allergens responsible, positivity of skin prick tests (SPT), patch tests and total and food-specific IgE.

Results

Atopic disease prevalence was higher in NCWS (32.8%) than in CD (19.3%) and IBS/FD (21.5%) (P=.001 for both). Similarly, NCWS subjects had a higher frequency of MFH (39.8%) and self-reported milk intolerance (SRMI) (65.9%) compared to the controls (P <.001 for both). Allergic asthma, either alone (P=.03) or associated with allergic rhinitis (P=.005), was more prevalent in NCWS compared to IBS/FD, which was more often associated with allergic conjunctivitis (P=.004) or allergic rhinitis alone (P=.02). Graminaceae hypersensitivity and nickel allergic contact dermatitis (Ni-ACD) were more frequent in patients with NCWS (70.1% and 17.8%) vs both CD (48.7% and 9.4%, P=.03 and P=.01, respectively) and IBS/FD (50.8% and 6.7%, P=.01 and P<.001, respectively). On multiple logistic regression analysis, a coexistent atopic disease (OR 1.481), MFH (OR 3.882) and SRMI (OR 2.259) were associated with the NCWS diagnosis. NCWS subjects with atopy compared to those without more frequently had Ni-ACD (P<.001) and SRMI (P=.03), positive patch test (P<.001), SPT for foods (P=0.001) and both total and food-specific serum IgE (P=.02 and P=.002, respectively). On multiple logistic regression analysis, positivity to patch test (OR 2.955), SPT for foods (OR 5.799), and food-specific serum IgE (OR 3.101) were confirmed as differentiating the 2 subgroups.

Conclusion

NCWS subjects have a higher frequency of atopic disease, MFH and SRMI compared to both CD and IBS/FD ones. These conditions could be expression of an underlying hypersensitivity milieu characterizing NCWS and might be of support in the differential diagnosis between NCWS and functional gastrointestinal disorders, if inserted into a broader diagnostic panel.

References

1) Zevallos VF, Raker V, Tenzer S, Jimenez-Calvente C, Ashfaq-Khan M, Rüssel N, et al. Nutritional Wheat Amylase-Trypsin Inhibitors Promote Intestinal Inflammation via Activation of Myeloid Cells. Gastroenterology. 2017;152:1100-1113.e12.
2) Uhde M, Ajamian M, Caio G, De Giorgio R, Indart A, Green PH, et al. Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut. 2016;65:1930–7.
3) Volta U, De Giorgio R, Caio G, Uhde M, Manfredini R, Alaedini A. Nonceliac Wheat Sensitivity. Gastroenterol Clin North Am. 2019;48:165–82.
4) Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G, et al. Diagnosis of Non-Celiac Gluten Sensitivity (NCGS): The Salerno Experts’ Criteria. Nutrients. 2015;7:4966–77.
5) Carroccio A, Mansueto P, Iacono G, Soresi M, D’Alcamo A, Cavataio F, et al. Non-Celiac Wheat Sensitivity Diagnosed by Double-Blind Placebo-Controlled Challenge: Exploring a New Clinical Entity. American Journal of Gastroenterology. 2012;107:1898–906.

Disclosure

This study is funded by the European Union - Next Generation EU, Mission 4, Component 1 CUP B53D23031860001, Project Code: P2022Z9RZY_001.

Conference

UEG Week Berlin 2025

Topics

Small Intestine & Nutrition

Submission format

Abstract

Session

Diagnostics in coeliac disease (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

More Like This:

Transglutaminase inhibition in CeD

Detlef Schuppan

Challenges of research and practice in diet and DGBI

Kevin Whelan

COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) PEPTIDE MEDIATES INTRACELLULAR CA2+ RELEASE IN SENSORY NEURONS AND INDUCES FIRING OF THE COLON-INNERVATING LUMBAR SPLANCHNIC NERVE

David Bulmer

GP perspective: How to diagnose, review lifestyle and diet

Jelena Rakic Matic

ATOPY AND OTHER (FOOD) HYPERSENSITIVITIES IN NON-CELIAC WHEAT SENSITIVITY: SHOULD WE RECLASSIFY THESE PATIENTS AS ‘ALLERGIC’? A RETROSPECTIVE CASE-CONTROL STUDY

Antonio Carroccio

WESTERNIZED DIETS EXACERBATE TUMORIGENESIS BY EXPANDING H2S-PRODUCING DESULFOVIBRIO IN MURINE MODELS OF ATF6-DRIVEN COLON CANCER

Miriam von Stern-Gwiazdowski

UEG Presentation

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

WESTERNIZED DIETS EXACERBATE TUMORIGENESIS BY EXPANDING H2S-PRODUCING DESULFOVIBRIO IN MURINE MODELS OF ATF6-DRIVEN COLON CANCER

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WESTERNIZED DIETS EXACERBATE TUMORIGENESIS BY EXPANDING H2S-PRODUCING DESULFOVIBRIO IN MURINE MODELS OF ATF6-DRIVEN COLON CANCER

Isabel Keidel 1, Jagadrupa Sahoo 1, Miriam von Stern-Gwiazdowski 2, Hélène Omer 1, Tingting Zheng 1, Miriam Wimmer 2, Andreas Dunkel 2, Katja Steiger 3, Olivia Coleman 2, Melanie Schirmer 1, Dirk Haller 1

Affiliations

1 Technical University of Munich, Freising, Germany|||Technical University of Munich, Freising, Germany

2 Technical University of Munich, Freising, Germany

3 Technical University of Munich, München, Germany

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Abstract

Introduction

The interplay of diet and the intestinal microbiome plays a key role in developing colorectal cancer (CRC), with westernization of diets, e.g., an increase in fat and sugar and a decrease in fiber content, being the main contributor. We recently demonstrated that the endoplasmic reticulum unfolded protein response (ER-UPR) effector activating transcription factor 6 (ATF6) is associated with early and late onset of CRC in patients. Furthermore, the overexpression of ATF6 observed in a subset of CRC patients is associated with the presence of certain gut bacteria. The specific expression of activated ATF6 (nATF6) in mouse intestinal epithelial cells (nATF6^IEC) induces spontaneous development of colonic tumors in a microbiota-dependent manner, highlighting the functional relevance of ATF6 as a novel oncogenic driver.

Aims & Methods

To elucidate the adverse role of dietary fat, sugar, and fiber in tumorigenesis, we exposed nATF6^IEC mice under SPF conditions to control (chow) and westernized diets for 7 weeks after weaning. Microbial and metabolite profiles were assessed through deep metagenomic sequencing and targeted/untargeted mass spectrometry (LC-MS) analysis. Microbiota transfer of diet-exposed mice into germ-free recipients was conducted to verify the microbiota-dependent transmissibility of tumor formation. Bismuth(II)subsalicylate (BSS) was used as a dietary additive to validate the impact of bacteria-produced H₂S on tumorigenesis.

Results

Westernized high lard (HL) diet, enriched in fat and sugar and depleted in fermentable fiber, increased tumor burden in biallelic nATF6^IEC mice. Unexpectedly, HL induced de novo tumorigenesis in otherwise tumor-free monoallelic nATF6^IEC mice. Surprisingly, modifying the HL diet by supplementing dietary fiber or lowering fat content failed to protect the HL-induced tumorigenic phenotype. Metabolite profiling clearly differentiated westernized from control diets and tumor bearing from control mice. Transferring microbiota from diet-exposed mice into germ-free nATF6^IEC mice was sufficient to trigger tumorigenesis. Metagenomic profiles of westernized diet-exposed mice identified an increased relative abundance of H₂S-producing Desulfovibrio species and genes related to dissimilatory sulfate reduction. Supplementing westernized diets with the H₂S-scavenger BSS resulted in a drastic change in microbial communities as well as the prevention of tumor formation in monoallelic nATF6^IECmice.

Conclusion

These results highlight the ability of westernized diets to enhance nATF6-related tumorigenesis while altering metabolite and microbial profiles. Westernized diets favor the growth of sulfate-reducing Desulfovibrionaceae, possibly resulting in increased H₂S production. H₂S scavenging significantly reduces diet-induced colonic tumor susceptibility, clearly demonstrating the impact of diet in shaping cancer-related microbiome alterations.

Event

UEG Week Berlin 2025

Topics

Digestive Oncology Gut Microbiota Immunology Mechanisms & Personalised Medicine Colorectal

Submission format

Abstract

Session

Oncobiome

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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