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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

Summary

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Westernized diets induce colorectal tumorigenesis in ATF6-overexpressing mice through expansion of hydrogen sulfide-producing Desulfovibrio bacteria, and scavenging H2S with bismuth subsalicylate prevents tumor formation.

Westernized high-lard diet induced de novo tumorigenesis in monoallelic nATF6-overexpressing mice that are otherwise tumor-free, and increased tumor burden in biallelic mice.
Supplementing dietary fiber or lowering fat content failed to protect against the westernized diet-induced tumorigenic phenotype.
Metagenomic profiling of westernized diet-exposed mice identified increased relative abundance of H2S-producing Desulfovibrio species and genes related to dissimilatory sulfate reduction.
Transferring microbiota from diet-exposed mice into germ-free nATF6 mice was sufficient to trigger tumorigenesis, demonstrating microbiota-dependent transmissibility.
Supplementing westernized diets with the H2S-scavenger bismuth subsalicylate prevented tumor formation in monoallelic mice and drastically altered microbial communities.
H2S scavenging significantly reduces diet-induced colonic tumor susceptibility, demonstrating the impact of diet in shaping cancer-related microbiome alterations.

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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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$Surgical treatment for refractory reflux$

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Surgical treatment for refractory reflux

Eric Hazebroek 1

Affiliations

1 Rijnstate Hospital, Arnhem, Netherlands

Summary

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Abstract

Event

UEG Week Berlin 2025

Topics

Oesophagus Primary Care Surgery

Session

Managing reflux at multiple levels

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

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GLPs: What should gastroenterologists know about them?

Prateek Sharma 1

Affiliations

1 University of Kansas School of Medicine Dept. of Gastroenterology, Leawood, United States of America

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Abstract

Event

UEG Week Berlin 2025

Topics

Endoscopy Mechanisms & Personalised Medicine Surgery

Session

Obesity in Pan America

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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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)

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2025

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AN IBD ASSOCIATED TNRC18 VARIANT IS LINKED TO INCREASED DISEASE BURDEN AND THE NEED FOR MORE INTENSIVE THERAPIES

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AN IBD ASSOCIATED TNRC18 VARIANT IS LINKED TO INCREASED DISEASE BURDEN AND THE NEED FOR MORE INTENSIVE THERAPIES

Anna Aarni 1, Arto Lehisto 1, Elisa Lahtela 1, Paavo Häppölä 1, Pauliina Molander 2, Jukka Koskela 1

Affiliations

1 University of Helsinki, Helsinki, Finland

2 Helsinki University Hospital, Peijas Hospital, Helsinki, Finland

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Abstract

Introduction

Genome-wide association studies (GWAS) have identified more than 250 risk variants linked to inflammatory bowel disease (IBD). Most genetic variants increase the risk of disease onset, and their impact on clinical presentation is limited.^1,2,³ Variants in NOD2 and IL23R not only modulate the risk of disease onset, but also influence disease behaviour and localisation. Their role in predicting treatment response remains unclear.^3,4
A variant in an intron of TNRC18 (rs7486781, allele frequency 3.6%) was recently identified as having a strong risk-increasing effect (OR 3.2, p=2.4x10-61) for IBD in the FinnGen biobank study. The same allele was also associated with a risk for ankylosing spondylitis (AS), uveitis and psoriasis.⁵The functional effect of rs7486781 is not yet fully established.⁶

Aims & Methods

The FinnGen biobank study includes the genotype data of 520 000 individuals and their longitudinal register data from national health registers, including 11 298 individuals with verified diagnosis for IBD. The data also include drug purchases, procedure codes and laboratory measurements of the individuals.
Our aim was to study the impact of the TNRC18-variant on IBD phenotype, particularly disease behavior. We assessed established aspects of disease severity⁷: use of immunosuppressants and advanced therapies, necessity to switch medications, frequent use of corticosteroids and risk of procedures. We also evaluated the presence of extraintestinal manifestations (EIM) and other disease complications.

Results

Regarding disease severity, the use of therapies beyond 5-ASA was more common among variant carriers; the use of thiopurines and other immunosuppressants (OR 1.21-1.27, p-values 1.35x10^-5 - 0.00849), ustekinumab and other IL-inhibitors (OR 1.46-1.48, p-values 0.00324 - 0.00286) and TNF-α-inhibitors (OR 1.26, p=0.00753) was more frequent.
In addition, perianal and anal canal operations were more prevalent with TNRC18 variant carriers (OR 2.44, p=1.41x10^-4), indicating perianal disease.
Assessing EIM, we observed that diagnoses for AS and uveitis (OR 1.62-1.67, p=1.3x10^-5 - 1.55x10^-4) were more frequent within IBD in patients with rs7486781.
Interestingly, a reduced risk of primary sclerosing cholangitis (PSC) was implicated by lower number of cholangitis (K83.0) diagnoses (OR 0.617, p=0.00221) and fewer purchases of ursodeoxycholic acid (OR 0.55, p=2.83x10^-5), in addition to lower levels of ALP (mean 75 vs 82, p=0.00296), IgG4 (mean 0.45 g/l vs 0.81 g/l, p=4.81x10^-5) and IgM (0.12 vs 0.15, p=0.00115) among variant carriers. All events survived the false discovery rate–adjusted p threshold of 0.05.
Our results also suggest that the cumulative risk for IBD related procedures⁸ (patients with procedures n=2209) from diagnosis and birth were elevated in TNRC18 variant carriers (HR=1.12 and HR=1.14, p=0.050 and p=0.023, assuming additive effect) using a Cox regression model.
Finally, our results in ulcerative colitis indicate that TNRC18 variant carriers are at higher risk of transitioning from 5-ASA/immunomodulators to biologics/JAK-inhibitors (HR=1.38, p=0.016). Variant carriers receiving immunomodulators or advanced therapies were not, however, in increased risk of colectomy (HR~0.97-1.34, p~0.86-0.37).

Conclusion

TNRC18 variant was associated with greater risk of operative treatment, the need of more advanced medication and perianal disease. AS and uveitis were more common EIMs, but PSC appeared less infrequent. Our preliminary results indicate that TNRC18 variant carriers might benefit from early intervention with immunomodulators or advanced therapies.

References

1. Chang, J. T. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med 383, 2652–2664 (2020).

2. Cleynen, I. et al. Inherited determinants of Crohn’s disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387, 156–167 (2016).

3. Atreya, R. & Neurath, M. F. Biomarkers for Personalizing IBD Therapy: The Quest Continues. Clin Gastroenterol Hepatol 22, 1353–1364 (2024).

4. Kayali, S. et al. NOD2 and Crohn’s Disease Clinical Practice: From Epidemiology to Diagnosis and Therapy, Rewired. Inflamm Bowel Dis 31, 552–562 (2025).

5. Kurki, M. I. et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 613, 508–518 (2023).

6. Rahimov, F. et al. A genome-wide CRISPR screen supported by human genetics identifies the TNRC18 gene locus as a novel regulator of inflammatory signaling. bioRxiv 2023.10.04.560902 (2023) doi:10.1101/2023.10.04.560902 .

7. Swaminathan, A. et al. The Disease Severity Index for Inflammatory Bowel Disease Is a Valid Instrument that Predicts Complicated Disease. Inflamm Bowel Dis 30, 2064–2075 (2024).

8. Forss, A. et al. Validating surgical procedure codes for inflammatory bowel disease in the Swedish National Patient Register. BMC Med Inform Decis Mak 19, 217 (2019).

Disclosure

Anna Aarni: Speaker fee from Abbvie, Clinic visit: travelling expenses from Tillots Pharma

Pauliina Molander: Speaker, consultancy and advisory board member fees from Abbvie, Johnson & Johnson, Lilly, Pfizer and Takeda. Clinic visit: traveling expenses from Tillots Pharma

Jukka Koskela: Pfizer-FinnGen genetic advisory board, traveling, clinic and congress visits: FinnGen partners, Tillots Pharma, Takeda, consulting: Pfizer

Event

UEG Week Berlin 2025

Topics

IBD Mechanisms & Personalised Medicine

Submission format

Abstract

Session

New insights into IBD pathology

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Getting to the bottom of Crohn´s: Gastroenterologist vs surgeon perspective

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Getting to the bottom of Crohn´s: Gastroenterologist vs surgeon perspective

Gianluca Pellino 1, Iago Rodríguez-Lago 2

Affiliations

1 Hospital Universitari Vall d’Hebron, Barcelona, Spain

2 Hospital Universitario de Galdakao, Bilbao, Spain

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Abstract

Event

UEG Postgraduate Teaching Programme Berlin 2025

Session

The Crohn´s disease journey

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Can we cure or palliate?

Albert J. Bredenoord 1

Affiliations

1 Amsterdam UMC, Amsterdam, Netherlands

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Abstract

Event

UEG Week Berlin 2025

Topics

Oesophagus Primary Care

Session

Spastic oesophagus: Is it curable?

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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