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PROTON PUMP INHIBITORS NEGATIVELY IMPACT THE COURSE OF ULCERATIVE COLITIS – A COHORT STUDY OF OVER 10000 NEWLY DIAGNOSED PATIENTS IN NORWAY

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Introduction

Ulcerative colitis (UC) occurs in genetically predisposed individuals. The influence of environmental factors and the gastrointestinal microbiome is thought to be of particular importance in this disorder. Proton pump inhibitors (PPIs) affect the microbiome along the entire GI tract and PPI use is the single factor that influences fecal microbial composition to the largest extent at a population level. Only few studies have previously investigated the association between PPI use and UC, but these suggest that PPIs may increase the risk of UC and possibly also affect the disease course. The objective of the study was to examine how PPI exposure is associated with disease course in a large national cohort of newly diagnosed UC patients.

Aims & Methods

Nationwide data from the Norwegian Patient Registry (NPR) and the Norwegian Prescription Database (NorPD) were linked and a study cohort including all newly diagnosed UC patients in Norway between 2010 and 2020 was drawn based on predefined case definitions. PPI exposure was included as a time dependent variable and defined as PPI dispensal of at least 0.5 defined daily doses for 28 days. A 30 day time lag from dispensal was added and the exposure period extended 60 days after the duration of the prescription. Outcomes were classed by use of advanced therapies (adalimumab, infliximab, golimumab, vedolizumab, ustekinumab and tofacitinib), systemic glucocorticoids, and starting any additional systemic anti-inflammatory medication and colectomy during follow-up. Time-dependent Cox regressions included the variables PPI use (time-dependent), first systemic glucocorticoid prescription (time-dependent), first UC hospitalization (time-dependent), age-groups 0-19, 20-39, 40-59, 60+ years and sex. In the multivariate analyses using systemic glucocorticoids and colectomy as outcomes, advanced therapies was also included as a variable. Patients were followed from time of diagnosis until the outcome of interest, death or December 2020, whichever came first.

Results

There were 10149 patients in the study cohort. The median age was 40 years (IQR 27-56) and 56% were males. PPI use independently increased the risk of starting glucocorticoids (HR 1.20, 95% CI 1.07-1.34), advanced therapies (HR 1.54, 95% CI 1.36-1.73), any additional anti-inflammatory treatment (HR 1.18, 95%CI 1.05-1.32) and undergoing colon surgery (HR 1.52, 95%CI 1.17-1.98). The strongest risk factor for starting glucocorticoids were hospitalization (HR 4.35 95%CI 3.96-4.77), while young age also was a significant risk factor. Use of glucocorticoids was the strongest risk factor for starting treatment advanced therapies (HR 13.19, 95%CI 11.12-15.63) and younger age was also a significant risk factor in this analysis. In the sensitivity analysis using outcomes occurring without time lag and with 60 days lag, the HR of PPI use were similar. In analyses where patients exposed to NSAID were excluded, PPI use remained a significant risk factor for starting advanced therapies HR 1.66 (1.47-1.88) and undergoing colectomy HR 1.64 (1.25-2.15), but PPI use was no longer a risk factor for starting glucocorticoids or starting any anti-inflammatory treatment.

Conclusion

In this national cohort of newly diagnosed patients with UC, PPI use was a risk factor for unfavorable outcomes including advanced therapy initiation, additional anti-inflammatory medications and undergoing colectomy. Although further studies are needed, the evidence suggests that PPIs could affect the course of UC and should be used cautiously in UC patients.

Disclosure

The project was funded by Takeda. The author SSL reports research funding from Takeda during the conduct of the study. RF has received lecture fee from Takeda. MLH reports investigator research grants from Takeda, Pfizer, Tillotts and Ferring, and speaker fees from Tillotts, Ferring, Galapagos, BMS, MSD and AbbVie as well as Advisory board honoraria from Takeda and AbbVie.

PROTON PUMP INHIBITORS NEGATIVELY IMPACT THE COURSE OF ULCERATIVE COLITIS – A COHORT STUDY OF OVER 10000 NEWLY DIAGNOSED PATIENTS IN NORWAY

Reidar Fossmark 1, Sandre Svatun Lirhus 2, Marte Lie Høivik 3

1 Norwegian University of Science and Technology, Trondheim, Norway

2 University of Oslo, Oslo, Norway

3 Oslo University Hospital, Oslo, Norway

Event

UEG Week Copenhagen 2023

Topics

IBD Paediatrics

Submission format

Abstract

Session

IBD aetiology

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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The diabetologist view: Alteration in pancreas-liver axis links diabetes and MASLD

Amalia Gastaldelli 1

1 Institute of Clinical Physiology, Pisa, Italy

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Gut Microbiota Hepatobiliary Mechanisms & Personalised Medicine

Session

Diabetes in GI disorders

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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DISRUPTION OF TUFT CELL–ILC2 IMMUNE HOMEOSTASIS BY THE NANOPLASTICS–GUT MICROBIOTA–SUCCINATE AXIS EXACERBATES ILEAL INFLAMMATION

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Introduction

Inflammatory bowel disease (IBD) is a growing global health concern, especially in industrializing nations where westernized lifestyles drive rising incidence. Its etiology involves genetic, immune, and environmental factors. ^[1]. Plastics are extensively used in industry and daily life, and global plastic production is projected to exceed 34 billion tonnes by 2050^[2]. After release into the environment, plastic waste degrade into micro- (0.1 µm–5 mm) and nanoplastics (<0.1 µm)^[3]. These emerging pollutants are persistent, bioaccumulative, and the gastrointestinal tract is the primary interface for NPs exposure. The gut is the primary exposure route: adults ingest 0.1–5 g/week of micro-/nanoplastics^[4]. Fecal microplastic levels correlate with IBD severity^[5]; animal studies show these particles disrupt microbiota, alter short-chain fatty acids, impair the barrier, and trigger inflammation^[6]. However, most existing research is limited to histopathological observations; the cellular and molecular mechanisms underlying NP toxicity in the small intestine remain poorly understood, hindering systematic risk assessment and development of IBD prevention strategies.

Aims & Methods

To elucidate the dynamics of NP distribution and toxicity, we established a fluorescent-tracking system and reared mice in a plastic-free environment. Mice were orally exposed to 100 nm polystyrene nanospheres for or 3 or 6 weeks. We used fluorescent imaging, histology (H&E, PAS), immunofluorescence, electron microscopy, targeted metabolomics, and 16S rRNA sequencing to assess toxicity across small-intestinal regions. We tested succinate supplementation and compared effects in germ-free mice and small-intestinal organoids to distinguish microbiota-dependent from direct epithelial toxicity.

Results

Fluorescent imaging provided in vivo evidence for an enterohepatic–gallbladder circulation of NPs: following intestinal absorption, NPs first accumulate in the liver, are secreted into the gallbladder with bile acids, become concentrated between meals, and are released back into the gut upon gallbladder contraction after feeding. Prolonged NPs exposure induced chronic inflammatory cell infiltration in the small intestine, with significant reductions in crypt density, Tuft cell, goblet cell, and Paneth cell numbers, accompanied by neutrophil infiltration and decreased group 2 innate lymphoid cells (ILC2s). These changes were most pronounced in the ileum. NPs exposure also significantly reduced succinate levels in cecal contents—without altering tissue succinate—and markedly decreased the relative abundance of succinate-producing bacterial taxa. Succinate supplementation effectively reversed all of these alterations. Under germ-free conditions, NP-induced toxicity was abolished, and no direct toxic effect on Tuft cells was observed in intestinal organoids.

Conclusion

Oral NP exposure undergoes enterohepatic–gallbladder recirculation, resulting in sustained high NPs concentrations in the intestinal mucosa. The ileum is the most susceptible region, and NP toxicity depends on the gut microbiota: NP-induced dysbiosis impairs luminal succinate production, leading to depletion of ileal Tuft cells, which in turn diminishes proliferation and activation of goblet cells, Paneth cells, and ILC2s. Succinate supplementation rescues NP-induced ileal immune dysfunction. While plastic products have provided immense convenience, their uncontrolled use may contribute to the rising incidence of IBD. Our study delineates the mechanism by which NPs exacerbate ileal inflammation and proposes a feasible intervention strategy.

References

1. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. Lancet. 2017;390(10114):2769-78.
2. Luo D, Chu X, Wu Y, Wang Z, Liao Z, Ji X, et al. J Hazard Mater. 2024;465:133412.
3. Kumar M, Chen H, Sarsaiya S, Qin S, Liu H, Awasthi MK, et al. J Hazard Mater. 2021;409:124967.
4. Senathirajah K, Attwood S, Bhagwat G, Carbery M, Wilson S, Palanisami T. J Hazard Mater. 2021;404(Pt B):124004.
5. Yan Z, Liu Y, Zhang T, Zhang F, Ren H, Zhang Y. Environ Sci Technol. 2022;56(1):414-21.
6. Zhang Z, Xu M, Wang L, Gu W, Li X, Han Z, et al. Environ Int. 2023;182:108353.

DISRUPTION OF TUFT CELL–ILC2 IMMUNE HOMEOSTASIS BY THE NANOPLASTICS–GUT MICROBIOTA–SUCCINATE AXIS EXACERBATES ILEAL INFLAMMATION

wentao shao 1, Yulong Yang 2, Anhua Huang 2, Zhaoyan Jiang 2, Aihua Gu 3

1 Nanjing Medical University, Nanjing, China|||Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China, Shanghai, China|||Southeast University, Nanjing, China

2 Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China, Shanghai, China

3 Nanjing Medical University, Nanjing, China|||Nanjing Medical University, Nanjing, China