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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

Event

UEG Week Berlin 2025

Topics

IBD Mechanisms & Personalised Medicine Small Intestine & Nutrition Radiology & Imaging

Submission format

Abstract

Session

IBD: What about the environment?

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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REAL-LIFE VS CLINICAL TRIAL ACCESS TO BIOLOGICAL THERAPY: FINDINGS FROM AN ITALIAN-AMERICAN STUDY ON INFLAMMATORY BOWEL DISEASE

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Introduction

Treatment goals in inflammatory bowel disease (IBD) have evolved beyond symptom control to include mucosal healing, prevention of disease-related complications, improvement of health-related quality of life, and reduction of long-term disability, as outlined by the STRIDE II initiative¹. Despite significant progress in the development of advanced therapies (ADTs), up to 50% of IBD patients fail to respond to currently available treatments, underscoring the urgent need for new therapies, which are investigated in randomized clinical trials (RCTs). However, stringent eligibility criteria in RCTs limit the inclusion of real-world IBD patients, potentially compromising the generalizability of trial findings to daily clinical practice.

Aims & Methods

The aim of this study was to evaluate the proportion of real-life IBD patients who would be eligible for ongoing RCTs and to assess the representativeness of this population. Moreover, we aimed to identify the most frequently unmet eligibility criteria leading to patient exclusion and to characterize the clinical profiles that differentiate eligible from ineligible patients.
This prospective, observational, multicenter study was conducted between October 2023 and October 2024 at 2 tertiary IBD referral centers: the Fondazione Policlinico Universitario “A. Gemelli” in Rome, Italy, and the Crohn’s & Colitis Center at the University of Miami, USA. Consecutive patients with IBD indicated for a new ADT were enrolled. Each patient was systematically screened for inclusion and exclusion criteria across all actively recruiting phase 2b and 3 RCTs available at each center at the time of evaluation (6 RCTs in Rome: 4 UC and 2 CD; 5 RCTs in Miami: 3 UC and 2 CD).

Results

A total of 166 IBD patients (69 UC and 97 CD) were enrolled, with 129 patients from the Italian cohort and 37 from the American cohort. Among UC patients, only 16 (23.2%) met the eligibility criteria for at least 1 RCT, whereas 53 (76.8%) were deemed ineligible (p<0.001). In the CD group, just 10 patients (10.3%) were eligible for at least 1 RCT, compared to 87 (89.7%) who were not (p<0.001). The most common reasons for ineligibility among UC patients included: Modified Mayo score not within the required range of 5–9 (50.7%), absence of bowel urgency (63.8%), Mayo Endoscopic Subscore <2 (39.1%), failure to comply with ADT washout requirements (56.5%), insufficient number of prior ADT failures (39.0%), and recent use of topical 5-ASA or steroids within 4 weeks prior to screening (62.3%).
In CD patients, the most frequently unmet criterion was a CDAI between 220 and 450 (92.8%), followed by insufficiently liquid stool frequency (≥4 very soft or liquid stools/day; 75.3%), SES-CD<6 (39.2%), and the presence of CD-related complications such as strictures or fistulas (13.1%).

Conclusion

The majority of real-life IBD patients, particularly those with CD, are ineligible for participation in current RCTs—primarily due to relatively mild disease activity or ongoing need for concomitant therapies that are not permitted by trial protocols. Importantly, many real-world CD patients initiate new ADTs based on radiologic signs of disease activity, the presence of disease complications, or as prophylaxis for post-surgical recurrence, rather than clinical activity scores alone. Similarly, UC patients may require ADTs even in the context of corticosteroid dependence and low-grade disease activity. These findings underscore the need to revisit and broaden eligibility criteria in future RCTs to ensure greater external validity and alignment with the heterogeneity of real-life IBD population.

References

1. Turner D, Ricciuto A, Lewis A, D'Amico F, Dhaliwal J, Griffiths AM, Bettenworth D, Sandborn WJ, Sands BE, Reinisch W, Schölmerich J, Bemelman W, Danese S, Mary JY, Rubin D, Colombel JF, Peyrin-Biroulet L, Dotan I, Abreu MT, Dignass A; International Organization for the Study of IBD. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology. 2021 Apr;160(5):1570-1583. doi: 10.1053/j.gastro.2020.12.031. Epub 2021 Feb 19. PMID: 33359090.

REAL-LIFE VS CLINICAL TRIAL ACCESS TO BIOLOGICAL THERAPY: FINDINGS FROM AN ITALIAN-AMERICAN STUDY ON INFLAMMATORY BOWEL DISEASE

Federica Di Vincenzo 1, Stephanie Ioannou 2, Chiara Principessa 3, Ivan Capobianco 1, Antonio Gasbarrini 4, Lucrezia Laterza 4, Maria T. Abreu 5, Franco Scaldaferri 4

1 Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy

2 University of Miami - Jackson Health System, Miami, United States

3 Università Cattolica del Sacro Cuore, Roma, Italy

4 Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy

5 University of Miami Miller School of Medicine, Department of Medicine, Division of Gastroenterology, Miami, FL 33136; F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, United States