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.

Introduction

Pneumococcal vaccination is essential in IBD patients. However, its efficacy in patients on immunosuppressive or anti-TNF therapy is much lower than in the normal population (45% vs 80%). Vaccine regimen recommendations vary according to the degree of immunodepression. The aim of our study was to identify an optimal vaccination strategy for immunocompromised IBD patients treated with anti-TNF, vedolizumab and/or IS.

Aims & Methods

This is a prospective, multicenter, randomized study comparing two vaccine regimens: intensified vaccine strategy (Prevenar13®/Prevenar13®/PSV-23® (or Pneumovax as a replacement for PSV-23) vs. normal strategy (Prevenar13®/PSV-23® (or Pneumovax as a replacement for PSV-23), (randomization 1: 1) on vaccine immunogenicity measured by antibody titer against at least 9 of the 13 pneumococcal serotypes contained in Prevenar13®. Any patient with confirmed IBD under biotherapy (anti TNF with or without immunosuppressive drugs or Vedolizumab) and in clinical remission (HBI <4 for CD and partial Mayo Score <3 for UC) was included. Vaccination and vaccine monitoring were carried out by the vaccination center of each center, with adverse events reported at each visit (8 for 36 months of follow-up), and ELISA and OPA serotype assays systematically collected and clinical activity was reported by the gastroenterologist at the same time. Correlate of protection in adults using serology testing was classically defined as at least 9 out of 13. Serotypes > 1µg/mL. For functional testing of antibodies using the Opsonophagocytic assays, we apply the well-defined 4 times increase of titer between pre and post-vaccination against at least 70% of serotypes. ClinicalTrials.gov Identifier: NCT02255227

Results

51 patients in the normal vaccination arm and 53 in the intensified vaccination arm were included (mean age: 42.9 years, male: 63%, CD: 68%, active smoking: 21%, duration of IBD: 10.2 years, 98% IBD inactive). Around 88% of patients were under anti-TNF monotherapy (28% on combotherapy) and 12% under vedolizumab. Serology criteria for good responders at M5 were 57.5% for the intensified regimen vs 25.6% for the standard regimen (RR: 2.25 (1.26;4.00), p = 0.003). For OPA correlate of protection, vaccine response was significantly greater in the intensified arm at all-time points: M5 (96% vs. 89%), M12 (76 vs. 58%) and M36 (68% vs. 36.8%). In multivariate analysis, two factors reduced vaccine response: anti-TNF use (RR: 6.84; CI95: 1.01-46.1; p=0.048) and CD type (RR: 9.48; CI95: 2.74-32.8; p:0.0004). The tolerability of the vaccine regimens was comparable throughout follow-up. In terms of IBD activity, percentage of clinical relapse was similar during follow-up (16.8% under the intensified regimen versus 25% under the normal regimen (p:NS).

Conclusion

In IBD on biotherapy and/or IS, the intensified pneumococcal vaccine regimen (2 injections of Prevenar followed by one of Pneumo 23) is significantly more immunogenic than a standard regimen, especially when using functional correlate of protection. The duration of the response is also greater in this intensified arm.