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REVIEW article

Front. Immunol.

Sec. Autoimmune and Autoinflammatory Disorders: Autoinflammatory Disorders

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1629060

The role of the tuft cell–interleukin-25 axis in the pathogenesis of inflammatory bowel disease

Provisionally accepted
Zishao  TaoZishao Tao1Li  LiLi Li1Ying  ZhangYing Zhang1Yufang  TangYufang Tang1Simeng  ZhangSimeng Zhang1Heying  YangHeying Yang1Guorong  JiangGuorong Jiang1Rui  ZhangRui Zhang2Zhiwei  WuZhiwei Wu1,2*Miao  HeMiao He1,3*
  • 1Dali University, Dali, China
  • 2Nanjing University, Nanjing, China
  • 3Shanghai Jiao Tong University, Shanghai, China

The final, formatted version of the article will be published soon.

Emerging evidence highlights the tuft cell—Interleukin-25 (IL-25) axis (tuft/IL-25 axis) as a critical orchestrator bridging luminal stimuli and intestinal immunity in Inflammatory Bowel Disease (IBD), which encompasses Crohn's Disease (CD) and Ulcerative Colitis (UC). This review synergises current understanding of how dysregulation within this axis contributes to IBD pathogenesis, arising from disrupted immune homeostasis involving aberrant microbiota responses, genetic susceptibility, and immune pathway dysregulation. Central to this axis, intestinal tuft cells act as chemosensory epithelial sentinels, differentiating in response to microbial and metabolic cues to become the primary source of IL-25. IL-25, signaling via IL-17RB, engages innate and adaptive immune cells, particularly group 2 innate lymphoid cells (ILC2s). While IL-33-responsive homeostatic ILC2s (nILC2s) promote mucosal repair, IL-25-driven inflammatory ILC2s (iILC2s) amplify inflammation, positioning them as pivotal effectors. Critically, IL-25 exhibits a context-dependent "double-edged" role: engagement with IL-25R⁺ T cells and modulation of downstream signaling can exert anti-inflammatory effects and enhance barrier integrity, yet dysregulation drives pro-inflammatory injury. The axis is dynamically regulated by diverse luminal factors: helminth infection activates the tuft-ILC2 circuit, inducing protective type 2 immunity; specific microbial metabolites (e.g., succinate, SCFAs) modulate its activity; and viral infections can disrupt homeostasis by remodeling tuft cell function. Dysregulation of the tuft/IL-25 axis, driven by infections, microbial metabolite fluctuations, or environmental factors (including regional variations in helminth exposure linked to the hygiene hypothesis), is increasingly recognized as a significant contributor to IBD pathogenesis. Consequently, precisely regulating this axis to harness its beneficial effects while mitigating its detrimental potential represents a promising therapeutic frontier. Future strategies should integrate microbiota remodeling, targeted metabolite interventions, and potentially virus-directed therapies. Furthermore, deeper investigation into the impact of geographical environmental factors on this axis and IBD risk is warranted. Ultimately, multi-pathway approaches aimed at restoring the "immune-microbiota-epithelial" triad via reprogramming the tuft/IL-25 axis hold significant promise for novel IBD management.

Keywords: Tuft cell, IL-25, inflammatory bowel disease, Group 2 innate lymphoid cells, Microbial

Received: 15 May 2025; Accepted: 02 Sep 2025.

Copyright: © 2025 Tao, Li, Zhang, Tang, Zhang, Yang, Jiang, Zhang, Wu and He. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Zhiwei Wu, Nanjing University, Nanjing, China
Miao He, Dali University, Dali, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.