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

Abstract

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: IL-25; group 2 innate lymphoid cells; inflammatory bowel disease; microbial; tuft cell.

Figure 1

The tuft/IL-25 signaling axis. Tuft cells detect luminal pathogens (e.g., bacteria, helminths) via apical receptors, activating the Gα-βγ/PLCβ2 cascade. This drives IP₃R2-mediated Ca²⁺ flux, triggering membrane depolarization and IL-25 secretion. IL-25 binds IL-17RA/IL-17RB on ILC2s, activating Act1-dependent NF-κB/MAPK pathways to upregulate type 2 cytokines (IL-4/IL-5/IL-13), which promote helminth expulsion. Concurrently, tuft cell-derived acetylcholine (ACh) stimulates epithelial mucus secretion, smooth muscle contraction, and paralyzes muscarinic ACh receptor-expressing helminths, amplifying the “weep and sweep” defense to eliminate parasites.

Figure 2

The tuft/IL-25 axis modulates intestinal immune homeostasis by enhancing Th2-mediated barrier restoration and suppressing Th1/Th17-driven inflammation. Under viruses or parasites infection, imbalance in this dynamic equilibrium leads to hyperactivation of Th1/Th17 immunity or amplification of Th2 inflammatory cascades, resulting in epithelial damage, barrier dysfunction, and progression of IBD.