Accumulating evidence suggests a strong link between tuft cell deficiency and IBD pathogenesis. Clinical studies reveal reduced tuft cell numbers in inflamed ileal tissues of CD patients, inversely correlating with disease severity (35), and a 55% decrease in colonic tuft cells in UC patients compared to controls (36). Consistently, DCLK1-knockout mice (lacking tuft cells) exhibit exacerbated colitis under dextran sulfate sodium (DSS) treatment or mucin O-glycan deficiency (DKO model) (37, 38). Tuft cells inherently generate IL-25 to uphold ILC2 homeostasis in the resting lamina propria (17). Meanwhile, existing studies have emphasized the non-redundant role of ILC2s in maintaining intestinal barrier integrity and type 2 immune homeostasis. Research has demonstrated that ILC2-deficient mice fail to mount an appropriate epithelial type 2 immune response, resulting in a profound defect in worm expulsion. This deficiency is characterized by the absence of goblet cell and tuft cell hyperplasia, as well as reduced mucus production—hallmarks of an impaired type 2 immune response (39). These findings further highlight the critical role of tuft cell—ILC2 crosstalk in intestinal inflammation.

In preclinical models, IL-25 is involved in the mitigation of intestinal inflammation as a key hub in the tuft cell—ILC2s axis (40). For example, oral berberine activates bitter taste receptor signaling, promoting tuft cell differentiation and secretion IL-25, which initiates a type 2 immune response, thereby ameliorating DSS-induced colitis through ILC2 and Th2 cell modulation (41). Similarly, exogenous succinate activates succinate receptor 1 (SUCNR1) on tuft cells, inducing downstream cells to secrete IL-25 and IL-13, which drive the differentiation of intestinal stem cells (ISCs) into tuft cells and goblet cells, repairing the epithelial barrier and reducing intestinal inflammation (42, 43). However, studies have shown that succinate, whose levels are elevated in patients with IBD (44), can disrupt the immunosuppressive function of Treg cells through a FOXP3-dependent post-translational modification switch, thereby exacerbating colitis. Specifically, in Treg cells from IBD patients, succinate downregulates Ogdh and Dlst expression, reducing succinyl-CoA production, which in turn decreases succinylation of FOXP3 at lysines K8/K263. This allows STUB1-mediated ubiquitination and proteasomal degradation of FOXP3 (45). Notably, the tuft cell—ILC2 axis is further modulated by neuroimmune signaling. Neuron-derived neuromedin U (NMU) can activate ILC2s. NMU stimulation induces amphiregulin (AREG) production in ILC2s, which promotes goblet cell hyperplasia and epithelial repair, thereby sustaining type 2 immunity and epithelial homeostasis (46). Beyond the canonical IL-25—tuft cell—ILC2 axis, tuft cells also deploy an IL-25-independent effector pathway via NAIP-NLRC4 inflammasome activation and PGD2 production to engage CRTH2⁺ ILC3s, driving IL-22-mediated antimicrobial defense, as demonstrated in Salmonella Typhimurium infection models (47).

As the main producer of intestinal IL-25, tuft cells transmit immune signals via the IL-25-mediated tuft cell—ILC2s axis, functioning as both sentinels and effectors in mucosal immunity (48). This process involves intricate intercellular crosstalk and feedback loops.

Lineage-tracing experiments employing an inducible Cre knock-in allele and Rosa26-lacZ reporter system in adult mice revealed that tuft cells share their origin with other epithelial cells (49, 50). Like various other intestinal epithelial cells such as enteroendocrine cells, paneth cells, and goblet cells, they originate from crypt-based columnar stem cells expressing leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) (18, 51). Delta-Notch-mediated lateral inhibition controls the fate of stem cell descendants, guiding hairy enhancer of split 1 (Hes1)-expressing progenitors to become absorptive cells, while those expressing atonal homolog 1 (Atoh1) differentiate into secretory lineages like goblet cells (52, 53). Two models of tuft cell differentiation have been proposed: one suggests their derivation from non-terminally differentiated Atoh1⁺ progenitors, while the other indicates Atoh1-independent differentiation (54, 55). The dependency on Atoh1 in small intestinal tuft cells is influenced by the surrounding context, with IL-13 enabling Atoh1-independent tuft cell generation (56). Notably, zinc-finger transcriptional repressor growth factor independent 1b (Gfi1b) is uniquely expressed in tuft cells but absent in other epithelial lineages, where it interacts with transcription factors Hes1 and Atoh1 to form a genetic network. This network functions as a Notch signaling-driven tri-stable regulatory module that regulates lineage commitment in intestinal epithelial cells (57).

Additionally, all murine tuft cells constitutively express POU class 2 homeobox 3 (POU2F3), a transcription factor critical for their development. For tuft cell development in most mucosal regions, the POU2F3 coactivator POU2AF2 is crucial. In the intestinal tract, tuft cells—apart from those in the colon and stomach—rely solely on the long isoform of POU2AF2 (58–61). Other regulators influencing intestinal tuft cell abundance include the transcription factor SOX4 (56), the taste receptor type 1 member 3 (TAS1R3) (62), the cell division control protein Cdc42 (63), and the DEAD-box RNA-binding protein DDX5 (64). Collectively, the lineage differentiation of intestinal tuft cells is intricately regulated, involving Notch signaling-mediated cell fate specification toward distinct lineages and microenvironment-dependent plasticity modulated by IL-13 and other factors.

As specialized chemosensory sentinel cells, tuft cells are activated through a diverse receptor system. Their chemosensory arsenal includes taste receptors such as TAS1R heterodimers for sweet and umami sensing (62), and TAS2R monomers for bitter compound detection (65), as well as metabolite sensors such as SUCNR1, which detects microbiota-derived succinate (66, 67). Additional ligand-receptor interactions include the Shigella metabolite N-undecanoylglycine with vomeronasal type-2 receptor 26 (VMN2R26) (68), and bitter substance salicin with TAS2R143 (69), demonstrating their multimodal sensing capacities. This multimodal receptor system facilitates comprehensive luminal surveillance, integrating nutrient and microbial signals to orchestrate context-dependent immune-epithelial crosstalk. Notably, tuft cells constitutively express IL-17RB, the receptor for IL-25, independently of luminal stimuli—a critical feature of their receptor regulatory network. Through intrinsic IL-17RB signaling, these cells bind autocrine IL-25 to limit its bioavailability, thereby preventing hyperactivation of ILC2s by persistent Il25 transcription and maintaining immune homeostasis (29).

Upon luminal stimulation, tuft cells initiate G protein-coupled signaling cascades: Gα-gustducin dissociates from Gβγ subunits, with the liberated Gβγ activating phospholipase Cβ2 (PLCβ2) to generate inositol trisphosphate (IP₃). IP₃ binding to endoplasmic reticulum IP₃ receptor 3 (IP₃R3) triggers Ca²⁺ release, while subsequent activation of the transient receptor potential cation channel subfamily M member 5 (TRPM5) channel mediates membrane depolarization ( Figure 1 ) (70–72). These coordinated events culminate in IL-25 biosynthesis and secretion. Crucially, IP₃R2-mediated Ca²⁺ mobilization has been identified as the critical step for succinate-induced IL-25 production (62, 66, 67). Secreted IL-25 engages IL-17RB receptors on ILC2s, recruiting IL-17RA to form a ternary complex (29, 73, 74). This interaction initiates Act1 adaptor-dependent signaling, triggering TRAF6-mediated ubiquitination that activates NF-κB and C/EBP transcription factors. Concurrent MAPK/ERK phosphorylation cascades synergistically promote type 2 cytokine expression, orchestrating antiparasitic immunity and tissue repair ( Figure 1 ) (75, 76). Such chemosensory-to-immunologic signal conversion underscores tuft cells’ pivotal role as mucosal immune regulators.

Tuft cells secrete IL-25 to activate ILC2s, which in turn produce IL-13 to promote tuft cell differentiation (20, 58). However, this IL-13-driven tuft cell hyperplasia is constrained by a bone morphogenetic protein (BMP)-dependent SOX4 inhibition (77). BMPs belong to the TGF-β family. In addition to their traditionally recognized role in regulating bone and cartilage formation, they are also involved in regulating gastrointestinal morphogenesis, maintenance of homeostasis, ISC function, and inflammatory responses (78). Their signal transduction is achieved through the classical Smad pathway (BMP binds to type I and type II receptors, then activates SMAD1/5/8, which form a complex with SMAD4 and enter the nucleus to regulate target genes) and non-Smad pathways (such as the MAPK pathway) (79, 80). Contextually, BMP signaling maintains ISC homeostasis through spatial regulation: BMP ligands (e.g., BMP2/4) in upper crypts suppress Wnt/β-catenin signaling to limit self-renewal, while antagonists (e.g., Grem1) in crypt bases preserve the stem niche (81–83). Notably, excessive tuft cell proliferation triggers IL-13-mediated induction of BMP2/8b secretion from intestinal epithelial cells. These ligands bind BMP receptors (BMPR1A/BMPR2) on ISCs, activating SMAD1/5/8 phosphorylation and nuclear translocation. The phospho-SMAD complex then recruits HDAC co-repressors to the SOX4 promoter, epigenetically silencing its transcription (77, 78). This pathway suppresses the development of SOX4⁺ tuft cell progenitors, establishing a self-limiting negative feedback loop (77). These findings highlight IL-25’s pivotal regulatory role in intestinal immune homeostasis: it not only initiates epithelial-immune crosstalk as an “alarmin”, but also orchestrates cellular lineage equilibrium through bidirectional regulatory circuits.

Intestinal ILC2s exhibit unique phenotypic and functional properties within the tuft cell—ILC2 axis. Notably, ILC2s can exert protective functions in specific contexts. In the DSS-induced murine acute colitis model, administration of exogenous recombinant murine IL-33 (rmIL-33) significantly ameliorated intestinal inflammation. Treg cells and ILC2s function as primary cellular targets of IL-33 to mediate this tissue-protective effect (84). Consistently, studies demonstrate that upon NMU stimulation, ILC2s produce AREG, which potentiates intestinal barrier repair during DSS-induced colitis, thereby effectively mitigating intestinal inflammation (46). Furthermore, they can produce IL-13 to recruit myeloid-derived suppressor cells (MDSCs), thereby reducing pro-inflammatory Th1/Th17 cells and improving intestinal barrier integrity (85). However, the pathological conversion of ILC2s can drive inflammatory diseases and tumor progression. In colorectal cancer (CRC), the IL-25—ILC2—MDSC axis suppresses anti-tumor immunity and fosters the formation of an immunosuppressive tumor microenvironment (86). Conversely, some studies have also demonstrated that in CRC, ILC2s are associated with enhanced tumor protection, strengthened anti-tumor immunity, and reduced metastatic dissemination. Indeed, the pro-tumor versus anti-tumor roles of ILC2s in CRC remain controversial (87, 88). An inulin fiber-enriched diet has been shown to induce iILC2s (ILC2^INFLAM) expressing Tph1 in the mouse colon; these cells produce IL-5 but fail to produce the tissue-protective factor AREG, leading to eosinophil accumulation and exacerbation DSS-induced intestinal damage (89). Concurrently, the ILC2^INFLAM produces type 2 inflammatory cytokines IL-5 and IL-13, which recruit eosinophils and exert dual immunomodulatory effects: conferring protection against helminth infections while promoting the pathogenesis of allergic diseases (90).

Regarding ILC2 subtypes, IL-33-responsive ILC2s residing in pulmonary and adipose-associated lymphoid tissues have been designated as homeostatic or natural ILC2s (nILC2s), while naming the KLRG1^hi cells that emerge exclusively upon IL-25 stimulation or infection are referred to inflammatory ILC2s (iILC2s) (91). Studies also show that IL-25 elicits iILC2s, which exhibit functional plasticity (iILC2s can differentiate into transient progenitor cells of nILC2-like cells), IL-17A production, high expression of the activation marker KLRG1, and low CD90/Thy1 expression (91, 92). Other studies have further defined two distinct ILC2 subsets based on surface marker expression: iILC2s, characterized as Lin^- CD45⁺ CD127⁺ ST2^- KLRG1^hi, and nILC2s, identified as Lin^- CD45⁺ CD127⁺ ST2⁺ KLRG1^int (93). Notch signaling drives this functional plasticity of iILC2s by inducing Rorc transcription, thereby mediating the conversion of nILC2s into iILC2s (94). Furthermore, studies demonstrate that iILC2s co-express high levels of GATA-3 alongside low amounts of RoRγt, enabling the coexistence of key functional attributes from both ILC2 and ILC3 subsets. This cell responds to IL-25 signaling and possess the capacity for dual IL-13/IL-17 production (91, 94). Similarly, iILC2s can be reprogrammed into IL-17-producing ILC3-like cells upon exposure to specific cytokines or during fungal infections. Over time after IL-25 exposure, a subset of lung iILC2s acquires ST2 expression while losing IL-25 receptor expression, phenotypically resembling nILC2s (95).

ST2^- KLRG1^hi iILC2s are characterized by high Il17rb expression and selective responsiveness to IL-25, in contrast to nILC2s, which predominantly express the IL-33 receptor (Il1rl1/ST2) and respond to IL-33 (91, 96). iILC2s serve as early producers of IL-13 and IL-4 during helminth infection (day 5 post-infection), preceding cytokine secretion by nILC2s, and can migrate from gut to lung to initiate anti-helminth immunity (96). Studies have revealed that lung-resident iILC2s, following colonization with the murine intestinal protozoan symbiont Tritrichomonas musculis, resemble IL-25-induced intestinal ILC2s. These iILC2s display lower levels of CD90, CD127, and ST2 (Il1rl1), but higher levels of inducible ICOS, Il17rb, RoRγt, OX40L, Il5, Il13 and Il17a (97). Furthermore, Adoptive transfer of total leukocytes isolated from CD45.1⁺ Rag1 ^−/− deficient mice into CD45.2⁺ Rag1 ^−/− deficient recipients, followed by IL-25 administration, revealed that only KLRG1⁺ ILC2s from the small intestinal lamina propria (siLP) robustly expanded into iILC2s in recipient lungs. In contrast, bone marrow-derived cells yielded minimal iILC2s, and lung-derived cells generated none, demonstrating that peripheral IL-25-induced iILC2s originate from intestinal-resident ILC2 subsets (98).

RNA-seq analysis revealed a remarkable transcriptomic similarity between intestinal ILC2s and IL-25-induced iILC2s, providing higher-resolution and conclusive evidence for their common intestinal origin (98). However, the mechanisms underlying their activation in the gut require further investigation. Intraluminal succinate injection into small intestinal organoids (SIOs) significantly upregulated the tuft cell marker DCLK1 and increased Il17e transcription. When co-cultured with succinate-treated SIOs, ILC2 precursors (ILC2Ps) differentiated into a higher proportion of KLRG1⁺ ILC2s, demonstrating that metabolite-activated tuft cells drive ILC2 maturation and expansion via IL-25 secretion (99). The relative expression levels of ILC2-related genes in the small intestine were determined in Vil1 ^Cre ; Il17rb ^fl/fl mice (which lack IL-17RB specifically in intestinal epithelial cells, resulting in tuft cell deficiency of IL-17RB) and Il17rb ^fl/fl mice (with normal IL-17RB expression) (29). The results revealed that the ILC2 signature genes, including Gata3, Rora, Id2, Il5, and Thy1, exhibited comparable expression levels between the two groups. This consistent expression ensures the preservation of their canonical ILC2 identity. In contrast, genes such as Klrg1, Icos, and Nmur1, along with ILC2 activation-associated genes (e.g., Il10, Il13, Cd69, Tigit, Il10rb, and Cxcr6 among others), were significantly upregulated in Vil1 ^Cre ; Il17rb ^fl/fl mice. These dynamically upregulated genes collectively show the core molecular signature of the iILC2 phenotype: iILC2s are characterized by high expression of KLRG1 and low expression of CD90 (96), along with elevated levels of IL-13, ICOS, and TIGIT (97, 98). Furthermore, when the expression of surface markers on colonic ILC2s in Rag2 ^−/− mice infected with Strongyloides ratti (following treatment with a pan-retinoic acid receptor inverse agonist, RAi) shifts toward a non-intestinal phenotype (such as Il-17rb ^lo CD90^hi KLRG1^lo ICOS^hi), it impairs the responsiveness of ILC2s to immune signals like IL-25 and disrupts mucosal defense mechanisms critical for anti-helminth immunity (100). Some studies suggest that iILC2s are absent from peripheral tissues under steady-state conditions but can be induced at multiple sites by helminth infection or IL-25 administration (101). We postulate that the synergistic interplay of these mediators, with IL-25 serving as the primary initiator, drives the differentiation of intestinal ILC2s into iILC2s. Among these regulatory mechanisms, the expression of IL-17RB in tuft cells is pivotal for maintaining ILC2 homeostasis—its deficiency results in the sustained stimulation of intestinal ILC2s by IL-25, thereby promoting their transition toward an inflammatory phenotype. However, the activation of intestinal ILC2s serves merely as a necessary condition for the generation of iILC2s; their full differentiation requires additional regulatory factors. The precise relationship between these two cell populations remains to be fully elucidated.

Collectively, ILC2s function as pivotal effectors within the tuft/IL-25 axis, exhibiting remarkable functional plasticity that dictates IBD outcomes. Their dichotomous role—switching between tissue-repairing (IL-33/nILC2-driven) and inflammation-promoting (IL-25/iILC2-driven) states—directly influences mucosal homeostasis and immune homeostasis.

IL-25 exerts protective roles in colitis by suppressing intestinal inflammation and maintaining immune homeostasis, primarily through modulating Th2 responses and inhibiting Th1/Th17 pathways. In DSS-induced acute colitis, recombinant IL-25 (rIL-25) elevates colonic IL-23 and TGF-β1, thereby alleviating intestinal inflammation and tissue damage. Within this IL-25-primed milieu, heightened IL-23 may cooperate with TGF-β1—which is produced via IL-25/IL-13 signaling and enhances IL-23R expression—to establish an anti-inflammatory network that suppresses Th1 responses and promotes repair. The mechanistic details of this interaction nevertheless warrant further validation (102). IL-25 is also proposed as a critical anti-inflammatory cytokine in trinitrobenzene sulfonic acid (TNBS)-induced colitis, where miR-31-mediated targeting of IL-25 suppresses IL-12/23-dependent Th1/Th17 inflammatory responses (103). Commensal bacteria-induced IL-25, secreted by intestinal epithelial cells (IECs), negatively regulates Th17 cell expansion by suppressing the IL-23/IL-17 pathway, thereby maintaining gut immune homeostasis (104). Additionally, IL-25 reduces the production of TNF-α, IFN-γ, and IL-17A in IBD CD4⁺ T cells while promoting IL-10 secretion, thereby inhibiting Th1/Th17 differentiation (105). In colorectal cancer models, IL-25 blockade increases tumor burden (106). All of this underscores its role in suppressing pro-inflammatory microenvironments. Critically, IL-25’s ability to maintain intestinal homeostasis aligns with, and may be supported by, functional autophagy—a fundamental cellular process essential for gut equilibrium. Autophagy supports intestinal equilibrium by clearing intracellular pathogens and damaged components, preserving epithelial barrier integrity, and regulating immune responses—processes essential for creating the stable cellular environment in which IL-25’s anti-inflammatory effects (e.g., Th1/Th17 suppression, IL-10 promotion) can optimally function (107, 108). Consequently, autophagy impairment, a recognized contributor to IBD pathogenesis, likely undermines the mucosal conditions necessary for IL-25’s full protective potential.

Conversely, IL-25 may exacerbate inflammation by amplifying Th2-mediated immune responses. Notably, UC exhibits a predominance of Th2-related cytokines (e.g., IL-5, IL-13) (109), rendering this pro-inflammatory effect particularly relevant to its pathogenesis. In oxazolone-induced UC, blocking IL-25 signaling with IL-25 neutralizing antibodies significantly improves colitis, implicating the role of IL-25 in Th2-driven pathology (110). Administering IL-25 systemically to naïve mice triggers the expression of IL-4, IL-5, and IL-13, driving Th2 polarization alongside elevated serum IgE, eosinophil infiltration, and mucosal abnormalities (e.g., mucus hypersecretion and epithelial hyperplasia) (111). IL-25 also upregulates colonic epithelial IL-33, IL-6, and TNF-α, forming a pro-inflammatory feedback loop that exacerbates tissue damage (112). Epithelial-specific IL-25 deletion reduces IL-1β, IL-6, TNF-α, and CCL2 levels in DSS-treated mice, correlating with decreased colitis-associated tumorigenesis (113).

In Th1/Th17-dominant inflammation, IL-25 suppresses hyperactive innate immunity and pro-inflammatory pathways, exerting protective effects. However, under Th2-skewed conditions, its overexpression disrupts immune equilibrium, driving pathological cascades. Thus, therapeutic strategies targeting IL-25 must consider the inflammatory context to achieve precise intervention, balancing its “double-edged sword” effects to restore mucosal integrity and immune homeostasis. The paradoxical dual effects of IL-25 in IBD—anti-inflammatory protection versus pro-inflammatory injury—are intriguing and the currently focus of the research.

Notable human-infecting species include Ascaris lumbricoides, Trichuris trichiura, Necator americanus, and Ancylostoma duodenale (128, 129). Intestinal tuft cells act as epithelial sentinels that promote type 2 immunity against helminths (130). Infection of mice with parasites such as Heligmosomoides polygyrus, Trichinella spiralis, or Nippostrongylus brasiliensis universally increases tuft cell abundance, indicating a conserved response to helminth colonization (20). Tuft cells secrete IL-25 and CysLTs to activate ILC2s by recognizing worms such as Nippostrongylus brasiliensis, Heligmosomoides polygyrus, and Trichinella spiralis, initiating a feedback loop to promote tuft cell proliferation (25). Studies indicate that tuft cells initiate IL-5/IL-13 signaling by emitting the alarmin cytokine IL-25, which in turn activates ILC2s. Once activated, ILC2s produce type 2 cytokines like IL-4, IL-5, and IL-13 (131). Especially, studies have identified a novel colonic IL-4⁺ ILC2 subpopulation that constitutively expresses IL-4 independently of the classical alarmin pathway (unaffected by IL-25 injection or IL-33/TSLP deletion), with its development of this subset is regulated through the vitamin B1 (VB1)-dependent metabolic axis involving glucose-6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP), establishing a unique stimulatory mechanism distinct from microbiota-derived signals and conventional cytokine networks (132). These cytokines signal via IL-13Rα1/IL-4Rα heterodimeric receptors on ISCs, driving their differentiation into tuft and goblet cell lineages. This feed-forward loop amplifies the immune response, promotes epithelial remodeling, and ultimately facilitates parasite expulsion (58). Tuft-goblet cell expansion restores the damaged epithelial barrier through enhanced tight junctions and mucus layer formation, creating a physical shield between immune cells and luminal microbiota (133). Notably, IL-13 secreted by ILC2s in the lung initiates an autoregulatory feedback circuit through bidirectional ILC2—T cell crosstalk, amplifying IL-2-dependent ILC2 proliferation and Th2 cell polarization, which further increases type 2 cytokine production and tissue remodeling. We speculate that a similar circuit may operate in the intestine (17, 134, 135).

Additionally, tuft cells, which uniquely express choline acetyltransferase (ChAT) within the intestinal epithelium (48), orchestrate antiparasitic defense through other signaling axes. Helminth-activated tuft cells release IL-25, driving ILC2-dependent IL-13 production that stimulates tuft cell hyperplasia and subsequent ACh release into the lumen. ACh exerts tripartite effects: stimulating neighboring epithelial cells to secrete fluid, binding to muscarinic ACh receptors on smooth muscle to enhance contractility (136, 137), and reducing pathogen fecundity via parasite-expressed muscarinic receptors (138). This “weep and sweep” mechanism not only facilitates parasite expulsion but also ameliorates gut dysbiosis in IBD by restoring microbial homeostasis, ultimately attenuating intestinal inflammation ( Figure 1 ). Notably, ILC2s activated by tuft-derived IL-25 are also key ACh producers, wherein autocrine muscarinic signaling enhances their proliferation and type 2 immunity to bolster anti-parasite defense (139). In allergy, ILC2-derived ACh shows dual effects: promoting eosinophilia via autocrine loops while inhibiting neutrophil recruitment through CXCL1/2 suppression and macrophage modulation (140). Thus, the ChAT/ACh pathway also operates as an effector arm of the core tuft/IL-25 axis.

The gut microbiota is acknowledged as a crucial factor in the development of IBD. Microbially derived metabolites serve as critical molecular mediators of interactions between the gut microbiome and host immunity or metabolism. For example, the fermentation of dietary fiber by gut microbiota results in the production of short-chain fatty acids (SCFAs), which are key metabolites that exhibit anti-inflammatory properties and regulate intestinal immune responses and barrier integrity (141). Clostridium sporogenes, a human commensal bacterium, generates metabolites such as indole-3-propionic acid (IPA), branched-chain fatty acids (BCFAs) such as isobutyrate and isovalerate, and SCFAs (142, 143). These metabolites orchestrate crosstalk among gut bacteria, IECs, antigen-presenting cells, and lymphocytes. Intestinal tuft cells sense SCFAs and BCFAs through G protein-coupled receptor 41 (Gpr41, encoded by FFAR3) receptor signaling, triggering their activation and expansion to promote epithelial regeneration, these metabolites also inhibit intestinal inflammation via enhanced IL-22 production and Foxp3⁺ Treg cells differentiation (144). During helminth infection, cytosolic phospholipase A2 (cPLA2) in tuft cells liberates arachidonic acid from phospholipids, which is subsequently metabolized by enzymes (e.g., Pla2g4a, Alox5ap, Ltc4s) into leukotrienes that synergize with IL-25 to activate ILC2s through CysLT receptors, thereby amplifying type 2 immune responses (25). These metabolites activate ILC2s to secrete IL-13 through different pathways, driving tuft and goblet cell proliferation and mucus hypersecretion, thereby facilitating the “weep and sweep” mechanism for parasite clearance (17). This potential metabolic communication network could facilitate tuft cell proliferation in response to luminal microbiome perturbations, which would be a mechanism potentially critical for suppressing intestinal inflammation and restoring epithelial barrier integrity. Moreover, this axis may play a key role in coordinating tuft/IL-25-mediated improvement in IBD inflammation.

The impact of viruses on the tuft cell compartment adds another layer of complexity to host-microbe interactions relevant to IBD. IBD patients may develop immunocompromised status due to pathological manifestations or immunosuppressive therapies (e.g., corticosteroids, anti-TNF-α agents), resulting in heightened susceptibility to viral infections (e.g., Epstein-Barr virus (EBV), cytomegalovirus (CMV), and enteroviruses) (145, 146). Tuft cells, rare chemosensory epithelial cells, serve dual roles as viral targets and immune mediators. Murine norovirus (MNVCR6) exploits CD300lf, an immunoregulatory receptor uniquely expressed on tuft cells, to establish persistent infection within this immune-privileged niche. Remarkably, the introduction of MNVCR6 into germ-free mice repairs the intestinal barrier, adjusts immune cell populations, and promotes homeostasis (147–150). Similarly, enteroviruses (e.g., EV71, CVA16, CVB3/4) enhance IL-25 expression and tuft cell expansion via folate metabolism. Folate metabolism, essential for purine and methyl donor synthesis, supports IL-25-mediated tuft cell expansion during RNA viral infections (151). Furthermore, EV71 induces functional remodeling of intestinal tuft cells by stimulating IL-25 production. This not only drives tuft cell expansion but also confers immune memory, enabling a potent secondary response characterized by enhanced IL-25 secretion and SAT1-mediated polyamine depletion to restrict viral replication (152). Rotavirus (RV) infection induces functional specialization within the intestinal tuft cell compartment: infected mature tuft cells activate antiviral defense pathways, while simultaneously inducing neighboring immature tuft cells to enhance luminal surveillance. This coordinated remodeling, which couples pathogen sensing in mature cells with heightened environmental monitoring in precursor cells, demonstrates a sophisticated mechanism for maintaining immune homeostasis during viral challenge (153, 154).