From mucus secretion to immune surveillance: the evolving roles of goblet cells in intestinal homeostasis and inflammation

Abstract

Background:

Intestinal goblet cells (GCs) are specialized epithelial cells essential for forming the protective mucus barrier. Recent research has significantly expanded our understanding of their roles beyond mucus secretion, revealing critical functions in immune regulation and mucosal homeostasis. Dysfunction of these cells is implicated in the pathogenesis of intestinal disorders, particularly inflammatory bowel disease (IBD).

Scope and methods:

This review synthesizes the current literature on intestinal GC biology, encompassing their developmental pathways, cellular heterogeneity, and multifaceted functions within the intestinal chemical, mechanical, immune, and biological barriers.

Key findings and contribution:

We highlight the remarkable plasticity and heterogeneity of GCs, detailing newly identified subtypes such as sentinel GCs and intercrypt GCs, and their distinct roles in mucosal defence. The review elucidates how GCs contribute to intestinal homeostasis not only through mucin (MUC2) production but also via antigen sampling, cytokine secretion, and interactions with the commensal microbiota. Furthermore, we consolidate evidence on the signalling pathways and molecular regulators governing GC differentiation and function.

Conclusion and implications:

The dysfunction or depletion of intestinal GCs is a hallmark of IBD, leading to barrier breakdown and sustained inflammation. This review underscores the emerging role of GCs as key guardians of intestinal health and promising therapeutic targets. A deeper understanding of GC biology paves the way for novel strategies aimed at restoring intestinal barrier function in IBD.

1 Introduction

The intestine is a complex and highly specialized epithelial barrier that plays a role in immune regulation, nutrient absorption, and barrier protection, all of which is crucial for maintaining intestinal homeostasis (1, 2). Intestinal epithelial cells, as a primary component of the intestinal barrier, perceive stimuli from the external environment and respond to them accordingly (3). As a type of specialized epithelial cells, intestinal goblet cells secrete mucin and water to form a protective mucus layer, serving as key components of the intestinal mechanical barrier; recent studies highlight their essential role in both intestinal and immune barrier function (4–7). Abnormalities in the number and function of intestinal goblet cells cause intestinal barrier dysfunction and predispose to the development of various intestinal diseases, and over the past few years, intestinal goblet cells have emerged as a core player in the regulation of intestinal barrier function (8–10).

In this review, we discuss the development of intestinal goblet cells, various influencing factors, and their roles in the development of inflammatory bowel disease (IBD).

2 Development of intestinal goblet cells

As a semi-permeable and highly regenerative tissue, the intestine primarily functions in digesting and absorbing ingested nutrients (11, 12). While performing its functions, the gut is constantly exposed to the external environment, necessitating the frequent renewal of the epithelial tissue to protect the gut against the invasion of various harmful substances and the occurrence of different intestinal diseases, a process accomplished by the proliferation of adult stem cells in the basal part of the crypts of the intestinal mucosa (13, 14). These adult stem cells differentiate into cell types with different functions during migration from the base of the crypt to the top and comprise two primary groups: the absorptive lineage, which includes enterocytes and microfold cells, and the secretory lineage, which includes goblet, Paneth, enteroendocrine, and Tuft cells (15–24). These intestinal cells collaborate to maintain intestinal homeostasis. Among them, the goblet cells are named for their resemblance to a cup, and there is a gradient in their distribution along the intestine, gradually increasing from near to far, with the duodenum having the lowest and the rectum exhibiting the highest (25, 26). Of the intestinal secretory lineage cells, goblet cells are the most abundantly produced (27). Intestinal goblet cells are secretory cells that originate from the bottom of the intestinal crypt (28). Within the crypt, crypt base columnar cells split successively to produce progenitor cells, which divide and proliferate rapidly after entering the transit expansion zone before differentiating and developing into mature goblet cells (28, 29). The differentiation of intestinal goblet cells is primarily regulated by signalling pathways such as those of Notch, Wnt/β-catenin, Hippo, and epidermal growth factor (EGF), whereas their early differentiation is primarily regulated by molecules such as atonal bHLH transcription factor 1 (Atoh1), and molecules such as Krüppel-like factor 4 (KLF4) and the SAM pointed domain ETS factor (SPDEF) primarily mediate their terminal differentiation (11, 30–35). Intestinal goblet cells are a class of short-lived cells that are renewed once every 7 days and play a crucial protective role in the intestinal barrier by producing and secreting mucus and releasing antimicrobial substances (26) (Figure 1).

Figure 1

3 Classification of intestinal goblet cells

Intestinal goblet cells were long thought to be a homogeneous population of secretory cells; however, advances in science and technology have revealed a greater degree of heterogeneity than previously appreciated (36) (Table 1). Birchenough et al. (37) analysed mouse colon tissues and identified a subtype of intestinal goblet cells in the upper crypt named sentinel goblet cells (senGCs). Located at the opening of colonic crypts, sentinel goblet cells (senGCs) are a specialized subset that can uniquely endocytose ligands of Toll-like receptors (TLRs), including agonists for TLR1/2, TLR4, and TLR5. The internalization of ligands activates these cells through the nod-like receptor family pyrin domain containing 6 (NLRP6), causing a swift, calcium-dependent secretion of stored mucin 2 (MUC2) from senGCs. Simultaneously, activated senGCs emit intercellular signals that cause adjacent responding goblet cells to release MUC2. The synchronized release of mucus from senGCs and nearby goblet cells helps to physically remove bacteria from the colonic crypts. This defence mechanism strengthens the intestinal mucus barrier, preventing bacterial invasion and reducing the risk of mucosal inflammation, which helps maintain intestinal balance (37).

Nyström et al. (36) revealed a dynamic system comprising different goblet cell subtypes by analysing mouse small intestinal and colonic cells expressing MUC2 and identified a unique differentiation trajectory and maturation process of goblet cells, which were divided into two distinct and mutually independent trajectories that included canonical goblet cells (canonical GCs) and noncanonical goblet cells (noncanonical GCs), with both trajectories originating from proliferating cells in the lower crypt and forming two small populations of goblet cells in the surface epithelium with high Schlafen 4 or aquaporin-8 expression. The canonical GCs predominantly express goblet cell-specific genes Atoh1, calcium-activated chloride channel regulator 1 (Clca1), MUC2, and IgGFc-binding protein (Fcgbp), whereas noncanonical GCs primarily express the genes Hes1, Gasdermin 4 (Gsdmc4), deleted in malignant brain tumors 1 (Dmbt1), mucin 17, and ion channels related to intestinal cells, which are reportedly specific to goblet and intestinal cells, respectively, in previous related studies (38–40). Similarly, this study demonstrated that canonical GCs have functions related to secretion, glycosylation, and endoplasmic reticulum stress, whereas noncanonical GCs function in lipid and amino acid metabolisms, detoxification, and intestinal absorption, improving the understanding of the functions of the different goblet cell subtypes (36) (Table 1). In analysing the single-cell RNA sequencing of mouse intestinal goblet cells, small intestinal and colon goblet cells were classified into nine and eight clusters, respectively, and these intestinal goblet cells were classified into four primary types according to their expressed markers: typical goblet cells expressing the typical cuprocyte-associated genes Clca1 and Fcgbp, proliferative goblet cells expressing the proliferative marker Mki67, nontypical goblet cells expressing the atypical goblet cell-related genes Gsdmc4, Dmbt1, and Sis, and fully differentiated goblet cells expressing the fully differentiated cell-associated gene MAX dimerisation protein 1 (36, 41–43)(Table 1). These intestinal goblet cells may have been formed during the differentiation process, and the relationships between the different goblet cell clusters indicate the potential plasticity of intestinal goblet cells.

In addition, goblet cells of a previously unrecognized and functionally distinct subtype were identified and named intercrypt goblet cells (icGCs) (36). icGCs include all goblet cells on the crypt surface, primarily comprising the most differentiated canonical GCs, and these intestinal goblet cells have a distinctive morphology and specific gene expression profiles that can be localized with the wheat germ agglutinin lectin and be detected using non-O glycosylated MUC2 antiserum (36). Wheat germ agglutinin and Ulex europaeus agglutinin 1 immunofluorescence double staining revealed that the mucus secreted by icGCs is primarily in the spatial region around the crypt plumes at the top of the colonic crypt openings and is called the intercrypt mucus (36). The intercrypt mucus keeps out bacteria of size 1 μm but not smaller molecules, while the crypt plume mucus is impenetrable to 1 μm-sized bacteria and smaller particles, and the two form a dense mesh structure on the mucosal surface, blocking the invasion of bacteria and other harmful substances and enhancing intestinal mucus homeostasis (36) (Figure 2). The mechanism of how intestinal goblet cells utilize the same set of core proteins to produce mucus of such different properties is poorly understood; however, the differences may be related to mucus processing, and further research is urgent (25) (Table 1). The identification of senGCs/icGCs creates new avenues for developing targeted therapies aimed at fortifying the crypt barrier against bacterial invasion in IBD.

Figure 2

4 Functions of intestinal goblet cells

As a special organ in direct contact with the external environment, the intestinal tract has been constantly subjected to various stimulations; thus, the formation of the intestinal barrier is essential to maintain intestinal homeostasis (44). The primary intestinal barriers include chemical, mechanical, immune, and biological forms (45). The intestinal goblet cells, as members of the intestinal epithelium, are crucial in the function and maintenance of the intestinal barrier.

4.1 Role of intestinal goblet cells in the chemical barrier

The intestinal chemical barrier, also known as the mucus barrier, primarily comprises mucus secreted by the epithelial cells of the intestinal mucosa, mucin, and various digestive enzymes, lysozyme, as well as bacteriostatic substances secreted by beneficial intestinal bacteria, which constitute the first defence line for the intestine against invasion by harmful luminal contents (46–48). Mucus is primarily synthesized and secreted by goblet cells and covers the surface of epithelial cells (46, 49–51). MUC2 is the primary component of mucus that serves as a skeleton, which is first dimerized in the intestinal goblet cell endoplasmic reticulum to form a dimer through intermolecular disulfide bonding and subsequently transferred to the Golgi to complete O-glycosylation modification; the MUC2 dimer is transformed into a trimer in the trans-Golgi network and finally encapsulated within secretory vesicles (52–54). In addition to MUC2, this secretory vesicle contains an Fc fragment of IgG-binding protein, chloride channel accessory, zymogen granule protein, and anterior gradient homologue 2 (52). During the upward movement of the goblet cells from the crypt base, this vesicle is continuously filled and consequently fuses with the apical membrane of the goblet cells, facilitating the excretion of its contents through the cytotoxic action of the goblet cells (52). Finally, for the accumulated mucin to be sufficiently swollen to form the dense meshwork, the mucin requires a high pH, low Ca²⁺ environment, and HCO₃^{• -} supplied by the cystic fibrosis transmembrane conductance regulator channel, which forms a dense meshwork that segregates the bacteria from the intestine by frequently renewing itself, preventing the bacterial invasion of the intestine (3, 46, 52, 55–59). Han et al. (60) found that β-hydroxybenzoic acid enhanced the function of the intestinal chemical barrier by increasing the levels of intestinal goblet cells and MUC2, which effectively alleviated DSS-induced colonic inflammation (Figure 3a). Therefore, intestinal goblet cells are vital in the maintenance and function of the intestinal chemical barrier.

Figure 3

4.2 Role of intestinal goblet cells in the mechanical barrier

The intestinal mechanical barrier, also known as the physical barrier, primarily comprises intestinal epithelial cells and the tightly connected proteins between them, which protect the intestine against the invasion of toxic substances from the environment and serve as the structural basis for maintaining the permeability of the intestinal epithelium and its barrier effect (45, 48). The integral intestinal mechanical barrier functions by restricting the invasion of detrimental substances and microorganisms and primarily comprises enterocytes, goblet cells, M-cells, and intestinal chromaffin cells, which are sealed by tight junctions (Tjs), side channels that control the passage of molecules, ions, and water, effectively sealing out detrimental intestinal luminal substances from the intestines (4).

Intestinal goblet cells are directly involved in the composition, as well as the functioning of the intestinal mechanical barrier, by secreting intestinal trefoil factor 3 (TFF3) and intestinal goblet cell specific protein resistin-like molecule β (RELM β), which are essential for maintaining the intestinal barrier integrity and stability and regulating colonic inflammatory susceptibility (4, 61–65). TFF3, a small peptide secreted by intestinal goblet cells, effectively improves the intestinal barrier function by regulating the TJs between intestinal epithelial cells to reduce the permeability of the paracellular pathway (4). In contrast, RELM β promotes increased interleukin (IL) 22 by recruiting CD4 T lymphocytes, which subsequently promotes epithelial cell proliferation, indirectly mitigating intestinal damage in the disease and protecting the intestinal barrier function (61) (Figure 3b). Thus, intestinal goblet cells are crucial in the formation and functioning of the intestinal mechanical barrier.

4.3 Role of the intestinal goblet cells in the immune barrier

The intestine is an organ that contains the most number of immune cells, making it crucial for human immune function (66). The intestinal goblet cells participate in the function of the intestinal immune barrier (25). Studies have shown that intestinal goblet cells form goblet cell-associated antigen passages (GAPs), which transport luminal antigens to CD103⁺ dendritic cells and other mononuclear phagocytes in the lamina propria. Some of these cells migrate to draining lymph nodes to initiate adaptive immune responses and promote intestinal immune tolerance (26, 67).

In addition to the above-mentioned role of antigen delivery, intestinal goblet cells perform immune functions by synthesizing and secreting RELMβ. Artis et al. (68, 69) demonstrated that RELMβ exerts an inhibitory effect on gastrointestinal nematode infections by binding to the nematode chemosensory apparatus. Elevated RELMβ levels have been associated with a Th2-type polarized immune response, indicating that intestinal goblet cells may also participate in immunomodulation through RELMβTh2 (70). Similarly, Wang et al. (40) identified a potential new marker for goblet cells in the human intestines, interectin-1 (ITLN1), when analysing the different nutrient absorption functions in the human intestines using a single-cell transcriptome. ITLN1 was specifically expressed by all goblet cells in the ileum, colon, and rectum, whereas previous studies have shown that ITLN1 binds to microbial glycans and functions in innate immunity, suggesting their role in innate immunity (71). Nyström et al. (36) found that intestinal goblet cells have a defence profile of expressing antimicrobial genes, implying that they may participate in the composition and functioning of the innate immune system. Moreover, the goblet cells regulate the immune response by secreting cytokines IL6, IL7, IL13, IL15, IL17, IL18, and IL25, as well as chemokine exotoxin C-C motif chemokine ligand (CCL) 6, CCL9, and CCL20 (72) (Figure 3c). These findings suggest that in addition to secreting mucus, intestinal goblet cells function in regulating intestinal immune responses.

4.4 Role of intestinal goblet cells in the biological barrier

The colonic mucus layer contains two layers, primarily composed of highly glycosylated MUC2, in which the inner mucus layer impedes the penetration of bacteria and other harmful substances, separating the microbiota from the intestinal mucosa, preventing their direct contact that induces the occurrence of related diseases; whereas, the outer mucus layer is relatively sparse, allowing the entry of bacteria and other harmful substances, making it the primary habitat for commensal bacteria on the surface of the intestinal tract (3, 52, 73, 74). The biological barrier on the intestinal surface is a complex microbial system, and the outer mucus layer formed by intestinal goblet cells provides attachment sites and serves as a nutrient source, while these microorganisms may also influence goblet cell differentiation and mucin maturation, possibly affecting the maintenance of intestinal homeostasis (74, 75). Park et al. (76) found that Bifidobacterium breve CBTBR could effectively alleviate intestinal inflammation by promoting goblet cell regeneration, whereas Bacillus subtilis inhibited the Notch pathway and decreased Hes1 expression in a Toll-like receptor 2-Myd88-dependent manner, causing the differentiation of intestinal stem cells (ISCs) towards the secretory spectrum (16). Troll et al. (77) demonstrated that microbiota-induced Myd88-dependent signalling pathways promote the differentiation of the intestinal secretory profiles by inhibiting the Notch signalling pathway, causing the intestinal goblet cells to interact with intestinal microbes to maintain intestinal homeostasis (Figure 3d).

5 Factors affecting intestinal goblet cells

5.1 Factors affecting intestinal goblet cell development

Intestinal goblet cells, as a type of secretory cells on the surface of the intestinal mucosa, are crucial in the formation and maintenance of the intestinal mucus barrier and the body’s immune response (4, 67). The developmental process of goblet cells involves multiple signalling pathways, which are simultaneously affected by various factors, including the Notch signalling pathway (11, 16, 76, 78–84), the Wnt/β-catenin pathway (30, 83, 85–93), the EGF pathway (30, 94), the Hippo pathway (31, 95–97), cytokines (11, 98–100), terminal differentiation-influencing factors such as SPDEF and KLF4 (32, 36, 72, 100–105), microorganisms, and energy metabolism (16, 36, 76–78, 106, 107). These signalling pathways and molecules play a role from the differentiation of ISCs into goblet cells to the stage of terminal differentiation and contribute to the overall development of goblet cells (Table 2).

5.1.1 Factors influencing initial differentiation

5.1.1.1 Signalling pathways

The Notch signalling pathway is significant in the fate of intestinal epithelial cells by regulating their differentiation into absorptive or secretory lineage cells (90). The Notch signalling pathway maintains intestinal goblet cell viability and is critical in regulating intestinal goblet cell differentiation and development (108). VanDussen et al. (109) reported that inhibition of Notch signalling led to increased differentiation of intestinal goblet cells in mice, whereas overexpression of the intracellular domain of Notch in the intestinal epithelium resulted in a reduction of secretory cell populations (110). Hes1, a major downstream transcriptional target of Notch, was shown to suppress goblet cell differentiation—Hes1-deficient mice exhibited upregulated expression of both goblet cell markers and Atoh1 (111). Similarly, Atoh1, another key downstream effector of Notch, has been established as essential for secretory lineage differentiation, with its overexpression promoting secretory cell fate (112, 113). However, apparent contradictions emerge regarding the regulatory relationships among these factors. While Notch signalling negatively regulates Atoh1 and indirectly inhibits goblet cell differentiation via Atoh1 suppression (95, 114–116), Kim et al. (117) proposed a more complex interaction: Atoh1 may act upstream of Notch and directly repress Hes1 expression, suggesting that Hes1 functions downstream of Atoh1 rather than solely as a direct Notch target. These seemingly conflicting results indicate that the regulatory network between Notch, Atoh1, and Hes1 may be context-dependent, exhibiting feedback mechanisms or tissue-specific effects. Rather than a simple linear pathway, the differentiation of intestinal stem cells into goblet cells appears to be regulated through a dynamic interplay between Notch signalling and its downstream targets Atoh1 and Hes1, with the latter also participating in cross-regulatory loops. Further studies are needed to clarify the precise hierarchical and temporal relationships under different physiological and experimental conditions. Furthermore, some molecules reportedly regulate goblet cell differentiation by altering the activity of the Notch pathway. By analysing the relationship between tryptophan metabolism and intestinal epithelial function, Alvarado et al. (79) showed that indoleamine 2, 3-dioxygenase 1 inhibits the Notch signalling pathway by binding to the aryl hydrocarbon receptor, which promotes ISC differentiation into the secretory lineage cells. Moreover, other studies have demonstrated that 6formylindolo[3,2-b]carbazole, the ultraviolet photoproduct of L-tryptophan, inhibits the Notch signalling pathway by activating aryl hydrocarbon receptor-pErk1/2, promoting goblet cell differentiation (118). These studies suggest that the Notch signalling pathway is crucial in the development of intestinal goblet cells.

In addition to the Notch signalling pathway, the Wnt/β-catenin pathway is significant in the determination of intestinal stem cell differentiation (90). Using transgenic mice ectopically expressing the Wnt secretory inhibitor Dickkopf1, Pinto et al. (91) found that Wnt deletion resulted in the loss of intestinal crypts, reduction of epithelial cell proliferation, and an essentially complete deletion of the intestinal secretory profile. Kuhnert et al. (92) demonstrated similar phenomena to those described above in intestinal epithelial cells by knocking down Dickkopf1. Furthermore, the Wnt/β-catenin pathway influences intestinal goblet cell development by interacting with effector molecules in the Notch signalling pathway (90). Kayet et al. (119) revealed that in the presence of Wnt, β-catenin inhibited Notch-mediated cellular oscillations induced by Hes1 transcription by directly binding to the Hes1 promoter and induced the cells to maintain a steady state. As a downstream of Notch, Atoh1 is regulated by Notch and the Wnt/β-catenin signalling pathway. When β-catenin conduction is activated, Atoh1 expression suppresses the forced differentiation induced by the Notch inhibition of Atoh1 expression, and the upregulated Atoh1 expression promotes goblet cell differentiation (93). Therefore, in addition to the Notch pathway, the development of intestinal goblet cells is simultaneously regulated by Wnt/β-catenin.

EGF, a cytoprotective peptide, participates in cell growth, proliferation, differentiation, and apoptosis, as well as in regulating the development of intestinal goblet cells (30, 94, 120–124). Shimoda et al. (94) demonstrated that the inhibition of disintegrin and metalloproteinase-17 expression at the cellular level maintained and promoted goblet cell differentiation through a disintegrin and metalloproteinase protein-17-EGFR signalling. Furthermore, a recent study showed that EGF maintains and promotes goblet cell (e.g., piglets intestinal goblet cells) differentiation through the EGFR and Wnt/β-catenin signalling pathways (30).

As an evolutionarily highly conserved signalling pathway, the Hippo signalling pathway comprises an upstream signal, a central kinase core, and downstream target genes, and this pathway restricts tissue overgrowth, suppressing tumorigenesis primarily through the inactivation of its downstream effector protein Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ), and YAP1/TAZ participate in intestinal cell proliferation and differentiation (95, 125). Fallah et al. (95) found a marked increase in intestinal goblet and absorptive cell differentiation by knocking down YAP1, while TAZ knockdown revealed that YAP1 exerted its inhibitory effect on intestinal goblet cell differentiation primarily through the intestinal transcription factor caudal-type homeobox transcription factor 2; thus, the Hippo pathway is involved in the regulation of intestinal stem cell activity and influences intestinal goblet cell differentiation (95, 126). Similarly, the Hippo pathway is associated with several other signalling pathways and affects EGF signalling pathway conductance by regulating EGF ligand expression and influences ISC activity by inhibiting the Wnt pathway activity. The Hippo pathway is also linked to the Notch signalling pathway (126, 127). Thus, the above pathways collectively regulate intestinal goblet cell development.

5.1.1.2 Cytokines

In addition to relevant signalling pathways, specific cellular molecules participate in regulating the intestinal goblet cell differentiation process. Using zebrafish and mouse intestinal goblet organoid models, Rodrigo et al. (11) found that the inhibition of the IL10-Notch axis suppressed goblet cell differentiation. Through an intestinal immune cell co-culture model, Waddell et al. (98) demonstrated that IL33 depended on the production of IL13 by two groups of innate lymphoid-like cells, indirectly inducing intestinal goblet cell differentiation. Furthermore, using multiple conditional deletion models of IL17, Xun et al. (99) showed that IL17 promoted differentiation into the intestinal secretory lineage, including intestinal goblet cells, by promoting Atoh1 expression. However, Roni et al. (100) demonstrated that IL18 inhibited intestinal goblet cell differentiation and maturation by regulating the transcriptional program of intestinal goblet cells. Therefore, the above studies confirm that many cytokines regulate intestinal goblet cell differentiation, improving the understanding of intestinal goblet cell development.

5.1.2 Factors influencing terminal differentiation

Terminal differentiation of intestinal goblet cells is influenced by various factors, including the protein disulfide isomerase Anterior gradient 2 (AGR2), SPDEF, the endoplasmic reticulum stress transducer OASIS, bone morphogenetic protein (BMP) signalling, the zinc-finger transcription factor KLF4, and growth factor independence 1 (Gfil1) (36, 72, 101–104). Chen et al. (101) demonstrated that AGR2 is essential for intestinal goblet cell terminal differentiation by knocking down and overexpressing AGR2 in zebrafish. SPDEF acts as a downstream molecule of Atoh1 and Gfil1 to reduce Paneth and enteroendocrine cells to promote the terminal differentiation of goblet cells (128). By assessing the goblet cell markers in OASIS-knockdown mice, Asada et al. (102) found that the mature goblet cell marker TFF3 exhibited a reduced expression, whereas the expression levels of the early goblet cell markers MUC2, AGR2, and RELM β were elevated, suggesting that OASIS regulates the developmental process of goblet cells primarily by affecting the terminal differentiation of goblet cells. Using BMP-knockout Bmpr1a mutant mice, Auclair et al. (103) revealed that BMP deficiency impairs the maturation of intestinal goblet cells by affecting their terminal differentiation. Analysis of KLF4 showed that the number of mature goblet cells was reduced in KLF4-knockout mice, whereas that of goblet cells at the initial differentiation stage was not significantly affected, demonstrating that KLF4 regulates terminal goblet cell differentiation (104). In addition, the terminal differentiation of intestinal goblet cells is reportedly regulated by specifically knocking down the molecular dedicator of the cytokinesis 4 gene in mice by decreasing the degree of transcriptional maturation of goblet cells and inhibiting goblet cell maturation and MUC2 production, and the dedicator of cytokinesis 4 function is regulated through the Gfil1-SPDEF pathway (32). In addition to the molecules in the above studies, IL18 affects the terminal differentiation of intestinal goblet cells. For example, Nowarski et al. (100) used IL18-deficient mice to show that IL18 inhibits the terminal differentiation of goblet cells and affects their maturation, contributing to the development of associated intestinal diseases. Hood et al. (105) found that the terminal differentiation of intestinal goblet cells was affected by knocking down tumor necrosis factor-alpha-induced protein 8 in mice and also identified a novel Nupr1, a new regulatory factor that may affect the terminal differentiation of intestinal goblet cells; however, the specific mechanism by which they affect the terminal differentiation of goblet cells requires further investigation. The above studies suggest that the terminal differentiation of intestinal goblet cells is influenced by several factors that regulate their functional performance by promoting or inhibiting their maturation.

5.1.3 Other factors

In addition to the above pathways and associated molecules that regulate the intestinal goblet cell differentiation process, other factors, such as microorganisms, influence goblet cell differentiation. For example, Troll et al. (77) found that the microbiota-induced signalling pathway promotes the differentiation of gut secretory lineage by inhibiting the Notch signalling pathway. In addition, energy metabolism affects goblet cell differentiation, and Marlies et al. (78) recently demonstrated that Forkhead box O increases mitochondrial fission by interacting with Notch, a phenomenon mediated by miR484 and FIS1, specifically leading to increased levels of secretory cells without affecting those of absorptive cells. In addition, Shijie et al. (106) showed that tissue sclerosis affects intestinal goblet cell differentiation when they observed the characteristics of patients with IBD, suggesting that it promotes the expansion of Olfactomedin4+ cells to villus-like regions by increasing YAP expression while inducing the nuclear translocation of YAP, benefiting the preferential differentiation of ISCs to goblet cells. Similarly, single-cell RNA sequencing and proteomic analysis of intestinal samples from mice and humans revealed the specific markers and transcription factors enriched in intestinal goblet cells, including breast carcinoma amplified sequence 1, serine protease inhibitor Kazal-type 4, REP15, cAMP-responsive element binding protein 3 L1, and forkhead box A3; however, the effects of these factors on intestinal goblet cell development require further investigation (36, 107).

5.2 Factors affecting the function of intestinal goblet cells

The intestinal mucus barrier is considered the first defence line against harmful substances, and as intestinal goblet cells are crucial in it, understanding the various factors that influence their function is essential. Naama et al. (129) analysed autophagy-initiating protein Beclin 1-knockout mice and found that Beclin activated the onset of autophagy, causing a reduction in endoplasmic reticulum stress and promoting the intestinal goblet cells to produce more mucus to maintain intestinal mucus barrier integrity under inflammatory conditions. Engevik et al. (47) demonstrated that the products secreted by Bifidobacterium, particularly γ-glutamylcysteine, promote the mucus secretion of intestinal goblet cells by inhibiting the ROS and NF-κB driving the endoplasmic reticulum stress while reducing the number of pro-inflammatory factors. Studies have shown that the transcription factor NF-κB increases the number of goblet cells; thus, γ-glutamylcysteine and NF-κB jointly promote the maintenance of intestinal homeostasis by affecting the intestinal goblet cell function (130). Furthermore, Pavel et al. (131) showed that long noncoding RNA-H19 impairs intestinal barrier function by inhibiting intestinal goblet and Paneth cell functions, as well as inhibiting the occurrence of intestinal autophagy.

MUC2, a major mucin secreted by intestinal goblet cells, is also crucial for intestinal goblet cell function. Shuailing et al. (132) found that somatostatin in mice promotes MUC2 secretion from intestinal goblet cells through the Notch-Hes1 pathway. Michael et al. (133) showed that ERN2/IRE1β, an analogue of the endoplasmic reticulum pressure sensor ERN1/IRE1α, forms an intestinal chemical barrier by modulating the maturation of intestinal goblet cells and their secretion of mucins.

In addition to these influences, signalling pathways regulate intestinal goblet cell function. For example, Nicolás et al. (134) found that defects in BMPs cause impaired intestinal goblet cell function, affecting the integrity of the mucus barrier. Min et al. (135) showed that histamine derived from conjunctival goblet cells promotes mucin production through the activation of EGFR. Mira et al. (136) demonstrated that EGF improved intestinal goblet cell-associated mucosal integrity. In addition, Wu et al. (137) found that Clostridium butyricum, a probiotic that produces butyrate, induces EGFR activation via its ligands, causing elevated levels of intestinal goblet cells and MUC2 secretion, corroborating the findings of Min et al. and Mira et al. above. Thus, intestinal goblet cells are regulated by various factors in the formation and maintenance of the intestinal mucus barrier, influencing intestinal homeostasis and mediating the development of different intestinal diseases.

In addition to their ability to form and maintain the intestinal chemical barrier, intestinal goblet cells function in immunomodulation. Through a specific lymphotoxin β receptor (LTβR) knockdown in mice, Yaya et al. (138) showed that LTβR is crucial for intestinal goblet cell proliferation and MUC2 expression during intestinal infection with Listeria monocytogenes and further analysed that single gene-deficient mice were informed that Type 3 Innate Lymphoid Cells through the lymphotoxinLTβR pathway to promote intestinal goblet cells differentiation and function as well as MUC2 expression, facilitating the host to improve intestinal defence function. The maintenance of homeostasis between gut microbes and the host is pivotal for the protection of intestinal health (139). Gao et al. (140) found that dysregulated microbiota, particularly E. coli, influences gasdermin D activation during colitis, while Roni et al. (100) showed that gasdermin D reduces the number of intestinal goblet cells by promoting IL18 secretion, which contributes to intestinal disease. In addition, a recent study revealed that IL18 of enteric nervous system origin influences the function of the intestinal immune system by promoting the secretion of antimicrobial peptides by intestinal goblet cells and that it modulates the intestinal mucosal barrier defence against bacterial invasion (141). Therefore, intestinal goblet cell function is influenced by various factors, and these data can provide insights into identifying novel approaches for treating intestinal disorders that are associated with abnormal intestinal goblet cell function.

6 Intestinal goblet cells and IBD

Inflammatory bowel disease (IBD), which mainly includes ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic inflammatory condition of the digestive tract marked by recurring flares and a complex, still not fully understood cause (142). While immune dysfunction has long been considered a main driver, more and more evidence points to primary defects in the intestinal epithelial barrier-especially problems with goblet cells-as major contributors to the disease (5, 8).As the primary mucus producers in the gut lining, goblet cells are key to building the protective layer that keeps microbes away from the epithelial surface. Goblet cell dysfunction or depletion is a known characteristic of IBD (Figure 4), but the specifics and severity of these issues vary significantly between UC and CD (73, 143, 144).

Figure 4

6.1 Distinct patterns of goblet cell dysfunction in ulcerative colitis and Crohn’s disease

UC and CD both have goblet cell abnormalities, but the root causes and how they show up are not the same (1, 5, 8, 145, 146). Table 3 breaks down the main differences in goblet cell pathology between the two. Gersemann et al. (145) dug into these differences by looking at colon samples from UC and CD patients with similar levels of inflammation. They found that inflammation ramps up the expression of goblet cell differentiation factors Atoh1 and KLF4 in CD, but not in UC (145). They also checked protein levels and got the same result for Atoh1 (145). Even with similar inflammation levels, both diseases lost goblet cells, but in UC, the loss was mainly in the top part of the crypts. This points to a problem with cells finishing their development, not just failing to become goblet cells in the first place (5, 145). For ileal CD, the main issue is with Paneth cells, not goblet cells. Their defensin levels drop because Wnt signalling is off, which throws off Paneth cell development (5, 8). Without enough defensin, the antimicrobial barrier weakens and bacteria can get through. So, UC has a mucus problem from faulty goblet cell development, while ileal CD has a chemical barrier problem from Paneth cells not doing their job (5, 8).

6.2 Microbiota alterations and their impact on goblet cells and the mucus barrier

The gut microbiota has a dual function in the development of IBD: while commensal bacteria are crucial for preserving epithelial balance, an imbalance in microbial composition, known as dysbiosis, can compromise the mucus barrier and worsen goblet cell dysfunction (74, 75, 139).

6.2.1 Mucus layer as a microbial habitat

The outer mucus layer acts as a main habitat for commensal bacteria, offering places to attach and a source of nutrients (74). These microorganisms, in turn, affect the differentiation of goblet cells and the maturation of mucin. Research has indicated that specific types of bacteria can alter goblet cell function via various methods: bifidobacterium breve aids in the regeneration of goblet cells and reduces intestinal inflammation; bacillus subtilis suppresses the Notch signalling pathway and reduces Hes1 expression through a TLR2-MyD88-dependent mechanism, promoting ISC differentiation into the secretory lineage; clostridium butyricum triggers EGFR activation through its ligands, leading to an increase in goblet cell numbers and MUC2 secretion (16, 76, 137). On the flip side, bad bacteria mess with the mucus barrier. When colitis flares up, E. coli moves in and messes with gasdermin D. That cranks up IL-18 and wipes out goblet cells (100, 140).

6.2.2 Dysbiosis in CD and UC

The gut microbiota composition varies between CD and UC patients, affecting the mucus barrier differently (139) (Table 4).

6.2.3 Mucus glycosylation and bacterial interactions

The effectiveness of mucus protection is heavily reliant on its glycosylation status. Yao et al. (146) showed that sialylation is vital in maintaining the integrity of the intestinal mucus barrier and preventing bacterial invasion. Whereas ST6GALNAC1 (ST6), the rate-limiting step in salivary acylation, is highly expressed in intestinal goblet cells, and ST6 deficiency causes decreased sialylation, leading to impaired intestinal mucus barrier integrity and early onset of IBD (146). By screening a national IBD cohort, Yao et al. (146) found that ST6 mutations are associated with the development of “very early-onset IBD,” and therefore, intestinal goblet cells participate in the development of IBD through the high expression of ST6. In addition, Yao et al. (146) speculated that the pathogenesis of IBD may be associated with changes in the biochemical composition of the intestinal mucus barrier, particularly sialylation and epithelial cell changes, as suggested by the present study and many previous reports (146). Therefore, it is proposed that in addition to anti-inflammatory and immunotherapeutic treatments, IBD treatment should consider therapeutic tools related to intestinal barrier and epithelial cell repair, providing a novel approach for IBD treatment (146). In a similar way, the maturation of sulfomucin by goblet cells aids in the function of the mucus barrier. Poly-β-hydroxybutyrate (PHB) eases colitis by boosting the secretion and maturation of sulfomucin, indicating that modifying mucus biochemistry could be a therapeutic strategy (147).

6.3 Integrated view: goblet cells, mucus barrier, tight junctions, and microbiota in IBD pathogenesis

The intestinal barrier consists of multiple layers, including: (1) the mucus layer, which acts as a chemical barrier, (2) the epithelial cell layer with tight junctions, serving as a mechanical barrier, (3) immune cells and their secretions (immune barrier), and (4) the resident microbiota (biological barrier) (45, 48). Goblet cells play a role in all four layers by secreting mucus, producing TFF3, sampling antigens (GAPs), and secreting cytokines. Nevertheless, their role cannot be viewed independently (4, 26, 67).

6.3.1 Tight junctions and paracellular permeability

Intestinal epithelial cells are connected by tight junctions, which create selectively permeable barriers to control paracellular transport. Recent progress has revealed three unique permeability routes through TJs: the pore pathway, which is selective for size and charge; the leak pathway, which permits larger molecules; and the unrestricted pathway, found at sites of epithelial damage (2, 4). In IBD, all three pathways have shown increased permeability (2). Significantly, primary TJ dysfunction can trigger mucosal immune responses and hasten the development of immune-mediated colitis, even without obvious inflammation (4).

TFF3 from goblet cells is essential for maintaining the integrity of tight junctions (4). It improves barrier function by influencing the expression and placement of tight junction proteins, thereby decreasing paracellular permeability (4). Therefore, goblet cell dysfunction in IBD not only weakens the mucus barrier but also worsens TJ defects, leading to a combined barrier failure.

6.3.2 A unifying view of barrier failure in IBD

Initial defects in certain epithelial lineages trigger unique pathological sequences in inflammatory bowel disease. In ulcerative colitis, the final differentiation of goblet cells is disrupted, resulting in decreased MUC2 production and changes in mucus characteristics (3, 5). In ileal Crohn’s disease, the malfunction of Paneth cells leads to a lack of defensins, weakening the antimicrobial barrier (5, 8). The mucus barrier is compromised by these epithelial abnormalities, which permits luminal bacteria to infiltrate the inner mucus layer and make direct contact with the intestinal lining (73, 146).

Dysbiosis worsens this issue. Harmful bacteria like adherent-invasive Escherichia coli in Crohn’s disease attach to and invade epithelial cells, whereas beneficial bacteria that typically aid goblet cell function and mucus production are depleted (16, 76, 137). The resulting epithelial stress responses, such as endoplasmic reticulum stress and oxidative stress, further damage goblet cell function and trigger apoptosis, worsening the initial issue (47, 129, 148).

At the same time, the disruption of tight junctions enhances paracellular permeability, permitting bacterial products and luminal antigens to reach the lamina propria (2, 4). TFF3 from goblet cells, which typically maintains tight junction integrity, is reduced when goblet cells malfunction, leading to a combined breakdown of the mucus barrier and paracellular seal (4). The breach of the epithelial barrier that results lead to immune activation, causing inflammatory damage that continues the cycle and further impairs epithelial function (5, 8).

In IBD pathogenesis, goblet cell dysfunction, mucus barrier defects, tight junction abnormalities, and dysbiosis are interlinked and reinforce each other. If the fundamental barrier defects remain, therapeutic approaches focusing solely on one aspect, like immunosuppression, might be inadequate. The inadequate reaction of VEO-IBD patients lacking IL10RA to standard anti-inflammatory treatments highlights the critical necessity for methods that repair epithelial barrier integrity (6, 11).

6.4 Therapeutic implications

Recognition of the multifaceted role of goblet cells and the mucus barrier in IBD opens new therapeutic avenues (Table 5).

6.5 Conclusions and future directions

Intestinal goblet cells are key to keeping the multilayered gut barrier in good shape. When they don’t work right, it feeds into IBD in a few ways-like not making enough mucus, messing up mucin sugar patterns, messing with antigen sampling, and throwing off talks with the microbiome. Worth noting, how goblet cells go wrong isn’t the same in UC and CD. In UC, the main hiccup is at the final stage of cell maturation, while in CD, the epithelial issues run wider, even pulling in Paneth cells. These differences actually matter when it comes to treatment angles. Getting a solid grip on goblet cell biology-especially how it ties into the mucus layer, tight junctions, and gut bugs-opens up fresh ways to fix the intestinal barrier in IBD. It’s about moving past just calming the immune system and aiming for real repair and lasting balance.

7 Conclusions

Intestinal goblet cells, a specialized epithelial cell type, play essential role in forming the protective mucus barrier via MUC2 secretion, which blocks pathogenic invasion and supports commensal microbes. Recent research reveals that goblet cells contribute not only to the mechanical barrier but also to immune and biological barrier functions, highlighting their broader role in mucosal immunity. Their remarkable plasticity and heterogeneity enable adaptive responses to environmental cues, thereby preserving intestinal integrity under physiological and pathological conditions. This review summarized advances in goblet cell differentiation, classification, functions, and their involvement in IBD, offering new insights into their role in intestinal health.

Emerging evidence indicates that dysfunction or depletion of intestinal goblet cells serves as a critical hallmark of IBD, leading to barrier impairment, microbial dysbiosis, and sustained inflammation. The identification of distinct goblet cell subtypes offers novel potential targets for IBD intervention. Meanwhile, signalling pathways and various molecules involved in regulating goblet cell differentiation also provide new insights for the treatment of IBD. Future translational research should focus on developing small molecules or biologics that can modulate specific goblet cell subtypes or their key regulatory pathways (e.g., boosting MUC2 production via Atoh1, or targeting senGC function). Additionally, goblet cell-derived molecules in stool or blood could be explored as biomarkers for early diagnosis or monitoring treatment response in IBD.

Therefore, a profound understanding of goblet cell biology may pave the way for novel therapeutic strategies aimed at restoring intestinal function in IBD and other gut disorders by targeting their multifaceted roles—such as mucus production, antigen sampling, and cytokine secretion. Developing targeted therapies based on these mechanisms holds significant potential for bridging basic research and clinical applications.

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