Vivian Naa Amua Wellington
Soudamani Singh- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
Exosomes, which are molecular cargo-containing, nanosized extracellular vesicles formed through double invagination of the plasma membrane, have emerged as important mediators of intercellular communication within the gastrointestinal tract. In addition to its established function in digestion and nutrient uptake, the gastrointestinal tract is central to immune regulation and maintenance of epithelial barrier integrity. Exosomes derived from intestinal epithelial cells, the gut microbiota and gut resident immune cells are key in sustaining intestinal homeostasis and regulating host-microbiota interactions. Dysregulation of these vesicles is increasingly linked to gastrointestinal disease pathogenesis, including inflammatory bowel disease. Currently, exosomes are being explored for use as diagnostic biomarkers and therapeutic agents in gastrointestinal ailments. In this review, we examine the roles of exosomes in gastrointestinal health and disease, highlighting their contributions in the regulation of epithelial barrier function, modulation of immune responses and communication with the gut microbiota. We further discuss the dysregulation of exosome-mediated signaling pathways in IBD and assess their potential as next-generation therapies for gastrointestinal disorders.
1 Introduction
The gastrointestinal (GI) tract is a continuous hollow tube extending from the mouth to the anus and forms a central component of the digestive system. It is essential for physiological processes such as ingestion, digestion, nutrient absorption and immune function (1). Within the gut ecosystem, heterogeneous cell populations coordinate the interaction of epithelial, immunologic, neural, and microbial cell networks in order to perform these crucial physiological functions (2). Thus, maintaining homeostasis in this complex environment relies heavily on intercellular communication. Notably, the GI tract is considered the body’s largest endocrine organ, reflecting its extensive role in systemic signaling pathways (3). While hormone-mediated intercellular communication in the gut has been substantially explored, extracellular vesicles (EVs) have emerged as key mediators of intercellular communication within the gut. EVs are cell-derived, membrane-bound vesicles that transport bioactive molecules between cells. These vesicles differ in origin and size and include apoptotic bodies, microvesicles, as well as exosomes (4). It is important to note that the ‘Minimum Information for Studies of Extracellular Vesicles’ (MISEV2023) guidelines recommend the use of the operational terms large EVs and small EVs “unless the subcellular origin can be demonstrated” (5, 6). However, use of previous terminology remains prevalent in current literature, including in studies that have not demonstrated subcellular origin. For consistency with existing studies discussed herein, the term exosome is used throughout this review.
Exosomes, the smallest of extracellular vesicles (30–150 nm in diameter), are secreted by diverse cell types into the extracellular environment (Figure 1). The sheer diversity of cell types that secrete exosomes as well as their presence in various biological fluids such as breast milk, urine, semen, saliva, plasma and gastric acid, strongly supports their physiological relevance (7–9). Once exclusively regarded as capsules of cellular debris, these nanovesicles facilitate the transfer of proteins, lipids, nucleic acids, and other bioactive molecules between cells. Through this cargo, they enable coordinated information transfer in an autocrine, paracrine, and endocrine manner (Figure 1C) (7, 10). Exosomal content can reflect the physiological or pathological state of their cells of origin and can significantly alter the function of recipient cells. Upon uptake, recipient cells may reprogram exosomal content to modulate vital physiological processes such as signal transduction, cell proliferation, apoptosis and immune activation (11, 12). Growing evidence has highlighted the pivotal role of exosomes in gut physiology and their involvement in gastrointestinal diseases (13–15). Consequently, exosome regulation of gut-relevant cellular processes continues to attract significant interest (16). Indeed, exosome dysregulation is associated with several GI disorders, including inflammatory bowel disease (IBD), colorectal cancer, and infectious enteric diseases. For example, aberrant exosome production by immune and epithelial cells contributes to tissue damage and persistent inflammation in IBD (17). In colorectal cancer, tumor-derived exosomes facilitate immune evasion, tumor development, and metastasis (18). At the same time, exosomes hold significant clinical potential as diagnostic biomarkers and targeted therapeutic agents for the management of gastrointestinal disorders. Their inherent biocompatibility, ability to traverse biological barriers, low toxicity and limited immunogenicity make exosomes particularly well-suited for therapeutic drug delivery applications (19).
Figure 1. Exosomes as intercellular shuttles. This figure provides a comprehensive overview of exosomes as key mediators of intercellular communication. The left panel, (A) Biogenesis, illustrates the formation of exosomes, beginning with the invagination of the plasma membrane (endocytosis) to form early and late endosomes. These mature into multivesicular bodies (MVBs), which contain intraluminal vesicles. Finally, the MVBs fuse can fuse with lysosomes for cargo degradation or traffic to the plasma membrane, where they release the ILVs into the extracellular space as exosomes. The right panel, (B) Composition & (C) Function, details the diverse molecular cargo carried by exosomes, including proteins, lipids, enzymes, DNA, and various RNAs (mRNA and miRNA). These components facilitate different forms of communication: autocrine/paracrine signaling and the direct transfer of functional molecules to recipient cells, which can result in functional reprogramming of recipient cells.
Here, we summarize the critical function of gut-derived exosomes in maintaining gut epithelial barrier integrity, regulating immune responses, and facilitating host-microbiota communication. We also examine how disruption of these mechanisms influences the pathogenesis of IBD and evaluate the potential of exosomes as diagnostic biomarkers and therapeutic agents. By shedding light on these processes, this review aims to enhance understanding of exosome-mediated mechanisms in gastrointestinal pathobiology and inform future strategies for diagnosis and treatment.
2 Biogenesis of exosomes:
Exosome biogenesis (Figure 1A) is a tightly regulated process that originates within the endosomal system (20). It begins with the formation of early endosomes through inward budding of the plasma membrane (endocytosis). Early endosomes may be recycled back to the plasma membrane or mature into late endosomes. During maturation, the limiting membrane of endosomes further invaginates, encapsulating cytoplasmic components to generate intraluminal vesicles (ILVs) (21). Late endosomal structures containing multiple ILVs are known as multivesicular bodies (MVBs) (22). MVBs then follow one of several fates: they may be directed to the trans-Golgi network for recycling, fuse with lysosomes for degradation, or be trafficked to the plasma membrane, where they release their ILVs as exosomes into the extracellular space (23). Two primary mechanisms govern ILV formation: the endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways (21, 24).
The ESCRT machinery consists of four distinct multimeric protein complexes (ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III) along with associated proteins such as the AAA ATPase VPS4. These complexes are sequentially recruited to endosomal membranes to coordinate the selective sorting and packaging of cargo into ILVs (25, 26). ESCRT-0 recognizes and sequesters ubiquitinated cargo within phosphatidylinositol-3-phosphate-enriched endosomal compartments. ESCRT-I and ESCRT-II are then recruited to induce membrane curvature and initiate bud formation. ESCRT-III, together with VPS4, mediates the scission of ILVs from the endosomal membrane and subsequent dissociation and recycling of the ESCRT-III complex (27). Scission completion results in the formation of MVBs containing ILVs loaded with specific cargo molecules. Alternative ESCRT-dependent mechanisms involving accessory proteins such as Alix, HD-PTP, and Tsg101 have also been described (24, 28).
Evidence for ESCRT-independent exosome biogenesis pathways have been reported and reviewed in detail (29–31). Briefly, these pathways rely on distinct lipid- and protein-mediated mechanisms. One notable mechanism involves ceramide-induced membrane budding and cargo sorting. Here, ceramide, generated by the enzymatic activity of neutral sphingomyelinase, promotes negative membrane curvature, facilitating ILV formation.
Lipid rafts, which are cholesterol- and sphingolipid-rich microdomains within endosomal membranes, also contribute to organizing associated proteins such as caveolin-1 and flotillins, which assist in cargo sorting and ILV budding (29). In parallel, tetraspanins, a family of integral membrane proteins enriched in exosomes, represent another ESCRT-independent mechanism. Tetraspanins such as CD9, CD63, CD81, and CD82 (29, 32, 33) may organize into tetraspanin-enriched microdomains that contribute to cargo sorting, vesicle formation, and membrane fusion events that facilitate exosome release. Notably, ESCRT-dependent and -independent pathways may overlap (34), resulting in the formation of heterogeneous populations of ILVs within a single MVB and highlighting the adaptable nature of exosome biogenesis.
3 Exosomes in gastrointestinal physiology
In the normal gut, mucosal homeostasis depends on the ability of the local immune system to maintain tolerance toward commensal microbiota while mounting efficient immune responses to eliminate enteric pathogens (35–37). Exosomes facilitate crosstalk between intestinal epithelial cells (IECs), immune cells, and the gut microbiota (38) (Figure 2). Hence, they are key players in sustaining normal physiological process within the gut.
Figure 2. Exosomes in maintaining gut homeostasis. Exosomes are central to maintaining gut homeostasis by mediating crucial communication across the intestinal lumen, epithelial barrier, and lamina propria. Bacteria exosomelike vesicles (BEVs) released by the gut microbiota in the intestinal lumen may cross the epithelial barrier and can influence the host. Concurrently, Intestinal Epithelial Cells (IECs) secrete exosomes both apically into the lumen and basolaterally into the lamina propria. These exosomes play a vital role in immune surveillance, healing and strengthening the epithelial barrier. Exosomes from immune cells and fibroblasts within the lamina propria also engage in this complex crosstalk. These interactions lead to the modulation of immune responses, promoting immune tolerance and anti-inflammation. Together, these exosome-mediated interactions ensure gut homeostasis.
3.1 Exosome-mediated regulation of epithelial homeostasis and barrier function:
The intestinal epithelium is a selective physical and biochemical barrier that separates luminal contents from the underlying tissue, protecting against microbial invasion and preserving tissue homeostasis (39). It is composed of a single layer of polarized columnar epithelial cells interconnected by tight junctions (TJs) and covered by a protective mucosal layer (40). Together, these features maintain a crucial separation between the host tissue and the gut microbiota, preventing microbial translocation and supporting immune tolerance (41). Disruption of TJs is often driven by an imbalance in cytokine signaling, particularly an excess of pro-inflammatory cytokines, which compromises barrier function and increases epithelial permeability, a common feature of many gastrointestinal disorders. Conversely, anti-inflammatory cytokines like IL-10, and transforming growth factor (TGF-β) play a protective role, preserving TJ integrity and promoting mucosal healing (42). Gut-derived exosomes may interact with various immune cell populations within the intestinal microenvironment. Through this interaction, and their bioactive cargo, they modulate immune responses and contribute to the maintenance of the epithelial barrier (21, 43).
Intestinal epithelial cells secrete exosomes. Van Niel et al. (38) demonstrated that IECs actively release exosome-like vesicles. These epithelial-derived exosomes were found to contain several key molecules, including MHC class I, MHC class II, CD68, CD63, CD26, and the A33 antigen (38, 44, 45). These findings suggested that IEC-derived exosomes participate in antigen presentation, potentially impacting mucosal and systemic immunity without necessitating direct contact between IECs and immune effector cells. Indeed, IECs can capture luminal antigens, package them into exosomes, and export this complex to local professional antigen-presenting cells (APCs) thus amplifying antigen presentation and shaping adaptive immune responses (46). Specifically, dendritic cells (DCs) exposed to IEC-derived exosomes laden with αvβ6/ovalbumin antigen produced active TGF-β, whereas DCs treated with antigen alone secreted only latent TGF-β. In vivo administration of these exosomes also promoted the development of antigen-specific regulatory T cells, while suppressing Th2-driven responses to food antigens (47). These findings highlight a critical immunoregulatory role for IEC-derived exosomes in enhancing peripheral tolerance and shaping mucosal immune responses. Moreover, IEC-derived exosomes originate from multiple epithelial subtypes, including enterocytes, goblet cells, Paneth cells, enteroendocrine cells, tuft cells, progenitor cells, transient-amplifying cells, and stem cells (48, 49). This diversity is reflected in the complexity of the exosomal cargo and its roles in regulating intestinal barrier integrity and mucosal homeostasis.
IECs secrete exosomes in a polarized fashion both apically into the intestinal lumen and basolaterally into the lamina propria (50). Apical exosome secretion supports host defense by delivering antimicrobial peptides such as cathelicidin LL-37 and β-defensin 2 (51), which bind and neutralize pathogenic bacteria, thus contributing to innate immune defense and reinforcing epithelial defense (51). During Cryptosporidium parvum infection, Toll-like receptor (TLR4) signaling-mediated suppression of the let-7 miRNA family increases the luminal release of these antimicrobial-laden exosomes, indicating that epithelial cells can adjust their exosomal output to augment innate immune responses to pathogens (51). Basolaterally secreted exosomes, on the other hand, are involved in immune surveillance and regulation. These vesicles can present antigens via MHC II molecules and carry costimulatory markers, functioning similarly to professional APCs. (38, 45, 46). One of the early demonstrations of this is from Karlsson et al.’s paper (52), which described “tolerosomes”, exosome-like vesicles secreted basolaterally by IECs, capable of inducing tolerance in naïve animals. Removal of these tolerosomes from circulation abrogated tolerance induction, emphasizing their immunological relevance.
IEC-derived exosomes are also enriched with anti-inflammatory and pro-resolving molecules. For example, transforming growth factor-beta 1 (TGF-β1)-containing exosomes that exhibit immunosuppressive properties were secreted by IECs under physiological conditions. These vesicles promoted regulatory T cells (Tregs) differentiation and the generation of tolerogenic DCs via ERK signaling, effects that were lost when EpCAM expression or exosome secretory pathways were disrupted (53). Complementarily, IECs generated tolerogenic exosomes enriched in IL-10 and antigen/MHC II complexes when exposed to a combination of ovalbumin antigen and the immunoregulatory peptide vasoactive intestinal peptide. These exosomes were able to convert antigen-specific CD4+ T cells into Tr1 regulatory cells, underscoring their significance in establishing antigen-specific immune tolerance (54). Leoni et al. (55) further showed that IECs secrete the endogenous pro-resolving mediator annexin A1 in exosomes, which promote mucosal wound healing by binding formyl peptide receptors and triggering epithelial repair.
IEC-derived exosomes play a pivotal role in regulating epithelial barrier function through the delivery of bioactive molecules involved in TJ dynamics. Exosomal RNAs can rapidly and locally remodel the extracellular matrix, regulate junctional proteins, coordinate immune recruitment, to maintain barrier integrity during injury and inflammation (40, 56). Exosomes from epithelial cell-derived miR-146a enhanced IL-10 production by monocytes (57), promoting an anti-inflammatory environment and protecting against ischemia/reperfusion injury by downregulating the pro-inflammatory TLR4/TRAF6/NF-κB pathway (58). Further, injured epithelial cells were found to release increased numbers of exosomes that stimulated fibroblast proliferation and upregulated α-smooth muscle actin, F-actin, and type I collagen. This activation was largely driven by the transfer of exosomal TGF-β1 mRNA as a rapid signaling mechanism for initiating tissue repair (59).
The intestinal epithelium undergoes continuous renewal through the proliferation and differentiation of intestinal stem cells (ISCs), located at the base of crypts. These stem cells rely on a sophisticated microenvironment of niche signals, including Wnt and epidermal growth factor (EGF) (60, 61). Wnt signaling regulates ISC maintenance, proliferation, differentiation, apoptosis, and migration (61). Wnts are secreted on the surface of exosomes which in turn activate Wnt signaling in recipient cells (62). Chen et al. (63) demonstrated polarity-dependent release of compositionally distinct Wnt-containing exosomes from epithelial cells, suggesting refined regional regulation of Wnt activity. Moreover, the exosomal marker A33 antigen, expressed predominantly in IECs, plays a role in epithelial migration and proliferation. A33-deficient mice exhibit defective wound healing and reduced epithelial cell turnover, underscoring the contribution of IEC-derived exosomes to mucosal repair (64). In addition to IECs, exosomes derived from fibroblasts, and other cell types within the gut mucosa and lamina propria also contribute to epithelial renewal. Oszvald et al. (60), using mouse and human intestinal organoids showed that intestinal fibroblast-derived small extracellular vesicles (sEVs) deliver EGF signals that support ISC niche function and organoid survival. Beyond local signaling, EVs may mediate long-range communication during tissue regeneration. Gurriarán-Rodríguez et al. (65) discovered the presence of an “exosome-binding peptide” motif within Wnts, required for their loading onto EV surfaces and showed that, following muscle injury, Wnt7a is secreted on EVs and transported over long distances, highlighting the systemic signaling potential of EV-associated Wnts. Similarly, Wnt5a, known to accumulate at epithelial wound sites has been detected in Caco-2 cell-derived exosomes, reinforcing the role of exosomes in epithelial repair after injury (66, 67).
Collectively, these findings demonstrate that IEC- and intestinal fibroblast-derived exosomes are multifaceted regulators of gastrointestinal homeostasis (Summarized in Table 1). They mediate immune modulation via antigen presentation and RNA transfer, support stem cell renewal through Wnt and EGF delivery, enhance antimicrobial defenses through apical secretion of antimicrobial peptides, and promote epithelial regeneration.
Table 1. Functions of intestinal epithelial cell (IEC) and fibroblast-derived exosomes in gastrointestinal physiology.
3.2 Exosomes in immune regulation and gut homeostasis
Immune cells mediate response against pathogens while maintaining tolerance to harmless antigens. Dendritic cells and macrophages, as classical APCs, internalize antigens and present them via MHC class I and II molecules to CD8+ and CD4+ T cells, respectively, thereby initiating adaptive immune responses (68). Exosomes released by immune cells are important modulators of innate and adaptive immune responses. By transporting antigen-MHC complexes, delivering immunomodulatory cytokines, lipids and regulatory nucleic acids, these vesicles enable immune cells to coordinate immune activation and tolerance locally in the intestinal mucosa and systemically (69). In this section, we examine the significance of immune cell-derived exosomes in the initiation and modulation of immune responses in the context of maintaining gut homeostasis and immune tolerance.
3.2.1 Mast cell-derived exosomes
Mast cells (MCs) release immunologically active exosomes (MC-EXOs) (70). These exosomes promote the activation of B and T lymphocytes and support the functional maturation of dendritic cells (71). By inducing potent antigen-presentation in dendritic cells, MC-EXOs facilitate robust T cell responses. They can drive Th1 polarization through stimulation of IL-12p70 secretion (72) and support Th2 differentiation via OX40L-mediated signaling (73), highlighting their ability to modulate immune polarization.
In addition to their immunomodulatory functions, MC-EXOs impact epithelial integrity through the transfer of regulatory RNAs. Wang et al. (74) demonstrated that exosomes from mast cells carried the long non-coding RNA (lncRNA) NEAT1, which acted as a molecular sponge for miR-211-5p. This released the repression of glial cell line-derived neurotrophic factor (GDNF), a protective factor for epithelial barrier integrity. MC-EXOs also interact with mast cells allowing for functional transfer of exosomal mRNAs and miRNAs and thus are conduits of indirect communication between mast cells (12).
3.2.2 Dendritic cell-derived exosomes
Dendritic cells are potent APCs important in immune surveillance. Depending on their maturation state, they may steer immune response towards tolerance or activation. Generally, immature DCs promote T-cell tolerance, whereas mature DCs induce robust T-cell-mediated immune activation (75). This functional duality is reflected in the properties of dendritic cell-derived exosomes (DEX). While DEX are commonly rich in key immunological molecules such as MHC I and II alongside associated co-stimulatory proteins (76–78), exosomes derived from mature DCs express higher levels of these molecules, making them significantly more effective in activating T cells (79, 80). Segura et al. (81) demonstrated that exosomes from mature LPS-treated DCs were significantly more efficient in activating antigen-specific T cells in vitro and could endow B cells with the capacity to prime naïve T cells. In vivo, only mature DEX were able to induce effector T cell responses, with functional studies confirming that MHC II and ICAM-1 were essential for this priming effect.
Besides T cell interactions, DCs also use exosomes to communicate with neighboring DCs. Montecalvo et al. (82) showed that DEX carry distinct miRNA profiles depending on the maturation state of the parent DC. These exosomes can fuse with recipient DCs, delivering their miRNA content directly into the cytosol, thus unveiling a mechanism of DC-DC communication and post-transcriptional regulation via exosome-shuttled miRNAs. Furthermore, mature DEX may enhance the antigen-presenting capability of their parent DCs by stimulating increased expression of MHC I/II and co-stimulatory molecules such as CD40, CD54, and CD80 (80). In line with this, Sobo-Vuljanovic et al. (83) reported that DEX can assist in DC sentinel function by binding and cross-presenting bacterial TLR ligands to neighboring “bystander” DCs, promoting DC maturation, increased pro-inflammatory cytokine secretion, and natural killer (NK) cell activation.
In addition to their roles in immune activation, DEX can also mediate immune tolerance. Exosomes from immature DCs have been shown to suppress alloreactive T cell responses and promote Treg expansion, partly through the upregulation of IL-10 production in CD4+CD25+ Tregs, in models of intestinal transplantation (84). These tolerogenic vesicles are themselves enriched in immunosuppressive cytokines such as IL-10 and TGF-β (85), supporting Treg induction and dampening excessive immune activation (86). Similarly, exosomes derived from genetically modified DCs expressing FasL or those treated with IL-10 exhibit anti-inflammatory and immunosuppressive properties (87, 88).
3.2.3 Macrophage-derived exosomes
Exosomes secreted by macrophages (MEX) display diverse immunomodulatory properties. The activation state of the macrophage is reflected in, and shapes, the molecular profile of their exosomes. LPS-stimulated RAW 264.7 macrophages release exosomes enriched in distinct cytokines and miRNAs compared to unstimulated cells. RNA sequencing of the exosomal contents from stimulated macrophages showed upregulation of genes linked to innate and adaptive immunity, including NF-κB signaling, TLR pathways, and MHC-mediated antigen presentation, collectively priming recipient cells for immune challenges (89). Under inflammatory conditions, MEX may deliver pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6, contributing to immune activation and tissue damage (90). Conversely, MEX may transport anti-inflammatory and pro-fibrotic factors, including TGF-β, fibroblast growth factors (FGFs), granulocyte colony-stimulating factor (G-CSF), and interleukin-1 receptor antagonist (IL-1Ra), which suppress pro-inflammatory cytokines and promote mucosal tolerance (89, 90).
Macrophage polarization influences exosomal function and can be reciprocally influenced by exosomal cargo. Exosomes from healthy tissues typically promote anti-inflammatory M2 polarization, whereas those from diseased or inflamed tissues favor a pro-inflammatory M1 phenotype (91). Han et al. (92) found that small extracellular vesicles (sEVs) derived from Ptpn1-deficient macrophages enhanced intestinal epithelial barrier integrity and suppressed inflammation. These vesicles, rich in lactadherin, inhibited NF-κB activation in both macrophages and IECs, and favored M2 polarization. This aligns with earlier findings by Yang et al. (93), who showed that exosomes from M2b-polarized macrophages alleviated DSS-induced colitis by expanding Tregs, increasing IL-4, and reducing pro-inflammatory cytokines. M2-derived exosomes also stimulated epithelial proliferation and recovery via miR-590-3p-mediated cytokine suppression (94), while miR-93-5p-enriched M2 exosomes inhibited NET formation, decreased intestinal inflammation, and promoted tissue repair (95).
Other regulatory RNAs also contribute to the reparative function of MEX. The MEG3, previously identified in exosomes (96), was detected in M2-derived EVs. When transferred into inflamed colonic epithelial cells, it increased cell viability and reduced pro-inflammatory cytokine expression, further supporting MEX’s role in mucosal healing (97).
3.2.4 T cell-derived exosomes
When acute inflammatory responses are insufficient, adaptive immune responses become necessary. In this context, T cell-derived extracellular vesicles (TEX) serve as important mediators of communication between T cells and other immune cells (98). Among these, Treg-derived exosomes are especially critical to maintaining immune homeostasis.
Treg secretion of enzymatically active, immunosuppressive exosomes in response to T cell receptor stimulation was demonstrated by Smyth et al. (99) and confirmed by Okoye et al. (100). Other suppressive T cell subsets, such as CD8+CD25+Foxp3+ cells, also release exosomes capable of inhibiting CD8+ T cell activity (101, 102). Similarly, thymic cell-derived exosome-like particles (ELPs) promote immune tolerance by supporting the generation Foxp3+ Tregs, which can convert CD4+CD25⁻ T cells into functional Tregs capable of suppressing effector T cell proliferation both in vitro and in vivo. This effect was partially mediated by TGF-β signaling, as neutralization of this cytokine impaired Treg induction (103). Clinical studies further support the immunosuppressive potential of TEX, as exosomes isolated from healthy individuals were more effective at inhibiting conventional CD4+ T cell proliferation (104).
A key mechanism of Treg-mediated regulation of immune response is the delivery of exosomal miRNAs to target cells. Activated Tregs release exosomes enriched with immunoregulatory miRNAs, including let-7d, miR-155, miR-150, and miR-142-3p, which are essential for their suppressive function (100, 101, 105). These exosomes may be taken up by Th1 cells, DCs, and B cells, reprogramming their functional phenotype. For instance, Treg-derived exosomes transfer miR-150-5p and miR-142-3p to DCs, inducing a tolerogenic phenotype characterized by increased IL-10 and reduced IL-6 production in response to LPS stimulation. The central role of miRNA cargo is underscored by the finding that Tregs lacking Dicer (essential for miRNA biogenesis) or Rab27a/b (required for exosome release) fail to suppress Th1 activity (100).
TEX also contributes to immune cell polarization. Treg-derived exosomes promote macrophage polarization toward M2 phenotype, elevating IL-10, IL-4, and IL-13 levels while reducing pro-inflammatory cytokine secretion (106). In line with this, Okoye et al. (100) demonstrated that delivery of Treg-derived exosomal Let-7d, to Th1 cells reduced Th1 proliferation and IFN−γ production. Collectively, these findings establish T cell-derived exosomes as key regulators of immune tolerance, acting through antigen-specific signaling, cytokine delivery, and miRNA-mediated reprogramming of immune cells.
3.2.5 Others
In addition to exosomes derived from mast cells, macrophages, dendritic cells, and T cells, other immune cell populations, such as natural killer (NK) cells, B cells, neutrophils, and eosinophils release exosomes with emerging roles in gastrointestinal immunity and homeostasis.
NK cell-derived exosomes participate in both innate and adaptive immunity. They stimulate monocytes and T cells by upregulating HLA-DR and CD80/86 on monocytes and inducing CD25 on T cells, even in the presence of cytokines such as IL-10 and TGF-β, thereby demonstrating sustained immune activation under immunosuppressive conditions (107). In addition to their immunostimulatory properties, NK exosomes carry cytotoxic proteins such as perforin and granzymes, enabling the direct elimination of infected or transformed cells (107, 108). They also deliver immunomodulatory cytokines and regulatory microRNAs, potentially reinforcing mucosal defense while preserving immune balance.
B cell-derived exosomes similarly contribute to adaptive immunity. These vesicles express MHC class II molecules, co-stimulatory proteins such as CD80 and CD86, and antigen-peptide complexes, enabling them to function in antigen presentation and T cell activation (109). Recent work suggests that B cell-derived exosomes may also promote mucosal tolerance and contribute to the maintenance of gut immune equilibrium (110).
Neutrophil-derived exosomes are increasingly recognized for their dual role in gastrointestinal inflammation. During active inflammation, they can disrupt epithelial adhesion and contribute to barrier dysfunction, as observed in inflammatory bowel disease (IBD) models (111). Conversely, they may also participate in tissue repair, thus contributing to the restoration of intestinal homeostasis (112).
Collectively, these studies highlight immune cell-derived exosomes as significant regulators of gut homeostasis (Summarized in Table 2). Through integrated crosstalk, these exosomes shape immune polarization and tolerance, allowing immune cells to rapidly adapt to tissue and microbial-derived cues. Thus, balancing cytotoxic defense and antigen presentation with anti-inflammatory and pro-resolving responses. Dysregulation of these exosome-mediated pathways may therefore contribute to chronic intestinal inflammation and impaired mucosal healing.
Table 2. Immunomodulatory roles of immune cell-derived exosomes in gut homeostasis.
3.3 Bacteria-derived exosome-like vesicles in gut communication
The gut microbiota, comprising trillions of microorganisms, plays a fundamental role in shaping host immunity and maintaining gastrointestinal homeostasis (113). Through sustained co-evolution, the host and its microbiota have developed a mutualistic relationship where gut microbes educate and regulate the mucosal immune system, while the gut-associated immune system maintains tolerance to commensals. Gastrointestinal homeostasis therefore depends on tightly coordinated communication between gut microbiota, IECs, and the immune system (114, 115). In addition to host-derived extracellular vesicles, vesicles released by gut microbes act as vehicles for this inter-kingdom communication.
Bacteria-derived extracellular vesicles (BEVs), referred to as membrane vesicles (MVs) when secreted by Gram-positive bacteria and outer membrane vesicles (OMVs) when secreted by Gram-negative bacteria, are produced by both commensal and pathogenic microbes. These vesicles carry a variety of proteins, lipids, nucleic acids, and other immunomodulatory molecules (116, 117). BEVs deliver microbial antigens and microbe-associated molecular patterns (MAMPs) that are recognized by host pattern recognition receptors, including Toll-like receptors and NOD-like receptors. This recognition initiates downstream signaling cascades involving NF-κB, MAPKs, and IRFs, which regulate inflammatory gene expression and cytokine production (116–118). Notable examples include the delivery of immunomodulatory polysaccharide A (PSA) from Bacteroides fragilis OMVs and lipoteichoic acid (LTA) from Gram-positive Lacticaseibacillus rhamnosus JB-1 MVs, both of which promote TLR2 signaling and subsequent immune response (119, 120).
Beyond indirect activation via IECs, BEVs may traverse the intestinal epithelium and interact directly with immune cells in the lamina propria. This interaction can induce anti-inflammatory cytokine production, suppress effector T cell responses, prime the immune system, and promote tolerance and intestinal homeostasis (121). For instance, MVs from the commensal Lactobacillus rhamnosus JB-1 cross the intestinal epithelium and reach Peyer’s patches, where they induce tolerogenic DC phenotype and promote the expansion of IL-10-secreting Tregs (122). Similarly, OMVs from Akkermansia muciniphila contribute to gastrointestinal homeostasis by entering Peyer’s patches, activating B cells and DC, and triggering mucosal immunoglobulin A production. Likewise, MVs from Bifidobacterium bifidum LMG13195 stimulate the differentiation of tolerogenic DC and Tregs (123). Comparable immunomodulatory effects have been reported with the Gram-negative Escherichia coli Nissle 1917 (EcN), whose OMVs are readily internalized by macrophages, enhancing antimicrobial activity and promoting IL-10-skewed cytokine production (124). These effects appear to be strain-specific. BEVs from EcN and related commensal E. coli strains promote DC maturation and condition downstream T cell responses toward Th1, Th2, or Treg phenotypes, reflecting strain-specific vesicle-mediated immune education and underscoring the gut microbiota’s capacity to induce balanced immune responses (125, 126)
In addition to immune regulation, BEVs support epithelial barrier integrity, an essential component of gut homeostasis. BEVs from EcN and ECOR63 maintain epithelial integrity by upregulating TJ proteins such as occludin and ZO-1. In epithelial monolayers infected with enteropathogenic E. coli (EPEC), these OMVs preserve cytoskeletal organization and prevent barrier breakdown (127, 128). OMVs from EcN and ECOR12 also stimulate IL-22 and human β-defensin-2 expression in human colonic explants, enhancing mucosal defense through goblet and Paneth cell activation (121, 129). OMVs from Akkermansia muciniphila further support intestinal barrier function by entering epithelial cells and increasing the expression of occludin, claudin-4, and ZO-2, as well as promoting mucus production (130, 131).
BEVs can also reach systemic circulation under homeostatic conditions. For example, OMVs from Bacteroides thetaiotaomicron migrate paracellularly and have been detected in extra-intestinal tissues, suggesting a role in long-range host communication (132). BEVs have even been found in the placenta and amniotic fluid, where they may contribute to the development of immune tolerance before birth and prime the fetal immune system for postnatal microbial exposure (133).
In addition to host-microbe communication, BEVs mediate interbacterial interactions and competition. Early studies by Li et al. (134) demonstrated that OMVs from various Gram-negative species possess broad-spectrum bactericidal activity through peptidoglycan-degrading enzymes, which can kill competing bacteria by degrading their cell walls. More recent work by Dean et al. (135) showed that MVs from Lactobacillus acidophilus deliver bacteriocin peptides to suppress opportunistic pathogens, highlighting BEVs as potential interbacterial weapons. On the other hand, OMVs from Akkermansia muciniphila can fuse with and selectively promote the growth of beneficial gut commensals (131). BEVs from EcN may also help restore intestinal homeostasis by reducing the uptake of pro-inflammatory bacterial peptides through the normalization of dysregulated colonic peptide transport (136).
In sum, BEVs participate in maintaining gastrointestinal homeostasis, acting through immune education, tolerance induction, barrier reinforcement, microbial competition, and inter-kingdom communication (Summarized in Table 3).
Table 3. Roles of microbiota-derived extracellular vesicles in intestinal homeostasis.
4 Exosomes in IBD pathophysiology
Inflammatory bowel disease, which encompasses Crohn’s disease (CD) and ulcerative colitis (UC), is a remitting and relapsing condition characterized by chronic inflammation of the gastrointestinal tract (137, 138). While the precise etiology of IBD remains incompletely understood, disruption of mucosal immune homeostasis and abnormal interactions between the host immune system and gut microbiota, particularly in genetically susceptible individuals, are known to contribute to disease pathogenesis (139). In the chronically inflamed intestinal mucosa, exosome-mediated signaling is dysregulated, leading to epithelial barrier dysfunction, aberrant immune activation, gut microbiota dysbiosis, and the persistent inflammation typical of IBD (13, 17). This section discusses key aspects of IBD-related exosomal abnormalities and explores the molecular mechanisms by which these vesicles may drive disease progression (Summarized in Table 4).
Table 4. Mechanisms of exosome-mediated pathogenesis in IBD.
4.1 Quantitative and molecular changes in exosomes
Alterations in the quantity and molecular composition of exosomes have been documented in individuals with IBD, suggesting that these changes contribute to disease pathogenesis while reflecting molecular alterations associated with disease. Elevated levels of circulating exosomes have been reported in the serum, feces, and saliva from patients with active IBD (140, 141). Moreover, the small GTPases RAB27A and RAB27B, which are involved in exosome secretion, are increased in immune cells from the colonic mucosa of patients with active UC (43, 142).
Compositional changes in both nucleic acids and proteins have also been reported. Most circulating miRNAs in serum and saliva are exosome-bound, and may become dysregulated in IBD (143, 144). For example, let−7b−5p was among differentially enriched miRNAs in CD-derived serum exosomes (145), the circular RNA Circ_0001187 was highly expressed in the serum exosomes of UC patients (Ouyang et al., 2022), while exosomal double-stranded DNA (dsDNA), including mitochondrial (mtDNA) and nuclear (nDNA) DNA, was elevated in the plasma of both experimental and human colitis (146).
Proteins involved in immunoregulation and inflammation are also altered in IBD exosomes. Pregnancy zone protein (PZP), an immunosuppressive factor, and the pro-resolving protein ANXA1 are significantly elevated in exosomes from IBD patients and colitic mice (55, 147). Proteasome subunit alpha type 7 (PSMA7), associated with proteasome activity and inflammation, is markedly increased in salivary exosomes from both Crohn’s and UC patients (140). More recently, Yang et al. (141) demonstrated that salivary exosomes from individuals with active IBD worsened experimental colitis, supporting the idea that these compositional changes are not merely byproducts of disease but may actively contribute to its progression.
Beyond systemic fluids, exosomes derived directly from inflamed intestinal tissues contain distinct molecular cargo. Elevated levels of exosomal dsDNA were detected in colon lavage samples from colitic mice and patients with active CD (146). Additionally, extracellular vesicles (mean size 146 ± 0.5 nm) from inflamed sites differed markedly in RNA content and exerted pro-inflammatory effects on epithelial and immune cells (147, 148). Collectively, these findings indicate that quantitative and compositional changes in exosomes not only reflect IBD activity but that these exosomes may actively participate in disease pathogenesis, highlighting their potential as non-invasive biomarkers for monitoring disease.
4.2 Exosomes as amplifiers of mucosal inflammation
In IBD, persistent activation of pro-inflammatory pathways and immune-cell recruitment drive chronic inflammation. Exosomes released by activated immune cells are key to sustaining this inflammatory state, carrying immunomodulatory molecules that aberrantly stimulate both innate and adaptive immune responses (Figure 3). For instance, exosomes from M1-polarized macrophages were shown to exacerbate colitis through aberrant activation of TLR4 signaling (149). Adding to this, CD14+ intestinal macrophages have been identified as a major source of pro-inflammatory exosomes in IBD. Liu et al. (150) showed that these intestinal macrophage-derived vesicles, enriched in membrane-bound TNF, protected CD4+ T cells from activation-induced cell death, thereby maintaining pools of activated T cells that drive chronic inflammation. Expanding on this, Zeng et al. (151) showed that the same TNF-bearing exosomes reprogrammed macrophage metabolism to sustain inflammation in CD. Mechanistically, exosomal TNF molecules engaged the TNFR2 receptor on intestinal macrophages, triggering glycolytic activation via NF-κB signaling in both an autocrine and paracrine manner. This glycolytic shift increased production of pro-inflammatory cytokines, creating a self-amplifying metabolic–immune feedback loop that perpetuates inflammation in CD.
Figure 3. Exosomes as drivers of chronic inflammation in IBD. Exosomes act as critical mediators sustaining mucosal inflammation in IBD through multiple interconnected mechanisms. M1-polarized macrophages release exosomes enriched in IL-1β, IL-18, and TNF-α, which aberrantly activate TLR4 signaling, disrupt epithelial integrity, and promote inflammation. CD14+ intestinal macrophages secrete TNF-bearing exosomes that engage TNFR2, driving NF-κB–dependent glycolytic reprogramming, amplifying cytokine release, and creating a self-sustaining inflammatory loop. These vesicles also protect CD4+ T cells from activation-induced cell death (AICD), maintaining pools of activated effector T cells that fuel chronic inflammation. Damaged IECs contribute by releasing exosomes carrying dsDNA, which activate STING signaling in macrophages, aggravating inflammatory cytokine production (IL-6, TNF-α, IFN-β) and further damaging the epithelium. Additionally, dysregulated exosomal non-coding RNAs drive immune dysregulation: lncRNA NEAT1 promotes M1 polarization via NF-κB activation, while circRNA Circ_0001187 exacerbates epithelial inflammation by sponging miR-1236-3p, upregulating MYD88, and enhancing NF-κB–dependent signaling. Collectively, these exosome-driven pathways amplify immune activation, impair barrier integrity, and perpetuate chronic mucosal inflammation in Crohn’s disease and ulcerative colitis.
Dysregulated expression of functional exosomal biomolecules also contributes to persistent mucosal inflammation (144). The lncRNA NEAT1, which is elevated in IBD, promoted exosome-mediated M1 polarization by stabilizing TNFRSF1B mRNA and activating NF-κB signaling, leading to increased IL-8, IL-23 and MCP-1 secretion (152, 153). Likewise, serum derived exosomal let-7b-5p activated macrophages through TLR4/NF-κB signaling (145), while circRNA Circ_0001187 promoted epithelial inflammation by sponging miR-1236-3p, upregulating MYD88, and driving NF-κB–dependent pathways (154). Exosomes released from damaged IECs also transported dsDNA to macrophages, triggering STING activation and aggravating inflammation in Crohn’s disease (146). In parallel, extracellular vesicles (~146 nm in diameter) derived from inflamed intestinal tissues contained elevated levels of IL-6, IL-8, IL-10, and TNF-α, which promoted IL-8 secretion and enhanced macrophage migration (148). In addition to nucleic acids and cytokines, exosomes may perpetuate inflammation by transporting bioactive lipids and enzymes involved in pro-inflammatory signaling. For example, exosomes from the immune cell line RBL-2H3 were found to contain phospholipases, arachidonic acid, prostaglandin E2, and cyclooxygenase enzymes, all key components of the arachidonic acid pathway implicated in IBD (155).
4.2.1 Inflammasomes activation
Activation of inflammasomes, cytosolic complexes that detect pathogen- or damage-associated molecular patterns, contributes to chronic intestinal inflammation (156). Among others, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which can be triggered by mitochondrial dysfunction, reactive oxygen species (ROS), lysosomal damage, or ion flux, is very relevant to IBD, as it drives the maturation of IL-1β and IL-18 and induces pyroptosis via gasdermin D (GSDMD) (157, 158). Exosomes facilitate this process by transporting relevant cytokines and inflammasome components. Qu et al. (159), while investigating the rapid export of IL-1β from monocytes/macrophages upon P2X7 receptor (P2X7R) activation, found that activation of the P2X7R by extracellular ATP led to the release of exosomes containing IL-1β, caspase-1, and inflammasome components. Subsequent work from the same group showed these exosomes were MHC-II positive and released from macrophages and dendritic cells (160). Since P2X7 is overexpressed and persistently activated by high extracellular ATP in IBD, this mechanism likely contributes to chronic exosome-driven inflammasome activity (160–162). Additional studies have linked GSDMD to non-pyroptotic exosome-mediated inflammasome regulation. In IECs, GSDMD facilitated the release of IL-1β–containing sEVs by tagging pro–IL-1β for sorting into secretory vesicles. These sEVs co-packaged GSDMD, NEDD4, caspase-8, and IL-1β, while expressing canonical exosomal markers such as CD63 and ALIX. Notably, GSDMD expression was elevated in both IBD patients and colitic mice, implicating this exosomal route in disease pathogenesis (163). Mitochondrial oxidative stress may further trigger NLRP3 activation via exosomal signaling. Knockdown of the mitochondrial antioxidant peroxiredoxin 3 in colonic epithelial cells worsened colitis by upregulating release of exosomal miR-1260b, which exacerbated inflammation (164). On the other hand, miR-223, enriched in MC-EXOs and upregulated in IBD tissues and preclinical colitis models, was shown to negatively regulate NLRP3 activation (165–167). Mice lacking miR-223 exhibited heightened susceptibility to experimental colitis, with increased expression of NLRP3 inflammasome components, elevated IL-1β, and greater monocyte infiltration (168). These studies suggest that miR-223 may be a regulatory mechanism to curb excessive inflammasome activation, although other studies have reported pro-inflammatory effects for this miRNA (165, 166, 169).
In summary, exosomes amplify mucosal inflammation in IBD through multiple complementary mechanisms, including the delivery of pro-inflammatory RNAs and proteins, metabolic reprogramming of immune cells, transport of bioactive lipids, and modulation of inflammasome activity.
4.3 Exosomes promote fibrosis in IBD
Exosomal signaling contributes to tissue remodeling and fibrosis, a common complication of IBD. Intestinal fibrosis is primarily driven by soluble mediators including growth factors (170). Among these, dysregulation of TGF-β signaling, a key regulator of immune homeostasis, is an important feature of IBD. Although TGF-β levels are elevated in inflamed tissues, its downstream signaling pathways are often impaired. As a result, TGF-β fails to exert sufficient immunosuppressive effects during chronic inflammation and may instead promote the fibrotic phenotype characteristic of IBD (171). Exosomes contribute to this process by transporting TGF-β and fibrosis-related regulatory molecules. For example, in response to injury, IECs themselves release TGF-β-containing exosomes that activate fibroblasts and initiate pro-fibrotic tissue regenerative processes (59). Moreover, miR-200b, often packaged in exosomes, inhibits TGF-β–driven pro-fibrotic responses but is significantly reduced in the intestinal mucosa of IBD patients (172, 173). A recent study also highlighted the contribution of mesenteric adipose tissue (MAT)–derived exosomes in promoting intestinal fibrosis in CD via the TINAGL1/SMAD4/TGF-β signaling axis (173). Using a dinitrobenzene sulfonic acid (DNBS)-induced chronic colitis mouse model to mimic fibrotic CD, these authors showed that exosomes from fibrotic MAT were enriched in TINAGL1, which binds directly to SMAD4 and activates TGF-β signaling. In vitro, these exosomes promoted human colonic fibroblast activation, increasing collagen and α−SMA expression. Furthermore, recombinant TINAGL1 treatment in vivo worsened intestinal fibrosis, underscoring the pathogenic role of this exosome-associated signaling axis in fibrostenotic IBD (173).
4.4 Exosome-mediated breakdown of epithelial barrier integrity
Epithelial barrier dysfunction is a central feature of IBD, and growing evidence implicates exosomes and their RNA cargo in driving this process. Among these, miR-21 is dysregulated in both IBD tissues and exosomes, where it targets genes essential for TJ maintenance (174). Elevated miR-21 levels have been detected in colonic biopsies and serum of UC patients, with localization specifically to IECs (175). The neuropeptide Substance P, which is elevated in IBD and implicated in both pro- (176) and anti-inflammatory (177) activities, enhanced exosome production and selectively enriched miR-21 in the exosomal cargo of colonic epithelial cells (178). Functional studies indicate that miR-21 disrupts epithelial barrier function by targeting RhoB and CDC42, key regulators of junctional integrity (175, 179). Li et al. (180) further identified a pro-inflammatory IL-9/miR-21/CLDN8 axis in CD, in which IL-9 upregulation increased miR-21, suppressing CLDN8 expression, thus resulting in barrier disruption. Interestingly, miR-21’s role in immune and barrier regulation may vary across inflammatory settings; its deletion worsened inflammation in TNBS and T-cell transfer colitis models but attenuated disease severity in DSS-induced colitis, suggesting a complex, model-specific function (181).
Immune cell-derived exosomes also impair epithelial integrity. miR-21a-5p, elevated in M1 macrophage-derived exosomes from UC patients and DSS-treated mice, disrupted the epithelial barrier by downregulating E-cadherin, activating ILC2s, and increasing Th2 cytokine release, ultimately amplifying inflammation (182). Similarly, exosomes from LPS-stimulated macrophages carry miR-223, which downregulates TMIGD1, a barrier-protective protein, further impairing mucosal integrity (183). Mast cell-derived exosomes, also enriched with miR-223, were taken up by epithelial cells where they reduced the expression of ZO-1, occludin, and claudin-8, increasing epithelial permeability (166). Note that an earlier study had established that miR-223 directly targets CLDN8 mRNA, thus identifying a IL-23/miR-223/CLDN8 pathway linking the IL-23/Th17 immune axis to barrier disruption (184). These findings are particularly significant since immune cell infiltration is markedly increased in the intestinal mucosa of IBD patients.
Other exosomal RNA similarly contribute to barrier breakdown (11, 185). Elevated exosomal miR-1260b activated p38 MAPK/NF-κB signaling, increasing ROS production, damaging TJs, and exacerbating colitis (164) Conversely, silencing of exosomal lncRNA NEAT1 improved barrier integrity by upregulating ZO-1, Occludin, and Claudin-5 (152, 185).
Lastly, exosomal lipids may impact epithelial barrier regulation. Exosomal lipid rafts play a fundamental role in exosome biogenesis and cargo selection (186). Cholesterol, a major raft component, is essential for epithelial barrier function as it supports tight junction (TJ) formation by organizing proteins such as occludin and claudins within these microdomains (187, 188). Its depletion disrupted this organization, resulting in TJ disassembly and increased epithelial permeability. Indeed, loss of cholesterol-rich rafts occurs early in both murine and human IBD, suggesting that lipid raft disruption may be an initiating event in barrier breakdown, rather than a consequence of established inflammation (189). Given these findings, it is plausible that disruption of exosomal lipid raft components, coupled with the dysregulated exosome release observed in IBD, contributes to barrier dysfunction. While direct evidence linking exosomal lipid rafts to barrier regulation in IBD is limited, these vesicles represent a potentially underexplored mechanism linking chronic inflammation to epithelial barrier failure.
4.5 Microbiota-exosome crosstalk in IBD pathogenesis
Gut microbiota dysbiosis is now a well-established hallmark of IBD. Altered exosomal signaling shapes microbial composition and contributes directly to disease pathogenesis (Figure 4). Carrière et al. (190) showed that exosomes released from epithelial and immune cells infected with adherent-invasive Escherichia coli (AIEC), a pathobiont linked to CD, activate host innate immunity. Xu et al. (191) further revealed that AIEC infection promotes intestinal fibrosis by suppressing epithelial release of exosomal let-7b, a microRNA that normally limits pro-fibrotic macrophage activity by targeting TGFβR1. Loss of let-7b therefore exacerbated intestinal fibrosis in CD. Similarly, AIEC-infected epithelial cells secreted exosomes enriched with miR-30c and miR-130a, which suppressed autophagy-related genes ATG5 and ATG16L1 in recipient cells. Impaired autophagy diminished bacterial clearance, facilitating AIEC persistence (192).
Figure 4. Pathobiont-driven exosome dysregulation in IBD pathogenesis. Pathobionts alter intestinal epithelial cell (IEC)-derived exosomal cargo, promoting inflammation, fibrosis, and barrier dysfunction. Adherent-invasive Escherichia coli (AIEC)infection induces IEC exosomes enriched with miR-30c and miR-130a, which suppress autophagy-related proteins ATG5 and ATG16L1, impairing bacterial clearance and sustaining intracellular replication. These exosomes activate proinflammatory macrophage pathways (NF-κB, p38, JNK), leading to increased TNFα and IL-6, bacterial persistence, and an inflammatory cycle. AIEC also downregulates exosomal let-7b, enhancing TGFβR1 signaling in macrophages, driving profibrotic polarization and intestinal fibrosis. Enterotoxigenic Bacteroides fragilis (ETBF) exposure decreases exosomal miR-149-3p from epithelial cells, enhancing Th17 differentiation and contributing to inflammation and tumorigenesis. In parallel, ETBF-secreted particles (ETBF-SP) stimulate IEC exosomes containing sphingosine-1-phosphate (S1P), CCL20, and PGE2, which promote Th17 recruitment and amplify mucosal inflammation. Fusobacterium nucleatum infection triggers exosomal miR-129-2-3p release, which targets the TIMELESS/ATM/ATR/p53 pathway, leading to DNA damage, cellular senescence, and disruption of tight junction proteins ZO-1 and occludin, thereby promoting epithelial barrier damage.
Other enteropathogens exert comparable effects. Fusobacterium nucleatum (Fn), elevated in the colonic tissue of UC patients, modifies the microRNA cargo of IEC-derived exosomes. Wei et al. (193) found that Fn-infected IEC exosomes were enriched in miR-129-2-3p, which targets TIMELESS, a regulator of DNA repair and senescence. By activating the ATM/ATR/p53 pathway, these vesicles induced epithelial senescence, impaired barrier function, and worsened colitis. Likewise, enterotoxigenic Bacteroides fragilis suppressed exosomal miR-149-3p in colonic epithelial cells, driving Th17 cell differentiation and promoting intestinal inflammation (194).
Enteropathogenic bacteria also stimulated IECs to secrete exosomes containing sphingosine-1-phosphate, CCL20, and prostaglandin E2, which amplified inflammatory response by promoting Th17 recruitment and proliferation, contributing to the Treg/Th17 imbalance that sustains IBD-associated inflammation (85, 195).
In addition to pathogen-induced disruption, host-derived exosomal microRNAs may also regulate the gut microbiota. Host-derived fecal miRNAs (often packaged in exosomes), primarily from IECs and Hopx-positive cells, can enter gut bacteria, regulate bacterial gene expression, and influence microbial growth. Mice lacking epithelial miRNAs (Dicer1^ΔIEC) developed microbial dysbiosis and aggravated colitis, both of which were reversed by fecal miRNA transplantation from wild -type mice, demonstrating a direct role for fecal miRNAs in microbiota regulation and intestinal inflammation (196). Consistent with this, Casado-Bedmar et al. (197) found that fecal miRNAs such as miR-21 and let-7b not only altered microbiota composition but also promoted secretion of myeloperoxidase and antimicrobial peptides, fostering microbiota dysbiosis, barrier dysfunction, and colitis. Collectively, these studies position exosomes as bidirectional messengers in host-microbiota interaction in IBD. Host-derived exosomal cargo drives gut dysbiosis and exacerbates gut inflammation. In parallel, pathogen-derived signals reshape host exosomal content to modulate microbial colonization of the gut and drive bacterial persistence, thereby altering epithelial barrier function, mucosal immune signaling, and sustaining chronic inflammation. However, the functional roles of individual exosomal cargo remain context-dependent, and their translational potential is still at an early stage.
5 Therapeutic potential of exosomes in IBD
Exosomes are a promising therapeutic tool for IBD due to their intrinsic ability to carry bioactive cargo, their biocompatibility, and their relative stability in the gastrointestinal tract. Native vesicles from milk, stem cells, plants, and other sources have shown anti-inflammatory, barrier-restorative, and microbiota-modulating effects in preclinical models, while engineering strategies are enhancing their cargo loading, targeting specificity, and stability during transit (Figure 5) (198, 199).
Figure 5. Therapeutic potential of exosomes in IBD. Exosomes from diverse sources, including milk, mesenchymal stem cells (MSCs), plants, and engineered sources, contribute to mucosal protection and repair. Their mechanisms include immune modulation through induction of regulatory T cells, promotion of M2 macrophage polarization, and restoration of Th17/Treg balance; regulation of programmed cell death pathways such as pyroptosis, ferroptosis, and apoptosis; reinforcement of epithelial barrier integrity and regeneration via Wnt/β-catenin signaling and fibrosis inhibition; modulation of gut microbiota composition and metabolite production; and suppression of oxidative stress and inflammation through NLRP3 inflammasome inhibition, reactive oxygen species scavenging, and NF-κB suppression. Collectively, these effects reduce inflammation, restore barrier function, and promote mucosal healing, highlighting the translational promise of exosome-based therapies in IBD.
Milk-derived exosomes from goat, cow, bovine, and human sources reduce inflammation, strengthen intestinal epithelial barrier function, and favorably modulate gut microbiota and metabolite profiles in colitis models (200, 201). These vesicles demonstrate significant bioavailability in target tissues, although therapeutic efficacy may require dose optimization or cargo enrichment (202).
Stem cell-derived exosomes from mesenchymal and perinatal sources exert potent immunoregulatory and regenerative effects. They promote Treg induction, drive M2 macrophage polarization, and deliver miRNAs that inhibit pyroptosis and ferroptosis in immune and epithelial cells (203–206). These vesicles also suppress NLRP3 inflammasome activation, restore Th17/Treg balance, promote epithelial repair through Wnt/β-catenin signaling, alleviate IBD-associated fibrosis via ERK inhibition, and suppress IEC apoptosis through modulation of histone acetylation (207–211). In another study, umbilical cord MSCs improved IBD-like symptoms, with greater therapeutic benefits when co-administered with MSC exosomes and mesalazine. Notably, exosomes alone lacked sufficient efficacy, suggesting they may be most effective in combination therapy (212). Early clinical data are also encouraging: in a phase I trial, MSC-derived exosomes for refractory perianal fistula was well tolerated, and showed significant therapeutic effect (213).
Plant-derived exosome-like nanoparticles (ELNs) from ginger, ginseng, and tea offer a scalable and edible option, naturally suited for oral delivery. ELNs can traverse the mucosal layer, and their lipid composition enhances stability and uptake, offering advantages over direct plant consumption. In colitis models, they support epithelial barrier resilience, anti-inflammatory pathways, and antimicrobial peptide expression (214–217).
Engineering strategies further extend the therapeutic potential of native exosomes. Current approaches have emphasized three main engineering goals: increasing cargo-loading efficiency, improving targeting to inflamed mucosa, and enhancing stability during gastrointestinal transit (198). Examples include milk exosomes loaded with anti-TNF siRNA for oral administration (218), hucMSC exosomes coated with poly(lactic-co-glycolic acid) (PLGA) to withstand the harsh environment of the gastrointestinal tract (219), and plant ELNs delivering CX5461 for macrophage-targeted therapy (217). Additional strategies that broaden therapeutic options include probiotic-conditioned IEC exosomes that modulate macrophage polarization (220), rectally delivered hydrogel-embedded miR-23a-3p-rich exosome releasing amniotic epithelial stem cells that suppress TNFR1–NF-κB signaling (221), as well as Treg-derived exosomes loaded with selenium and modified with a mitochondria-targeting peptide for site-specific activation in inflamed tissue (222). Similar recently developed novel exosome systems such as cerium oxide-loaded Treg exosomes ameliorated IBD by scavenging ROS and modulating inflammatory responses (223).
Overall, vesicle source, cargo engineering, and delivery format shape the therapeutic potential of exosome-based therapy for IBD. Optimizing these parameters may allow for tailored interventions that address specific clinical needs.
6 Conclusion and future perspective
Exosomes have emerged as important regulators of gastrointestinal homeostasis and therefore IBD pathogenesis. Their normal physiological functions provide a framework for understanding how dysregulation of exosome secretory and regulatory pathways may contribute to disease progression. Advances in exosome bioengineering are also expanding what exosomes can do, allowing for improved targeting, enhanced gastrointestinal stability, and more efficient loading of therapeutic cargo. These developments suggest that exosome-based therapies could become valuable additions to existing IBD treatments, especially for patients who do not respond well to conventional drugs. At the same time, questions remain. Their heterogeneous nature and source-dependent differences in cargo profiles provide unique challenges. Further, their complex interactions with and within the gastrointestinal tract are only beginning to be understood. As such, future progress will depend on bridging mechanistic insights with translational work. In conclusion, this field is clearly important and better understanding of the contribution of exosomes in driving IBD pathogenesis could reshape how IBD is managed.
Author contributions
VW: Data curation, Writing – original draft, Writing – review & editing. SS: Conceptualization, Data curation, Funding acquisition, Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This research was supported by the National Institute of General Medical Sciences, P20GM121299, Project 4 to SS.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declared that generative AI was not used in the creation of this manuscript.
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References
1. Tuma I.O.J.G.K.R.S.F. Physiology, Gastrointestinal. Treasure Island (FL): StatPearls Publishing (2023).
2. Medina-Rodríguez EM, Martínez-Raga J, and Sanz Y. Intestinal Barrier, Immunity and microbiome: partners in the depression crime. Pharmacol Rev. (2024) 76:956–69. doi: 10.1124/pharmrev.124.001202
3. Bany Bakar R, Reimann F, and Gribble FM. The intestine as an endocrine organ and the role of gut hormones in metabolic regulation. Nat Rev Gastroenterol Hepatol. (2023) 20:784–96. doi: 10.1038/s41575-023-00830-y
4. Kumar MA, Baba SK, Sadida HQ, Marzooqi SA, Jerobin J, Altemani FH, et al. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduct Target Ther. (2024) 9:27. doi: 10.1038/s41392-024-01735-1
5. Théry C, Witwer E, Aikawa MJ, Alcaraz JD, Anderson R, Andriantsitohaina A, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. (2018) 7:1535750. doi: 10.1080/20013078.2018.1535750
6. Welsh JA, Goberdhan DCI, O'Driscoll L, Buzas EI, Blenkiron C, Bussolati B, et al. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J Extracell Vesicles. (2024) 13:e12404. doi: 10.1002/jev2.12404
7. Doyle LM and Wang MZ. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. (2019) 8. doi: 10.3390/cells8070727
8. Lässer C, Alikhani VS, Ekström K, Eldh M, Paredes PT, Bossios A, et al. Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages. J Transl Med. (2011) 9:9. doi: 10.1186/1479-5876-9-9
9. Pisitkun T, Shen RF, and Knepper MA. Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci U.S.A. (2004) 101:13368–73.
10. Kalluri R and LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. (2020) 367:6478. doi: 10.1126/science.aau6977
11. Chen S, He R, He B, Xu L, and Zhang S. Potential roles of exosomal lncRNAs in the intestinal mucosal immune barrier. J Immunol Res. (2021) 2021:7183136. doi: 10.1155/2021/7183136
12. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, and Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. (2007) 9:654–9. doi: 10.1038/ncb1596
13. Ayyar KK and Moss AC. Exosomes in intestinal inflammation. Front Pharmacol. (2021) 12:658505. doi: 10.3389/fphar.2021.658505
14. Ye Q, Yu ZH, Nie L, Wang FX, Mu G, Lu B, et al. Understanding the complex role of exosomes in intestinal ischemia-reperfusion injury: from pathogenesis to protection. Front Pharmacol. (2025) 16:1533628. doi: 10.3389/fphar.2025.1533628
15. Kim KU, Kim J, Jang H, Dan KB, Kim BK, Ji YW, et al. Protective effects of human breast milk-derived exosomes on inflammatory bowel disease through modulation of immune cells. NPJ Sci Food. (2025) 9:34. doi: 10.1038/s41538-025-00400-3
16. Wellington VNA and Singh S. The adipose tissue-derived secretome (ADS) in obesity uniquely regulates the na-glucose transporter SGLT1 in intestinal epithelial cells. Cells. (2025) 14:1241. doi: 10.3390/cells14161241
17. Zhang H, Wang L, Li C, Yu Y, Yi Y, Wang J, et al. Exosome-induced regulation in inflammatory bowel disease. Front Immunol. (2019) 10:1464. doi: 10.3389/fimmu.2019.01464
18. Mehta MJ, Shin D, Park HS, An JS, Lim SI, Kim HJ, et al. Exosome-based theranostic for gastrointestinal cancer: advances in biomarker discovery and therapeutic engineering. Small Methods. (2025) 9:e2402058. doi: 10.1002/smtd.202402058
19. Li J, Wang J, and Chen Z. Emerging role of exosomes in cancer therapy: progress and challenges. Mol Cancer. (2025) 24:13. doi: 10.1186/s12943-024-02215-4
20. Dixson AC, Dawson TR, Di Vizio D, and Weaver AM. Context-specific regulation of extracellular vesicle biogenesis and cargo selection. Nat Rev Mol Cell Biol. (2023) 24:454–76. doi: 10.1038/s41580-023-00576-0
21. van Niel G, D’Angelo G, and Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. (2018) 19:213–28. doi: 10.1038/nrm.2017.125
22. Gruenberg J. Life in the lumen: The multivesicular endosome. Traffic. (2020) 21:76–93. doi: 10.1111/tra.12715
23. Xu M, Ji J, Jin D, Wu Y, Wu T, Lin R, et al. The biogenesis and secretion of exosomes and multivesicular bodies (MVBs): Intercellular shuttles and implications in human diseases. Genes Dis. (2023) 10:1894–907. doi: 10.1016/j.gendis.2022.03.021
24. Lee YJ, Shin KJ, and Chae YC. Regulation of cargo selection in exosome biogenesis and its biomedical applications in cancer. Exp Mol Med. (2024) 56:877–89. doi: 10.1038/s12276-024-01209-y
25. Colombo M, Raposo G, and Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. (2014) 30:255–89. doi: 10.1146/annurev-cellbio-101512-122326
26. Juan T and Fürthauer M. Biogenesis and function of ESCRT-dependent extracellular vesicles. Semin Cell Dev Biol. (2018) 74:66–77. doi: 10.1016/j.semcdb.2017.08.022
27. Henne WM, Buchkovich NJ, and Emr SD. The ESCRT pathway. Dev Cell. (2011) 21:77–91. doi: 10.1016/j.devcel.2011.05.015
28. Parkinson MD, Piper SC, Bright NA, Evans JL, Boname JM, Bowers K, et al. A non-canonical ESCRT pathway, including histidine domain phosphotyrosine phosphatase (HD-PTP), is used for down-regulation of virally ubiquitinated MHC class I. Biochem J. (2015) 471:79–88. doi: 10.1042/BJ20150336
29. Han QF, Li WJ, Hu KS, Gao J, Zhai WL, Yang JH, et al. Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer. Mol Cancer. (2022) 21:207. doi: 10.1186/s12943-022-01671-0
30. Stuffers S, Sem Wegner C, and Stenmark H. Multivesicular endosome biogenesis in the absence of ESCRTs. Traffic. (2009) 10:925–37. doi: 10.1111/j.1600-0854.2009.00920.x
31. Raposo G and Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. (2013) 200:373–83. doi: 10.1083/jcb.201211138
32. Escola JM, Kleijmeer MJ, Stoorvogel W, Griffith JM, Yoshie O, and Geuze HJ. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. J Biol Chem. (1998) 273:20121–7. doi: 10.1074/jbc.273.32.20121
33. Chairoungdua A, Smith DL, Pochard P, Hull M, and Caplan MJ. Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol. (2010) 190:1079–91. doi: 10.1083/jcb.201002049
34. Gurung S, Perocheau D, Touramanidou L, and Baruteau J. The exosome journey: from biogenesis to uptake and intracellular signalling. Cell Commun Signal. (2021) 19:47. doi: 10.1186/s12964-021-00730-1
35. Dupaul-Chicoine J, Dagenais M, and Saleh M. Crosstalk between the intestinal microbiota and the innate immune system in intestinal homeostasis and inflammatory bowel disease. Inflammatory Bowel Dis. (2013) 19:2227–37. doi: 10.1097/MIB.0b013e31828dcac7
36. Zhou X, Wu Y, Zhu Z, Lu C, Zhang C, Zeng L, et al. Mucosal immune response in biology, disease prevention and treatment. Signal Transduction Targeted Ther. (2025) 10:7. doi: 10.1038/s41392-024-02043-4
37. Mantis NJ, Rol N, and Corthésy B. Secretory IgA’s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. (2011) 4:603–11. doi: 10.1038/mi.2011.41
38. van Niel G, Raposo G, Candalh C, Boussac M, Hershberg R, Cerf-Bensussan N, et al. Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology. (2001) 121:337–49. doi: 10.1053/gast.2001.26263
39. Allaire JM, Crowley SM, Law HT, Chang SY, Ko HJ, and Vallance BA. The intestinal epithelium: central coordinator of mucosal immunity. Trends Immunol. (2018) 39:677–96. doi: 10.1016/j.it.2018.04.002
40. Mowat AM and Agace WW. Regional specialization within the intestinal immune system. Nat Rev Immunol. (2014) 14:667–85. doi: 10.1038/nri3738
41. Rawat M, Govindappa PK, Gupta Y, and Ma TY. MicroRNA in intestinal tight junction regulation. NPJ Gut Liver. (2025) 2:11. doi: 10.1038/s44355-025-00022-2
42. Al-Sadi R, Boivin M, and Ma T. Mechanism of cytokine modulation of epithelial tight junction barrier. Front Biosci (Landmark Ed). (2009) 14:2765–78. doi: 10.2741/3413
43. Xu AT, Lu JT, Ran ZH, and Zheng Q. Exosome in intestinal mucosal immunity. J Gastroenterol Hepatol. (2016) 31:1694–9. doi: 10.1111/jgh.13413
44. Smythies LE and Smythies JR. Exosomes in the gut. Front Immunol. (2014) 5:104. doi: 10.3389/fimmu.2014.00104
45. Lin XP, Almqvist N, and Telemo E. Human small intestinal epithelial cells constitutively express the key elements for antigen processing and the production of exosomes. Blood Cells Mol Dis. (2005) 35:122–8. doi: 10.1016/j.bcmd.2005.05.011
46. Mallegol J, Van Niel G, Lebreton C, Lepelletier Y, Candalh C, Dugave C, et al. T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology. (2007) 132:1866–76. doi: 10.1053/j.gastro.2007.02.043
47. Chen X, Song CH, Feng BS, Li TL, Li P, Zheng PY, et al. Intestinal epithelial cell-derived integrin αβ6 plays an important role in the induction of regulatory T cells and inhibits an antigen-specific Th2 response. J Leukoc Biol. (2011) 90:751–9. doi: 10.1189/jlb.1210696
48. Haber AL, Biton M, Rogel N, Herbst RH, Shekhar K, Smillie C, et al. A single-cell survey of the small intestinal epithelium. Nature. (2017) 551:333–9. doi: 10.1038/nature24489
49. Wang Y, Song W, Wang J, Wang T, Xiong X, Qi Z, et al. Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine. J Exp Med. (2020) 217. doi: 10.1084/jem.20191130
50. Komori T and Fukuda M. Two roads diverged in a cell: insights from differential exosome regulation in polarized cells. Front Cell Dev Biol. (2024) 12:1451988. doi: 10.3389/fcell.2024.1451988
51. Hu G, Gong AY, Roth AL, Huang BQ, Ward HD, Zhu G, et al. Release of luminal exosomes contributes to TLR4-mediated epithelial antimicrobial defense. PLoS Pathog. (2013) 9:e1003261. doi: 10.1371/journal.ppat.1003261
52. Karlsson M, Lundin S, Dahlgren U, Kahu H, PetterssonI, and Telemo E. ‘Tolerosomes’ are produced by intestinal epithelial cells. Eur J Immunol. (2001) 31:2892–900. doi: 10.1002/1521-4141(2001010)31:10<2892::AID-IMMU2892>3.0.CO;2-I
53. Jiang L, Shen Y, Guo D, Yang D, Liu J, Fei X, et al. EpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance. Nat Commun. (2016) 7:13045. doi: 10.1038/ncomms13045
54. Zeng HT, Liu JQ, Zhao M, Yu D, Yang G, Mo LH, et al. Exosomes carry IL-10 and antigen/MHC II complexes to induce antigen-specific oral tolerance. Cytokine. (2020) 133:155176. doi: 10.1016/j.cyto.2020.155176
55. Leoni G, Neumann PA, Kamaly N, Quiros M, Nishio H, Jones HR, et al. Annexin A1-containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair. J Clin Invest. (2015) 125:1215–27. doi: 10.1172/JCI76693
56. Bui TM, Mascarenhas LA, and Sumagin R. Extracellular vesicles regulate immune responses and cellular function in intestinal inflammation and repair. Tissue Barriers. (2018) 6:e1431038. doi: 10.1080/21688370.2018.1431038
57. Luo X, Han M, Liu J, Wang Y, Luo X, Zheng J, et al. Epithelial cell-derived micro RNA-146a generates interleukin-10-producing monocytes to inhibit nasal allergy. Sci Rep. (2015) 5:15937. doi: 10.1038/srep15937
58. He X, Zheng Y, Liu S, Shi S, Liu Y, He Y, et al. MiR-146a protects small intestine against ischemia/reperfusion injury by down-regulating TLR4/TRAF6/NF-κB pathway. J Cell Physiol. (2018) 233:2476–88. doi: 10.1002/jcp.26124
59. Borges FT, Melo SA, Özdemir BC, Kato N, Revuelta I, Miller CA, et al. TGF-β1-containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis. J Am Soc Nephrol. (2013) 24:385–92. doi: 10.1681/ASN.2012101031
60. Oszvald Á., Szvicsek Z, Sándor GO, Kelemen A, Soós ÁÁ, Pálóczi K, et al. Extracellular vesicles transmit epithelial growth factor activity in the intestinal stem cell niche. Stem Cells. (2020) 38:291–300. doi: 10.1002/stem.3113
61. Flanagan DJ, Austin CR, Vincan E, and Phesse TJ. Wnt signalling in gastrointestinal epithelial stem cells. Genes (Basel). (2018) 9. doi: 10.3390/genes9040178
62. Gross JC, Chaudhary V, Bartscherer K, and Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. (2012) 14:1036–45. doi: 10.1038/ncb2574
63. Chen Q, Takada R, Noda C, Kobayashi S, and Takada S. Different populations of Wnt-containing vesicles are individually released from polarized epithelial cells. Sci Rep. (2016) 6:35562. doi: 10.1038/srep35562
64. Pereira-Fantini PMJ, Judd LM, Kalantzis A, Peterson A, Ernst M, Heath JK, et al. A33 antigen-deficient mice have defective colonic mucosal repair. Inflammatory Bowel Dis. (2010) 16:604–12. doi: 10.1002/ibd.21114
65. Gurriaran-Rodriguez U, Yamamoto H, Kishida S, Kishida M, Awada C, Takao T, et al. Identification of the Wnt signal peptide that directs secretion on extracellular vesicles. Sci Adv. (2024) 10:eado5914. doi: 10.1126/sciadv.ado5914
66. Miyoshi H. Wnt-expressing cells in the intestines: guides for tissue remodeling. J Biochem. (2017) 161:19–25. doi: 10.1093/jb/mvw070
67. Harada T, Yamamoto H, Kishida S, Kishida M, Awada C, Takao T, et al. Wnt5b-associated exosomes promote cancer cell migration and proliferation. Cancer Sci. (2017) 108:42–52. doi: 10.1111/cas.13109
68. Cruz-Tapias P CJ and Anaya JM. Major histocompatibility complex: Antigen processing and presentation. In: Anaya JM, Rojas-Villarraga A, et al, editors. From Bench to Bedside. El Rosario University Press, Bogota (Colombia (2013).
69. Liu J, Zhang X, Cheng Y, and Cao X. Dendritic cell migration in inflammation and immunity. Cell Mol Immunol. (2021) 18:2461–71. doi: 10.1038/s41423-021-00726-4
70. Elieh-Ali-Komi D, Shafaghat F, Alipoor SD, Kazemi T, Atiakshin D, Pyatilova P, et al. Immunomodulatory significance of mast cell exosomes (MC-EXOs) in immune response coordination. Clin Rev Allergy Immunol. (2025) 68:20. doi: 10.1007/s12016-025-09033-6
71. Skokos D, Le Panse S, Villa I, Rousselle JC, Peronet R, Namane A, et al. Nonspecific B and T cell-stimulatory activity mediated by mast cells is associated with exosomes. Int Arch Allergy Immunol. (2001) 124:133–6. doi: 10.1159/000053691
72. Skokos D, Botros HG, Demeure C, Morin J, Peronet R, Birkenmeier G, et al. Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol. (2003) 170:3037–45. doi: 10.4049/jimmunol.170.6.3037
73. Li F, Wang Y, Lin L, Wang J, Xiao H, Li J, et al. Mast cell-derived exosomes promote th2 cell differentiation via OX40L-OX40 ligation. J Immunol Res. (2016) 2016:3623898. doi: 10.1155/2016/3623898
74. Wang J, Gu S, and Qin B. Eosinophil and mast cell-derived exosomes promote integrity of intestinal mucosa via the NEAT1/miR-211-5p/glial cell line-derived neurotrophic factor axis in duodenum. Environ Toxicol. (2023) 38:2595–607. doi: 10.1002/tox.23895
75. Mellman I and Steinman RM. Dendritic cells: specialized and regulated antigen processing machines. Cell. (2001) 106:255–8. doi: 10.1016/S0092-8674(01)00449-4
76. Zitvogel L, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med. (1998) 4:594–600. doi: 10.1038/nm0598-594
77. Théry C, Duban L, Segura E, Véron P, Lantz O, and Amigorena S. Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol. (2002) 3:1156–62.
78. André F, Chaput N, Schartz NE, Flament C, Aubert N, Bernard J, et al. Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol. (2004) 172:2126–36. doi: 10.4049/jimmunol.172.4.2126
79. Wei G, Jie Y, Haibo L, Chaoneng W, Dong H, Jianbing Z, et al. Dendritic cells derived exosomes migration to spleen and induction of inflammation are regulated by CCR7. Sci Rep. (2017) 7:42996. doi: 10.1038/srep42996
80. Hao S, Bai O, Li F, Yuan J, Laferte S, and Xiang J. Mature dendritic cells pulsed with exosomes stimulate efficient cytotoxic T-lymphocyte responses and antitumour immunity. Immunology. (2007) 120:90–102. doi: 10.1111/j.1365-2567.2006.02483.x
81. Segura E, Nicco C, Lombard BRR, Véron P, Raposo GA, Batteux FDR, et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood. (2005) 106:216–23. doi: 10.1182/blood-2005-01-0220
82. Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, et al. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood. (2012) 119:756–66. doi: 10.1182/blood-2011-02-338004
83. Sobo-Vujanovic A, Munich S, and Vujanovic NL. Dendritic-cell exosomes cross-present Toll-like receptor-ligands and activate bystander dendritic cells. Cell Immunol. (2014) 289:119–27. doi: 10.1016/j.cellimm.2014.03.016
84. Yang X, Meng S, Jiang H, Zhu C, and Wu W. Exosomes derived from immature bone marrow dendritic cells induce tolerogenicity of intestinal transplantation in rats. J Surg Res. (2011) 171:826–32. doi: 10.1016/j.jss.2010.05.021
85. Cai Z, Zhang W, Yang F, Yu L, Yu Z, Pan J, et al. Immunosuppressive exosomes from TGF-β1 gene-modified dendritic cells attenuate Th17-mediated inflammatory autoimmune disease by inducing regulatory T cells. Cell Res. (2012) 22:607–10. doi: 10.1038/cr.2011.196
86. Elashiry M, Elashiry MM, Elsayed R, Rajendran M, Auersvald C, Zeitoun R, et al. Dendritic cell derived exosomes loaded with immunoregulatory cargo reprogram local immune responses and inhibit degenerative bone disease in vivo. J Extracell Vesicles. (2020) 9:1795362. doi: 10.1080/20013078.2020.1795362
87. Kim SH, Lechman ER, Bianco N, Menon R, Keravala A, Nash J, et al. Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis. J Immunol. (2005) 174:6440–8. doi: 10.4049/jimmunol.174.10.6440
88. Kim SH, Bianco N, Menon R, Lechman ER, Shufesky WJ, Morelli AE, et al. Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol Ther. (2006) 13:289–300. doi: 10.1016/j.ymthe.2005.09.015
89. McDonald MK, Tian Y, Qureshi RA, Gormley M, Ertel A, Gao R, et al. Functional significance of macrophage-derived exosomes in inflammation and pain. Pain. (2014) 155:1527–39. doi: 10.1016/j.pain.2014.04.029
90. Ye C, Li H, Bao M, Zhuo R, Jiang G, and Wang W. Alveolar macrophage - derived exosomes modulate severity and outcome of acute lung injury. Aging (Albany NY). (2020) 12:6120–8. doi: 10.18632/aging.103010
91. Ma F, Zhang S, Akanyibah FA, Zhang W, Chen K, Ocansey DKW, et al. Exosome-mediated macrophage regulation for inflammatory bowel disease repair: a potential target of gut inflammation. Am J Transl Res. (2023) 15:6970–87.
92. Han D, Lu D, Huang S, Pang J, Wu Y, Hu J, et al. Small extracellular vesicles from Ptpn1-deficient macrophages alleviate intestinal inflammation by reprogramming macrophage polarization via lactadherin enrichment. Redox Biol. (2022) 58:102558. doi: 10.1016/j.redox.2022.102558
93. Yang R, Liao Y, Wang L, He P, Hu Y, Yuan D, et al. Exosomes derived from M2b macrophages attenuate DSS-induced colitis. Front Immunol. (2019) 10:2346. doi: 10.3389/fimmu.2019.02346
94. Deng F, Yan J, Lu J, Luo M, Xia P, Liu S, et al. M2 Macrophage-Derived Exosomal miR-590-3p Attenuates DSS-Induced Mucosal Damage and Promotes Epithelial Repair via the LATS1/YAP/β-Catenin Signalling Axis. J Crohns Colitis. (2021) 15:665–77. doi: 10.1093/ecco-jcc/jjaa214
95. Liu G, Cao R, Liu Q, Li H, Yan P, Wang K, et al. M2 macrophages-derived exosomes for osteonecrosis of femoral head treatment: modulating neutrophil extracellular traps formation and endothelial phenotype transition. Bone Res. (2025) 13:42. doi: 10.1038/s41413-025-00412-5
96. Zhang J, Liu SC, Luo XH, Tao GX, Guan M, Yuan H, et al. Exosomal long noncoding RNAs are differentially expressed in the cervicovaginal lavage samples of cervical cancer patients. J Clin Lab Anal. (2016) 30:1116–21. doi: 10.1002/jcla.21990
97. Wang YX, Lin C, Cui LJ, Deng TZ, Li QM, Chen FY, et al. Mechanism of M2 macrophage-derived extracellular vesicles carrying lncRNA MEG3 in inflammatory responses in ulcerative colitis. Bioengineered. (2021) 12:12722–39. doi: 10.1080/21655979.2021.2010368
98. Wang Y, Ma H, Zhang X, Xiao X, and Yang Z. The increasing diagnostic role of exosomes in inflammatory diseases to leverage the therapeutic biomarkers. J Inflammation Res. (2024) 17:5005–24.
99. Smyth LA, Ratnasothy K, Tsang JY, Boardman D, Warley A, Lechler R, et al. CD73 expression on extracellular vesicles derived from CD4+ CD25+ Foxp3+ T cells contributes to their regulatory function. Eur J Immunol. (2013) 43:2430–40. doi: 10.1002/eji.201242909
100. Okoye IS, Coomes SM, Pelly VS, Czieso S, Papayannopoulos V, Tolmachova T, et al. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity. (2014) 41:89–103. doi: 10.1016/j.immuni.2014.05.019
101. Bryniarski K, Ptak W, Jayakumar A, Püllmann K, Caplan MJ, Chairoungdua A, et al. Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity. J Allergy Clin Immunol. (2013) 132:170–181.e9. doi: 10.1016/j.jaci.2013.04.048
102. Xie Y, Zhang X, Zhao T, Li W, Xiang J, et al. Natural CD8+25+ regulatory T cell-secreted exosomes capable of suppressing cytotoxic T lymphocyte-mediated immunity against B16 melanoma. Biochem Biophys Res Commun. (2013) 438:152–5. doi: 10.1016/j.bbrc.2013.07.044
103. Wang GJ, Liu Y, Qin A, Shah SV, Deng ZB, Xiang X, et al. Thymus exosomes-like particles induce regulatory T cells. J Immunol. (2008) 181:5242–8. doi: 10.4049/jimmunol.181.8.5242
104. Azimi M, Ghabaee M, Moghadasi AN, Noorbakhsh F, and Izad M. Immunomodulatory function of Treg-derived exosomes is impaired in patients with relapsing-remitting multiple sclerosis. Immunol Res. (2018) 66:513–20. doi: 10.1007/s12026-018-9008-5
105. Tung SL, Boardman DA, Sen M, Letizia M, Peng Q, Cianci N, et al. Regulatory T cell-derived extracellular vesicles modify dendritic cell function. Sci Rep. (2018) 8:6065. doi: 10.1038/s41598-018-24531-8
106. Xiong YY, Gong ZT, Tang RJ, and Yang YJ. The pivotal roles of exosomes derived from endogenous immune cells and exogenous stem cells in myocardial repair after acute myocardial infarction. Theranostics. (2021) 11:1046–58. doi: 10.7150/thno.53326
107. Federici C, Shahaj E, Cecchetti S, Camerini S, Casella M, Iessi E, et al. Natural-killer-derived extracellular vesicles: immune sensors and interactors. Front Immunol. (2020) 11:262. doi: 10.3389/fimmu.2020.00262
108. Si C, Gao J, and Ma X. Natural killer cell-derived exosome-based cancer therapy: from biological roles to clinical significance and implications. Mol Cancer. (2024) 23:134. doi: 10.1186/s12943-024-02045-4
109. Muntasell A, Berger AC, and Roche PA. T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. EMBO J. (2007) 26:4263–72. doi: 10.1038/sj.emboj.7601842
110. Xiong J, Chi H, Yang G, Zhao S, Zhang J, Tran LJ, et al. Revolutionizing anti-tumor therapy: unleashing the potential of B cell-derived exosomes. Front Immunol. (2023) 14:1188760. doi: 10.3389/fimmu.2023.1188760
111. Butin-Israeli V, Bui TM, Wiesolek HL, Mascarenhas L, Lee JJ, Mehl LC, et al. Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing. J Clin Invest. (2019) 129:712–26. doi: 10.1172/JCI122085
112. Hsu AY, Huang Q, Pi X, Fu J, Raghunathan K, Ghimire L, et al. Neutrophil-derived vesicles control complement activation to facilitate inflammation resolution. Cell. (2025) 188:1623–1641.e26. doi: 10.1016/j.cell.2025.01.021
113. Wellington VNA, Sundaram VL, Singh S, and Sundaram U. Dietary supplementation with vitamin D, fish oil or resveratrol modulates the gut microbiome in inflammatory bowel disease. Int J Mol Sci. (2021) 23. doi: 10.3390/ijms23010206
114. Garavaglia B, Vallino L, Amoruso A, Pane M, Ferraresi A, and Isidoro C. The role of gut microbiota, immune system, and autophagy in the pathogenesis of inflammatory bowel disease: Molecular mechanisms and therapeutic approaches. Aspects Mol Med. (2024) 4:100056. doi: 10.1016/j.amolm.2024.100056
115. Belkaid Y and Timothy W. Hand, role of the microbiota in immunity and inflammation. Cell. (2014) 157:121–41. doi: 10.1016/j.cell.2014.03.011
116. Mobarak H, Javid F, Narmi MT, Mardi N, Sadeghsoltani F, Khanicheragh P, et al. Prokaryotic microvesicles Ortholog of eukaryotic extracellular vesicles in biomedical fields. Cell Communication Signaling. (2024) 22:80. doi: 10.1186/s12964-023-01414-8
117. Díaz-Garrido N, Badia J, and Baldomà L. Microbiota-derived extracellular vesicles in interkingdom communication in the gut. J Extracell Vesicles. (2021) 10:e12161.
118. Margutti P, D’Ambrosio A, and Zamboni S. Microbiota-derived extracellular vesicle as emerging actors in host interactions. Int J Mol Sci. (2024) 25:8722. doi: 10.3390/ijms25168722
119. Shen Y, Torchia MLG, Lawson GW, Christopher Karp CL, Ashwell JD, et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe. (2012) 12:509–20. doi: 10.1016/j.chom.2012.08.004
120. Champagne-Jorgensen K, Mian MF, McVey Neufeld KA, Stanisz AM, and Bienenstock J. Membrane vesicles of Lacticaseibacillus rhamnosus JB-1 contain immunomodulatory lipoteichoic acid and are endocytosed by intestinal epithelial cells. Sci Rep. (2021) 11:13756. doi: 10.1038/s41598-021-93311-8
121. Fábrega MJ, Aguilera L, Giménez R, Varela E, Alexandra Cañas M, Antolín A, et al. Activation of immune and defense responses in the intestinal mucosa by outer membrane vesicles of commensal and probiotic escherichia coli strains. Front Microbiol. (2016) 7:705. doi: 10.3389/fmicb.2016.00705
122. Al-Nedawi K, Mian MF, Hossain N, Karimi K, Mao YK, Forsythe P, et al. Gut commensal microvesicles reproduce parent bacterial signals to host immune and enteric nervous systems. FASEB J. (2015) 29:684–95. doi: 10.1096/fj.14-259721
123. López P, González-Rodríguez I, Sánchez B, Gueimonde M, Margolles A, Suárez A, et al. Treg-inducing membrane vesicles from Bifidobacterium bifidum LMG13195 as potential adjuvants in immunotherapy. Vaccine. (2012) 30:825–9. doi: 10.1016/j.vaccine.2011.11.115
124. Hu R, Lin H, Li J, Zhao Y, Wang M, Sun X, et al. Probiotic Escherichia coli Nissle 1917-derived outer membrane vesicles enhance immunomodulation and antimicrobial activity in RAW264.7 macrophages. BMC Microbiol. (2020) 20:268. doi: 10.1186/s12866-020-01953-x
125. Diaz-Garrido N, Fábrega MJ, Vera R, Giménez R, Badia J, and Baldomà L. Membrane vesicles from the probiotic Nissle 1917 and gut resident Escherichia coli strains distinctly modulate human dendritic cells and subsequent T cell responses. J Funct Foods. (2019) 61:103495. doi: 10.1016/j.jff.2019.103495
126. Díaz-Garrido N, Bonnin S, Riera M, Gíménez R, Badia J, and Baldomà L. Transcriptomic microRNA profiling of dendritic cells in response to gut microbiota-secreted vesicles. Cells. (2020) 9. doi: 10.3390/cells9061534
127. Alvarez CS, Badia J, Bosch M, Giménez R, and Baldomà L. Outer membrane vesicles and soluble factors released by probiotic escherichia coli nissle 1917 and commensal ECOR63 enhance barrier function by regulating expression of tight junction proteins in intestinal epithelial cells. Front Microbiol. (2016) 7:1981. doi: 10.3389/fmicb.2016.01981
128. Alvarez CS, Giménez R, Cañas MA, Vera R, Díaz-Garrido N, Badia J, et al. Extracellular vesicles and soluble factors secreted by Escherichia coli Nissle 1917 and ECOR63 protect against enteropathogenic E. coli-induced intestinal epithelial barrier dysfunction. BMC Microbiol. (2019) 19:166. doi: 10.1186/s12866-019-1534-3
129. Klotskova HB, Kidess E, Nadal AL, and Brugman S. The role of interleukin-22 in mammalian intestinal homeostasis: Friend and foe. Immun Inflammation Dis. (2024) 12:e1144. doi: 10.1002/iid3.1144
130. Ashrafian F, Behrouzi A, Shahriary A, Ahmadi Badi S, Davari M, Khatami S, et al. Comparative study of effect of Akkermansia muciniphila and its extracellular vesicles on toll-like receptors and tight junction. Gastroenterol Hepatol Bed Bench. (2019) 12:163–8.
131. Wang X, Lin S, Wang L, Cao Z, Zhang M, Zhang Y, et al. Versatility of bacterial outer membrane vesicles in regulating intestinal homeostasis. Sci Adv. (2023) 9:eade5079. doi: 10.1126/sciadv.ade5079
132. Jones EJ, Booth C, Fonseca S, Parker A, Cross K, Miquel-Clopés A, et al. Uptake trafficking, and biodistribution of bacteroides thetaiotaomicron generated outer membrane vesicles. Front Microbiol. (2020) 11:57. doi: 10.3389/fmicb.2020.00057
133. Amabebe E, Kumar A, Tatiparthy M, Kammala AK, Taylor BD, and Menon R. Cargo exchange between human and bacterial extracellular vesicles in gestational tissues: a new paradigm in communication and immune development. Extracellular Vesicles Circulating Nucleic Acids. (2024) 5:297–328. doi: 10.20517/evcna.2024.21
134. Li Z, Clarke AJ, and Beveridge TJ. Gram-negative bacteria produce membrane vesicles which are capable of killing other bacteria. J Bacteriol. (1998) 180:5478–83. doi: 10.1128/JB.180.20.5478-5483.1998
135. Dean SN, Rimmer MA, Turner KB, Phillips DA, Caruana JC, Hervey WJ, et al. Lactobacillus acidophilus membrane vesicles as a vehicle of bacteriocin delivery. Front Microbiol. (2020) 11. doi: 10.3389/fmicb.2020.00710
136. Olivo-Martínez Y, Martínez-Ruiz S, Cordero C, BadiaJ, and Baldoma L. Extracellular Vesicles of the Probiotic Escherichia coli Nissle 1917 Reduce PepT1 Levels in IL-1β-Treated Caco-2 Cells via Upregulation of miR-193a-3p. Nutrients. (2024) 16.
137. Zhang YZ and Li YY. Inflammatory bowel disease: pathogenesis. World J Gastroenterol. (2014) 20:91–9. doi: 10.3748/wjg.v20.i1.91
138. Mousa RS, Invernizzi P, and Mousa HS. Innate immune cells in the pathogenesis of inflammatory bowel disease - from microbial metabolites to immune modulation. Front Gastroenterol. (2024) 3. doi: 10.3389/fgstr.2024.1452430
139. Shi N, Li N, Duan X, and Niu H. Interaction between the gut microbiome and mucosal immune system. Mil Med Res. (2017) 4:14. doi: 10.1186/s40779-017-0122-9
140. Zheng X, Chen F, Zhang Q, Liu Y, You P, Sun S, et al. Salivary exosomal PSMA7: a promising biomarker of inflammatory bowel disease. Protein Cell. (2017) 8:686–95. doi: 10.1007/s13238-017-0413-7
141. Yang C, Chen J, Zhao Y, Wu J, Xu Y, Xu J, et al. Salivary exosomes exacerbate colitis by bridging the oral cavity and intestine. iScience. (2024) 27:111061. doi: 10.1016/j.isci.2024.111061
142. Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. (2010) 12:19–30. doi: 10.1038/ncb2000
143. Gallo A, Tandon M, Alevizos I, and Illei GG. The majority of microRNAs detectable in serum and saliva is concentrated in exosomes. PLoS One. (2012) 7:e30679. doi: 10.1371/journal.pone.0030679
144. Wani S, Man Law IK, and Pothoulakis C. Role and mechanisms of exosomal miRNAs in IBD pathophysiology. Am J Physiol Gastrointest Liver Physiol. (2020) 319:G646–g654. doi: 10.1152/ajpgi.00295.2020
145. Gong L, Xiao J, Yi J, Xiao J, Lu F, and Liu X. Immunomodulatory effect of serum exosomes from crohn disease on macrophages via let-7b-5p/TLR4 signaling. Inflammation Bowel Dis. (2022) 28:96–108. doi: 10.1093/ibd/izab132
146. Zhao F, Zheng T, Gong W, Wu J, Xie H, Li W, et al. Extracellular vesicles package dsDNA to aggravate Crohn’s disease by activating the STING pathway. Cell Death Dis. (2021) 12:815. doi: 10.1038/s41419-021-04101-z
147. Shao J, Jin Y, Shao C, Fan H, Wang X, and Yang G. Serum exosomal pregnancy zone protein as a promising biomarker in inflammatory bowel disease. Cell Mol Biol Lett. (2021) 26:36. doi: 10.1186/s11658-021-00280-x
148. Mitsuhashi S, Feldbrügge L, Csizmadia E, Mitsuhashi M, Robson SC, and Moss AC. Luminal extracellular vesicles (EVs) in inflammatory bowel disease (IBD) exhibit proinflammatory effects on epithelial cells and macrophages. Inflammation Bowel Dis. (2016) 22:1587–95. doi: 10.1097/MIB.0000000000000840
149. Du R, Chen S, Han C, He Z, Pei H, and Yang Y. M1 intestinal macrophages-derived exosomes promote colitis progression and mucosal barrier injury. Aging (Albany NY). (2024) 16:5703–10. doi: 10.18632/aging.205672
150. Liu H, Liang Z, Wang F, Zheng X, Zeng Z, He X, et al. Intestinal CD14+ Macrophages protect CD4+ T cells from activation-induced cell death via exosomal membrane TNF in crohn’s disease. J Crohn’s Colitis. (2020) 14:1619–31. doi: 10.1093/ecco-jcc/jjaa083
151. Zeng Z, Cheng S, Li X, Liu H, Lin J, Liang Z, et al. Glycolytic activation of CD14+ Intestinal macrophages contributes to the inflammatory responses via exosomal membrane tumor necrosis factor in crohn’s disease. Inflammatory Bowel Dis. (2023) 30:90–102.
152. Liu R, Tang A, Wang X, Chen X, Zhao L, Xiao Z, et al. Inhibition of lncRNA NEAT1 suppresses the inflammatory response in IBD by modulating the intestinal epithelial barrier and by exosome-mediated polarization of macrophages. Int J Mol Med. (2018) 42:2903–13. doi: 10.3892/ijmm.2018.3829
153. Pan S, Liu R, Wu X, Ma K, Luo W, Nie K, et al. LncRNA NEAT1 mediates intestinal inflammation by regulating TNFRSF1B. Ann Trans Med. (2021) 9:773. doi: 10.21037/atm-21-34
154. Ouyang W, Wu M, Wu A, and and Xiao H. Circular RNA_0001187 participates in the regulation of ulcerative colitis development via upregulating myeloid differentiation factor 88. Bioengineered. (2022) 13:12863–75. doi: 10.1080/21655979.2022.2077572
155. Subra C, Grand D, Laulagnier K, Stella A, Lambeau G, Paillasse M, et al. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins[S. J Lipid Res. (2010) 51:2105–20. doi: 10.1194/jlr.M003657
156. Zhang J, Fu S, Sun S, Li Z, and and Guo B. Inflammasome activation has an important role in the development of spontaneous colitis. Mucosal Immunol. (2014) 7:1139–50. doi: 10.1038/mi.2014.1
157. Martín-Sánchez F, Diamond C, Zeitler M, Gomez AI, Baroja-Mazo A, Bagnall J, et al. Inflammasome-dependent IL-1β release depends upon membrane permeabilisation. Cell Death Differentiation. (2016) 23:1219–31.
158. Li X, Ji LJ, Feng KD, Huang H, Liang MR, Cheng SJ, et al. Emerging role of exosomes in ulcerative colitis: Targeting NOD-like receptor family pyrin domain containing 3 inflammasome. World J Gastroenterol. (2024) 30:527–41. doi: 10.3748/wjg.v30.i6.527
159. Qu Y, Ramachandra L, Mohr S, Franchi L, Harding CV, Nunez G, et al. P2X7 receptor-stimulated secretion of MHC class II-containing exosomes requires the ASC/NLRP3 inflammasome but is independent of caspase-1. J Immunol. (2009) 182:5052–62. doi: 10.4049/jimmunol.0802968
160. Wan P, Liu X, Xiong Y, Ren Y, Chen J, Lu Ns, et al. Extracellular ATP mediates inflammatory responses in colitis via P2 × 7 receptor signaling. Sci Rep. (2016) 6:19108. doi: 10.1038/srep19108
161. Cheng N, Zhang L, and Liu L. Understanding the role of purinergic P2X7 receptors in the gastrointestinal system: A systematic review. Front Pharmacol. (2021) 12:786579. doi: 10.3389/fphar.2021.786579
162. Santana PT, de Lima IS, Silva ESKCD, Barbosa PHS, and de Souza HSP. Persistent activation of the P2X7 receptor underlies chronic inflammation and carcinogenic changes in the intestine. Int J Mol Sci. (2024) 25. doi: 10.3390/ijms252010874
163. Bulek K, Zhao J, Liao Y, Rana N, Corridoni D, Antanaviciute A, et al. Epithelial-derived gasdermin D mediates nonlytic IL-1β release during experimental colitis. J Clin Invest. (2020) 130:4218–34. doi: 10.1172/JCI138103
164. Jin J, Jung M, Sonn SK, Seo S, Suh J, Kweon HY, et al. Peroxiredoxin 3 Deficiency Exacerbates DSS-Induced Acute Colitis via Exosomal miR-1260b-Mediated Barrier Disruption and Proinflammatory Signaling. Antioxid Redox Signal. (2025) 42:133–49. doi: 10.1089/ars.2023.0482
165. Chen J and Vitetta L. Is miR-223 upregulation in inflammatory bowel diseases a protective response? Front Biosci (Elite Ed). (2023) 15:5. doi: 10.31083/j.fbe1501005
166. Li M, Zhao J, Cao M, Liu R, Chen G, Li Ss, et al. Mast cells-derived MiR-223 destroys intestinal barrier function by inhibition of CLDN8 expression in intestinal epithelial cells. Biol Res. (2020) 53:12. doi: 10.1186/s40659-020-00279-2
167. Wang X, Zhou G, Zhou W, Wang X, Wang X, and Miao C. Exosomes as a new delivery vehicle in inflammatory bowel disease. Pharmaceutics. (2021) 13:1644. doi: 10.3390/pharmaceutics13101644
168. Neudecker V, Haneklaus M, Jensen O, Khailova L, Masterson JC, Tye H, et al. Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. J Exp Med. (2017) 214:1737–52. doi: 10.1084/jem.20160462
169. Jiao P, Wang XP, Luoreng ZM, Yang J, Jia L, Ma Y, et al. miR-223: an effective regulator of immune cell differentiation and inflammation. Int J Biol Sci. (2021) 17:2308–22. doi: 10.7150/ijbs.59876
170. D’Alessio S, Ungaro F, Noviello D, Lovisa S, Peyrin-Biroulet L, and Danese S. Revisiting fibrosis in inflammatory bowel disease: the gut thickens. Nat Rev Gastroenterol Hepatol. (2022) 19:169–84. doi: 10.1038/s41575-021-00543-0
171. Ihara S, Hirata Y, and Koike K. TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota. J Gastroenterol. (2017) 52:777–87. doi: 10.1007/s00535-017-1350-1
172. Chen Y, Xiao Y, Ge W, Zhou K, Wen J, Yan W, et al. miR-200b inhibits TGF-β1-induced epithelial-mesenchymal transition and promotes growth of intestinal epithelial cells. Cell Death Dis. (2013) 4:e541. doi: 10.1038/cddis.2013.22
173. Cheng Z, Yang L, and Chu H. The role of gut microbiota, exosomes, and their interaction in the pathogenesis of ALD. J Advanced Res. (2025) 72:353–67. doi: 10.1016/j.jare.2024.07.002
174. Ando Y, Mazzurana L, Forkel M, Okazaki K, Aoi M, Schmidt PT, et al. Downregulation of microRNA-21 in colonic CD3+ T cells in UC remission. Inflammatory Bowel Dis. (2016) 22:2788–93. doi: 10.1097/MIB.0000000000000969
175. Yang Y, Ma Y, Shi C, Chen H, Zhang H, Chen N, et al. Overexpression of miR-21 in patients with ulcerative colitis impairs intestinal epithelial barrier function through targeting the Rho GTPase RhoB. Biochem Biophys Res Commun. (2013) 434:746–52. doi: 10.1016/j.bbrc.2013.03.122
176. Patel M, Valaiyaduppu Subas S, Ghani MR, Busa V, Dardeir A, Marudhai S, et al. Role of substance P in the pathophysiology of inflammatory bowel disease and its correlation with the degree of inflammation. Cureus. (2020) 12:e11027. doi: 10.7759/cureus.11027
177. Lan J, Deng Z, Wang Q, Li D, Fan K, Chang J, et al. Neuropeptide substance P attenuates colitis by suppressing inflammation and ferroptosis via the cGAS-STING signaling pathway. Int J Biol Sci. (2024) 20:2507–31. doi: 10.7150/ijbs.94548
178. Bakirtzi K, Man Law IK, Fang K, Iliopoulos D, and Pothoulakis C. MiR-21 in Substance P-induced exosomes promotes cell proliferation and migration in human colonic epithelial cells. Am J Physiology-Gastrointestinal Liver Physiol. (2019) 317:G802–10. doi: 10.1152/ajpgi.00043.2019
179. Shi C, Liang Y, Yang J, Xia Y, Chen H, Han H, et al. MicroRNA-21 knockout improve the survival rate in DSS induced fatal colitis through protecting against inflammation and tissue injury. PLoS One. (2013) 8:e66814. doi: 10.1371/journal.pone.0066814
180. Li L, Huang S, Wang H, Chao K, Ding L, Feng R, et al. Cytokine IL9 triggers the pathogenesis of inflammatory bowel disease through the miR21-CLDN8 pathway. Inflammation Bowel Dis. (2018) 24:2211–23. doi: 10.1093/ibd/izy187
181. Wu F, Dong F, Arendovich N, Zhang J, Huang Y, and Kwon JH. Divergent influence of microRNA-21 deletion on murine colitis phenotypes. Inflammation Bowel Dis. (2014) 20:1972–85. doi: 10.1097/MIB.0000000000000201
182. Lu J, Liu D, Tan Y, Deng F, and and Li R. M1 Macrophage exosomes MiR-21a-5p aggravates inflammatory bowel disease through decreasing E-cadherin and subsequent ILC2 activation. J Cell Mol Med. (2021) 25:3041–50. doi: 10.1111/jcmm.16348
183. Chang X, Song YH, Xia T, He ZX, Zhao SB, Wang ZJ, et al. Macrophage-derived exosomes promote intestinal mucosal barrier dysfunction in inflammatory bowel disease by regulating TMIGD1 via mircroRNA-223. Int Immunopharmacol. (2023) 121:110447. doi: 10.1016/j.intimp.2023.110447
184. Wang H, Chao K, Ng SC, Bai AH, Yu Q, Yu J, et al. Pro-inflammatory miR-223 mediates the cross-talk between the IL23 pathway and the intestinal barrier in inflammatory bowel disease. Genome Biol. (2016) 17:58. doi: 10.1186/s13059-016-0901-8
185. Heydari R, Karimi P, and Meyfour A. Long non-coding RNAs as pathophysiological regulators, therapeutic targets and novel extracellular vesicle biomarkers for the diagnosis of inflammatory bowel disease. BioMed Pharmacother. (2024) 176:116868. doi: 10.1016/j.biopha.2024.116868
186. de Gassart A, Geminard C, Fevrier B, Raposo G, and Vidal M. Lipid raft-associated protein sorting in exosomes. Blood. (2003) 102:4336–44. doi: 10.1182/blood-2003-03-0871
187. Lambert D, O’Neill CA, and Padfield PJ. Depletion of Caco-2 cell cholesterol disrupts barrier function by altering the detergent solubility and distribution of specific tight-junction proteins. Biochem J. (2005) 387:553–60. doi: 10.1042/BJ20041377
188. Shigetomi K, Ono Y, Matsuzawa K, and Ikenouchi J. Cholesterol-rich domain formation mediated by ZO proteins is essential for tight junction formation. Proc Natl Acad Sci U.S.A. (2023) 120:e2217561120. doi: 10.1073/pnas.2217561120
189. Bowie RV, Donatello S, Lyes C, Owens MB, Babina IS, Hudson L, et al. Lipid rafts are disrupted in mildly inflamed intestinal microenvironments without overt disruption of the epithelial barrier. Am J Physiol Gastrointest Liver Physiol. (2012) 302:G781–93. doi: 10.1152/ajpgi.00002.2011
190. Carrière J, Bretin A, Darfeuille-Michaud A, Barnich N, and Nguyen HT. Exosomes released from cells infected with crohn’s disease-associated adherent-invasive escherichia coli activate host innate immune responses and enhance bacterial intracellular replication. Inflammation Bowel Dis. (2016) 22:516–28.
191. Xu Y, Qian W, Huang L, Wen W, Li Y, Guo F, et al. Crohn’s disease-associated AIEC inhibiting intestinal epithelial cell-derived exosomal let-7b expression regulates macrophage polarization to exacerbate intestinal fibrosis. Gut Microbes. (2023) 15:2193115. doi: 10.1080/19490976.2023.2193115
192. Larabi A, Dalmasso G, Delmas J, Barnich N, and Nguyen HTT. Exosomes transfer miRNAs from cell-to-cell to inhibit autophagy during infection with Crohn’s disease-associated adherent-invasive E. coli. Gut Microbes. (2020) 11:1677–94. doi: 10.1080/19490976.2020.1771985
193. Wei S, Wu X, Chen M, Xiang Z, Li X, Zhang J, et al. Exosomal-miR-129-2-3p derived from Fusobacterium nucleatum-infected intestinal epithelial cells promotes experimental colitis through regulating TIMELESS-mediated cellular senescence pathway. Gut Microbes. (2023) 15:2240035. doi: 10.1080/19490976.2023.2240035
194. Cao Y, Wang Z, Yan Y, Ji L, He J, Xuan B, et al. Enterotoxigenic bacteroidesfragilis promotes intestinal inflammation and Malignancy by inhibiting exosome-packaged miR-149-3p. Gastroenterology. (2021) 161:1552–1566.e12.
195. Deng Z, Mu J, Tseng M, Wattenberg B, Zhuang X, Egilmez NK, et al. Enterobacteria-secreted particles induce production of exosome-like S1P-containing particles by intestinal epithelium to drive Th17-mediated tumorigenesis. Nat Commun. (2015) 6:6956. doi: 10.1038/ncomms7956
196. Liu S, da Cunha AP, Rezende RM, Cialic R, Wei Z, Bry L, et al. The host shapes the gut microbiota via fecal microRNA. Cell Host Microbe. (2016) 19:32–43. doi: 10.1016/j.chom.2015.12.005
197. Casado-Bedmar M, Roy M, Berthet L, Hugot JP, Yang C, Manceau H, et al. Fecal let-7b and miR-21 directly modulate the intestinal microbiota, driving chronic inflammation. Gut Microbes. (2024) 16:2394249. doi: 10.1080/19490976.2024.2394249
198. Ma X, Liu B, Fan L, Liu Y, Zhao Y, Ren T, et al. Native and engineered exosomes for inflammatory disease. Nano Res. (2023) 16:6991–7006. doi: 10.1007/s12274-022-5275-5
199. Donoso-Meneses D, Figueroa-Valdés AI, Khoury M, and Alcayaga-Miranda F. Oral administration as a potential alternative for the delivery of small extracellular vesicles. Pharmaceutics. (2023) 15. doi: 10.3390/pharmaceutics15030716
200. Gao F, Wu S, Zhang K, Xu Z, Zhang X, Zhu Z, et al. Goat milk exosomes ameliorate ulcerative colitis in mice through modulation of the intestinal barrier, gut microbiota, and metabolites. J Agric Food Chem. (2024) 72:23196–210. doi: 10.1021/acs.jafc.4c03212
201. Reif S, Elbaum-Shiff Y, Koroukhov N, Shilo I, Musseri M, and Golan-Gerstl R. Cow and human milk-derived exosomes ameliorate colitis in DSS murine model. Nutrients. (2020) 12:2589. doi: 10.3390/nu12092589
202. López de las Hazas M-C, del Pozo-Acebo L, Hansen MS, Gil-Zamorano J, Mantilla-Escalante DC, Gómez-Coronado D, et al. Dietary bovine milk miRNAs transported in extracellular vesicles are partially stable during GI digestion, are bioavailable and reach target tissues but need a minimum dose to impact on gene expression. Eur J Nutr. (2022) 61:1043–56. doi: 10.1007/s00394-021-02720-y
203. Heidari N, Abbasi-Kenarsari H, Namaki S, Baghaei K, Zali MR, Ghaffari Khaligh S, et al. Adipose-derived mesenchymal stem cell-secreted exosome alleviates dextran sulfate sodium-induced acute colitis by Treg cell induction and inflammatory cytokine reduction. J Cell Physiol. (2021) 236:5906–20. doi: 10.1002/jcp.30275
204. Xu X, Peng J, Wang N, Ocansey DKW, Zhang X, and Mao F. hucMSC-Ex alleviates inflammatory bowel disease in mice by enhancing M2-type macrophage polarization via the METTL3-Slc37a2-YTHDF1 axis. Cell Biol Toxicol. (2024) 40:74. doi: 10.1007/s10565-024-09921-1
205. Wang D, Xue H, Tan J, Liu P, Qiao C, Pang C, et al. Bone marrow mesenchymal stem cells-derived exosomes containing miR-539-5p inhibit pyroptosis through NLRP3/caspase-1 signalling to alleviate inflammatory bowel disease. Inflammation Res. (2022) 71:833–46. doi: 10.1007/s00011-022-01577-z
206. Wei Z, Hang S, Ocansey DKW, Zhang Z, Wang B, Zhang X, et al. Human umbilical cord mesenchymal stem cells derived exosome shuttling mir-129-5p attenuates inflammatory bowel disease by inhibiting ferroptosis. J Nanobiotechnology. (2023) 21:188. doi: 10.1186/s12951-023-01951-x
207. Cai X, Zhang Zy, Yuan J-t, Ocansey DKW, Tu Q, Zhang X, et al. hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis. Stem Cell Res Ther. (2021) 12:416. doi: 10.1186/s13287-021-02492-6
208. Heidari N, Abbasi-Kenarsari H, Namaki S, Baghaei K, Zali MR, Mirsanei Z, et al. Regulation of the Th17/Treg balance by human umbilical cord mesenchymal stem cell-derived exosomes protects against acute experimental colitis. Exp Cell Res. (2022) 419:113296. doi: 10.1016/j.yexcr.2022.113296
209. Liang X, Li C, Song J, Liu A, Wang C, Wang W, et al. HucMSC-exo promote mucosal healing in experimental colitis by accelerating intestinal stem cells and epithelium regeneration via wnt signaling pathway. Int J Nanomedicine. (2023) 18:2799–818. doi: 10.2147/IJN.S402179
210. Wang Y, Zhang Y, Lu B, Xi J, Ocansey DKW, Mao F, et al. hucMSC-ex alleviates IBD-associated intestinal fibrosis by inhibiting ERK phosphorylation in intestinal fibroblasts. Stem Cells Int. (2023) 2023:2828981. doi: 10.1155/2023/2828981
211. Yang JZ, He LY, and Lu XZ. The therapeutic potential of mesenchymal stem cells in intestinal diseases: from mechanisms to clinical translation. Stem Cell Res Ther. (2025) 16:393. doi: 10.1186/s13287-025-04523-y
212. Kheradmand F, Rahimzadeh SFY, Esmaeili SA, Negah SS, Farkhad NK, Nazari SE, et al. Efficacy of umbilical cord-derived mesenchymal stem cells and exosomes in conjunction with standard IBD drug on immune responses in an IBD mouse model. Stem Cell Res Ther. (2025) 16:5. doi: 10.1186/s13287-024-04062-y
213. Nazari H, Alborzi F, Heirani-Tabasi A, Hadizadeh A, Asbagh RA, Behboudi B, et al. Evaluating the safety and efficacy of mesenchymal stem cell-derived exosomes for treatment of refractory perianal fistula in IBD patients: clinical trial phase I. Gastroenterol Rep (Oxf). (2022) 10:goac075. doi: 10.1093/gastro/goac075
214. Zhang M, Viennois E, Prasad M, Zhang Y, Wang L, Zhang Z, et al. Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer. Biomaterials. (2016) 101:321–40. doi: 10.1016/j.biomaterials.2016.06.018
215. Yang S, Li W, Bai X, Di Nunzio G, Fan L, Zhao Y, et al. Ginseng-derived nanoparticles alleviate inflammatory bowel disease via the TLR4/MAPK and p62/Nrf2/Keap1 pathways. J Nanobiotechnology. (2024) 22:48. doi: 10.1186/s12951-024-02313-x
216. Sriwastva MK, Deng ZB, Wang B, Teng Y, Kumar A, Sundaram K, et al. Exosome-like nanoparticles from Mulberry bark prevent DSS-induced colitis via the AhR/COPS8 pathway. EMBO Rep. (2022) 23:e53365. doi: 10.15252/embr.202153365
217. Zhang M, Xu X, Su L, Zeng Y, Lin J, Li W, et al. Oral administration of Sophora Flavescens-derived exosomes-like nanovesicles carrying CX5461 ameliorates DSS-induced colitis in mice. J Nanobiotechnology. (2024) 22:607. doi: 10.1186/s12951-024-02856-z
218. Han G, Kim H, Jang H, Kim ES, Kim SH, and Yang Y. Oral TNF-α siRNA delivery via milk-derived exosomes for effective treatment of inflammatory bowel disease. Bioact Mater. (2024) 34:138–49. doi: 10.1016/j.bioactmat.2023.12.010
219. Liu Z, Yuan J, Wang L, AzharUd Din M, Tian Y, and Mao F. PLGA-hucMSC-ex ameliorates colitis by reversing epithelial-mesenchymal transition. Curr Stem Cell Res Ther. (2025) 9(6):1534. doi: 10.2174/011574888X344050250320233038
220. Xu X, Liu R, Zhou X, Zhang Z, Zhu T, Huang Y, et al. Characterization of exosomes derived from IPEC-J2 treated with probiotic Bacillus amyloliquefaciens SC06 and its regulation of macrophage functions. Front Immunol. (2022) 13:1033471. doi: 10.3389/fimmu.2022.1033471
221. Kou Y, Li J, Zhu Y, Liu J, Ren R, Jiang Y, et al. Human amniotic epithelial stem cells promote colonic recovery in experimental colitis via exosomal miR-23a-TNFR1-NF-κB signaling. Adv Sci (Weinh). (2024) 11:e2401429. doi: 10.1002/advs.202401429
222. Gong W, Liu Z, Wang Y, Huang W, Yang K, Gao Z, et al. Reprogramming of Treg cell-derived small extracellular vesicles effectively prevents intestinal inflammation from PANoptosis by blocking mitochondrial oxidative stress. Trends Biotechnol. (2025) 43:893–917. doi: 10.1016/j.tibtech.2024.11.017
Keywords: epithelial barrier function, exosomes, immune modulation, gut, inflammatory bowel disease, intestinal pathophysiology, intestinal physiology
Citation: Wellington VNA and Singh S (2026) Role of exosomes in gastrointestinal physiology and pathophysiology. Front. Immunol. 16:1717977. doi: 10.3389/fimmu.2025.1717977
Received: 10 October 2025; Accepted: 18 December 2025; Revised: 17 December 2025;
Published: 16 January 2026.
Edited by:
Marcello Chieppa, University of Salento, ItalyReviewed by:
Vini John, Children’s Hospital of Los Angeles, United StatesDiana Vardanyan, University of Salento, Italy
Copyright © 2026 Wellington and Singh. 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) and the copyright owner(s) 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: Soudamani Singh, c2luZ2hzQG1hcnNoYWxsLmVkdQ==