Kawasaki disease (KD) is an acute febrile illness and systemic vasculitis that predominantly affects children under 5 years old (1). This condition frequently results in cardiovascular complications, including coronary artery lesions (CALs), coronary aneurysms, systemic artery aneurysms, and myocarditis. In addition to these cardiovascular issues, gastrointestinal (GI) symptoms such as abdominal pain, vomiting, and diarrhea are commonly observed, particularly in severe cases (2, 3). These manifestations can lead to significant long-term cardiovascular complications, such as vascular remodeling—characterized by the thickening and stiffening of blood vessel walls due to chronic inflammation—and myocardial fibrosis, involving the excessive accumulation of scar tissue in the heart muscle. These complications increase the risk of ischemic heart disease, myocardial infarction, and even death, making KD the leading cause of acquired heart disease in children in developed countries (4). A major complication associated with KD is the development of CAL. Without timely treatment, approximately 25% of children with KD may develop CAL, significantly increasing the risk of long-term cardiovascular issues (5). However, treatment with high-dose intravenous immunoglobulin (IVIG) combined with aspirin can significantly reduce this risk (6). Despite these measures, 10%–20% of patients exhibit resistance to IVIG, leading to an increased risk of developing coronary artery aneurysms (5). These data underscore the critical need for early diagnosis and effective treatment strategies to mitigate severe cardiac outcomes in KD.

Recently, the GI manifestations of KD have attracted increasing scholarly attention as potentially significant contributors to the disease’s etiology. A notable multicenter retrospective study from Italy reported that 35% of KD patients presented with GI symptoms, which were independently associated with a higher risk of IVIG resistance and the development of coronary artery aneurysms (3). When GI symptoms precede the hallmark clinical features of KD, diagnosis and treatment may be delayed, potentially leading to unnecessary surgical interventions and a heightened risk of CAL (2, 3). This suggests that GI manifestations might not merely be a secondary symptom but could play a pivotal role in influencing KD’s clinical course.

While the precise cause of KD remains unclear, it likely originates from an aberrant immune response to environmental triggers in genetically susceptible individuals (7, 8). Key immune cells involved in KD pathogenesis include monocytes, platelets (PLT) (9), macrophages (10), neutrophils (11), CD8⁺ T cells (12), and antigen-specific IgA plasma cells (13). Monocytes and macrophages are early responders, producing proinflammatory cytokines like tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6, which amplify inflammation and contribute to vascular damage (10, 14). Activated PLT form aggregates with immune cells like monocytes, enhancing the release of proinflammatory cytokines such as IL-1β, contributing to the development of CAL and disease severity (9). Neutrophils, as the initial responders in acute inflammation, generate reactive oxygen species (ROS) that can damage the endothelium and stimulate the release of proinflammatory cytokines like IL-1β and TNF (11). CD8⁺ T cells are key contributors to the development of coronary arteritis in KD, infiltrating coronary tissues and driving inflammation that leads to vascular damage (12). These cellular elements are crucial in activating several signaling pathways that contribute to KD’s pathology. Notable among these are the CD40–CD40L signaling pathway (15), the interleukin (IL)-33–suppression of tumorigenicity 2 (ST2) axis (16), and the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome–IL-1 pathway (17), all of which play vital roles in the inflammatory and immune responses characteristic of KD.

As research into KD progresses, it is becoming increasingly evident that the interactions among the cardiovascular, immune, and GI systems are complex yet critical in determining the disease’s clinical trajectory. The recent recognition of GI manifestations as potential drivers of disease progression and therapeutic response opens new pathways for research and clinical intervention. This review aims to consolidate and analyze existing knowledge concerning the role of the GI tract in KD. By examining the intricate interactions within the GI system that may influence the pathogenesis of KD, it seeks to identify gaps in the current research and propose areas for future investigation. A deeper understanding of these mechanisms could contribute to the development of more effective diagnostic tools, targeted therapies, and comprehensive management strategies, ultimately improving patient outcomes in KD. This approach aligns with the broader objective of advancing the understanding and treatment methodologies for this condition.

Early recognition of GI symptoms in KD is crucial, as they often indicate a more severe disease course, with a higher likelihood of resistance to IVIG therapy and an increased incidence of CAL (2, 3). A multicenter retrospective study in Italy reported that 35% of children with KD displayed GI symptoms, which were identified as independent risk factors for IVIG resistance and the development of coronary artery aneurysms (3). Moreover, the early presentation of GI symptoms, rather than the characteristic clinical features of the disease, may delay diagnosis and treatment, potentially leading to unnecessary surgical interventions and an increased risk of CAL (2, 3). Furthermore, in a comprehensive domestic study involving 1,490 children with KD, patients were categorized into three groups based on the early appearance of GI symptoms relative to the typical KD phenotype. The study revealed that the rate of IVIG resistance was significantly higher in the GI symptom group compared to the control group, highlighting GI symptoms as a risk factor for IVIG unresponsiveness and CAL (18). Most recently, Huang et al. showed that children presenting with jaundice as a predominant symptom of KD have a higher risk of IVIG-refractory disease, CAL, and more frequent recurrence of KD symptoms (19). The pathophysiology of jaundice in KD remains unclear but is thought to involve several factors, including vasculitis of the hepatobiliary vessels, cystic duct wall edema, inflammation of the liver and gallbladder serosa, and cholangitis (19, 20). Notably, 58.3% of these patients also presented with GI symptoms, suggesting that GI mechanisms might play a significant role in the development of coronary artery aneurysms and IVIG resistance (19). In addition, some researchers propose that the GI tract may be the primary site of onset for KD (21). However, the role of the GI tract in the pathogenesis of KD and its related molecular mechanisms warrants further research. The association between GI symptoms and KD outcomes is summarized in Table 1 .

The intestinal barrier plays a vital role in maintaining overall health by regulating the entry of substances from the gut into the bloodstream. It selectively permits essential nutrients while blocking harmful agents and pathogens. This barrier’s protective function is achieved through three key components: the mucus layer, epithelial barrier, and gut vascular barrier (GVB) (23). The mucus layer is a protective gel-like coating that lines the intestines, preventing harmful substances and pathogens from reaching the epithelial cells (24). The epithelial barrier consists of tightly connected cells that defend against potential threats in the gut (25). Finally, the GVB regulates the movement of substances between the bloodstream and the gut, ensuring that only essential nutrients are absorbed while harmful substances are blocked (26). Together, these components facilitate the absorption of essential nutrients while preventing harmful substances and pathogens from entering the bloodstream. This helps protect the host physiology and regulate gut functions (27).

The exact etiology of KD remains unclear (8). Currently, KD is thought to be triggered by infectious agents interacting with genetic and environmental factors, leading to an abnormal immune response characterized by elevated inflammation in the acute phase (7, 68). Although infections are acknowledged as a significant factor in KD onset, the exact pathogens responsible remain unidentified (7). This review explores a critical pathway—the enhancement of gut permeability and its role as a catalyst for inflammatory responses in KD. The focus on gut permeability stems from recent research revealing its intricate interactions with the immune system, which may contribute to KD progression (69, 70). The following sections will discuss how impairments in gut barrier function could allow pathogens to enter the bloodstream from the gut, thereby initiating systemic inflammatory responses in individuals with KD.

The gut epithelial barrier serves as the body’s first line of defense, providing a separation from the external environment while facilitating nutrient absorption (27). This barrier is strengthened by microbial communities and their metabolites, along with structural and functional elements such as tight junctions, antimicrobial peptides, secretory immunoglobulin A (sIgA), and a protective mucus layer (27, 71). Together, these components foster a symbiotic relationship between the host and its microbiota, ensuring a stable and healthy gut environment (71). An increasing number of clinical and preclinical studies have identified impairments in intestinal epithelial barrier function in KD (1, 70, 72, 73). The direct consequence of gut barrier dysfunction is an increase in gut permeability (37). Factors impacting barrier function, such as imbalances in gut microbiota, changes in the expression of intercellular junction proteins (27), and decreased sIgA, can increase gut permeability (27, 74). Specifically, microbial dysbiosis can disrupt the composition of gut-resident communities, leading to changes in microbial metabolites, which impact the integrity of the gut barrier through modulation of TJ proteins and immune responses. This disruption often results in increased paracellular permeability, facilitating the translocation of antigens and triggering inflammatory pathways (27). sIgA plays a crucial role in maintaining gut barrier integrity by preventing the adherence and invasion of pathogens. It helps in immune exclusion by binding to microorganisms and toxins, thereby inhibiting their contact with epithelial cells. A decrease in sIgA can compromise this barrier function, leading to increased gut permeability and a higher risk of inflammation. The presence of sIgA is vital in sustaining a balanced interaction between the host and the gut microbiota, contributing to overall intestinal homeostasis (74). Recent studies have consistently highlighted the role of gut microbiota in KD, indicating a pattern of dysbiosis that could contribute to disease susceptibility and progression. Teramoto et al. demonstrated that dysbiosis—marked by an increase in proinflammatory Ruminococcus gnavus and a decrease in inflammation-suppressing Blautia—could heighten susceptibility to KD by affecting microbial diversity and inflammatory responses (68). Similarly, metagenomic analysis of Kinumaki et al. on 28 KD patients revealed a significant presence of Streptococcus spp. during the acute phase and Ruminococcus during the non-acute phase, suggesting specific bacterial roles in the disease’s progression (75). In alignment with these findings, Shen et al. found significant dysbiosis in children with acute KD, particularly a reduction in Bacteroidetes and Dorea—bacterial groups associated with healthy gut function—further linking altered microbiota to KD’s pathogenesis (76). Expanding on these insights, Chen et al. linked gut microbiota alterations with systemic inflammation in children with KD, noting that decreased fecal microbial diversity and increased inflammatory markers like IL-6 associated with specific bacteria such as Enterococcus and Helicobacter highlighting their potential role in exacerbating inflammatory responses in KD (77). Together, these studies provide a cohesive view of how shifts in gut microbiota—both in diversity and specific bacterial populations—might underpin KD’s immune dysfunction, warranting further exploration of gut-based interventions to mitigate disease severity. Although these studies primarily focus on gut microbiota alterations and their association with systemic inflammation in KD, they suggest a broader implication. Microbial dysbiosis can disrupt the composition of gut-resident communities, leading to changes in microbial metabolites. These alterations are known to affect the integrity of the gut barrier by modulating TJ proteins and influencing immune responses. Therefore, while these studies do not explicitly investigate gut permeability, their findings highlight a potential pathway through which microbiota-driven changes could compromise the gut barrier in KD. This calls for future research to examine whether the observed dysbiosis in KD patients is linked to increased gut permeability and, consequently, to systemic inflammatory responses. Building on the observed microbial imbalances, Kaneko et al. proposed that dysbiosis—characterized by reduced butyrate-producing bacteria—could contribute to KD’s etiology by disrupting the balance of T helper 17 (Th17) cells and regulatory T (Treg) cells, potentially triggering hypercytokinemia (7). Recently, a comprehensive retrospective case–control study encompassing 17,818 KD patients and 89,090 matched control subjects revealed that antibiotic usage within the past 6 or 12 months is linked to KD. Moreover, this association becomes more pronounced as the variety of antibiotic classes used increases (78). Taken together, these studies suggest that dysbiosis of the gut microbiota may be linked to the pathogenesis of KD. However, a critical methodological issue in recent studies is that fecal samples from KD patients are often collected after antibiotic treatments, making it difficult to distinguish microbiota changes due to KD from those caused by antibiotics. In the diagnosis of KD, antibiotics are typically administered before a definitive diagnosis is made, especially in atypical cases, which relies on meeting five clinical criteria (79, 80). Consequently, changes in the gut microbiota detected by 16S rRNA or metagenomic sequencing might not truly represent the pathogenesis of KD but instead reflect the effects of antibiotics. This underscores the importance of prospective studies that collect fecal samples from febrile patients before diagnosis, providing a clearer understanding of the actual microbiota alterations in KD, separate from antibiotic influence.

Research indicates that patients with KD exhibit increased gut permeability, suggesting a compromised gut barrier that allows pathogens and other harmful substances to translocate into the bloodstream, triggering immune responses and potentially contributing to systemic inflammation and vascular damage (70, 73). This is evidenced by heightened serum concentrations of sIgA, indicative of impaired gut barrier function (3, 72). Changes in the gut microbiota, including a decrease in SCFAs-producing bacteria, are linked to increased permeability (81, 82) and inflammation in KD (1). Wang et al. demonstrated in a KD mouse model that a decline in SCFAs-producing bacteria led to reduced expression of key gut barrier proteins—such as claudin-1, JAM-1, occludin, and ZO-1—and higher plasma D-lactate levels, intensifying inflammation. However, administration of the probiotic Clostridium butyricum improved barrier function by boosting SCFAs production (1). Furthermore, clinical studies showed that fecal butyrate concentrations were significantly lower in KD patients compared to health control although the sample size was limited (n = 4 for both groups) (7). These data suggest that reduced SCFAs levels may be linked to increased gut permeability in children with KD. SCFAs fortify the gut barrier by enhancing the mucus layer that shields the IECs from pathogens, primarily through the secretion of mucins and antimicrobial peptides, which are crucial for both microbial and chemical barriers (83). Furthermore, SCFAs promote barrier stability by encouraging a balanced microbial environment, inhibiting harmful pathogen colonization while supporting beneficial microbiota growth. This activity driven by the secretion of mucins and antimicrobial peptides bolsters both microbial and chemical barriers, enhancing the protective mucus layer over the IECs (83). SCFAs also regulate inflammatory processes by controlling innate immune sensors such as TLR and NLRP3 inflammasomes, thereby mitigating excessive inflammatory signaling (84). Consequently, reduced SCFAs levels may lead to increased gut permeability, allowing pathogens and toxins to enter the bloodstream, triggering abnormal activation of subepithelial immune cells and overproduction of inflammatory mediators like TNF-α, IFN-γ, and IL-1β, which may contribute to the pathogenesis of KD (82, 85). IL-1β, for instance, increases IECs TJ permeability by activating signaling pathways involving NF-κB, upregulating the myosin light-chain kinase gene, and post-transcriptionally regulating the occludin gene via microRNA, thereby influencing intestinal inflammation (86). IL-1 signaling plays a crucial role in KD’s pathogenesis, as IL-1α and IL-1β, once activated, create a local proinflammatory environment, prompting vasodilation and recruiting monocytes and neutrophils to damaged tissue sites. Both IL-1α and IL-1β have been implicated in myocarditis and aneurysm formation in the Lactobacillus casei cell-wall extract (LCWE) mouse model of KD (87). Moreover, IL-1 signaling in IECs increases intestinal permeability, while deleting IL-1R specifically in these cells prevents permeability increases and reduces heart inflammation and abdominal aorta aneurysms in LCWE-injected KD mice (70). These findings highlight the need for further research on increased gut permeability in children with KD, as well as the role of SCFAs levels, gut microbiome imbalances, and their link to the disease. Early intervention to correct gut permeability and restore gut microbiome balance or SCFAs levels may offer promising strategies for treating or preventing KD. A comparative hypothesis of gut permeability in a healthy state versus KD is depicted in Figures 1A, B .

The increase in gut permeability observed in KD patients may be intricately linked to liver damage. Due to the liver’s proximity to the GI tract, metabolites from the gut microbiota can directly enter the liver through the portal vein, potentially impacting liver function (48). This relationship is central to the gut–liver axis, which describes how gut microbiota and their by-products impact liver function and the progression of liver diseases (88). Normally, an intact gut barrier protects the body and the portal circulation from harmful substances. However, a compromised barrier allows microorganisms and their by-products to migrate to the liver via the portal vein (89, 90). These gut-derived bacterial products activate TLR on various liver cells—such as Kupffer cells, endothelial cells, dendritic cells, and hepatocytes—contributing to both acute and chronic liver conditions (90). Liver dysfunction is common in children with KD, ranging from mild enzyme elevation to severe cholestatic hepatitis or gallbladder hydrops (18). A study of 210 KD patients found that 90.95% had abnormal liver function test (LFT), with hypoalbuminemia being the most common, followed by elevated aspartate aminotransferase (AST), reduced total protein (TP), low albumin/globulin (A/G) ratio, and hyperbilirubinemia (91). Furthermore, meta-analyses and retrospective cohort studies have linked liver abnormalities with increased IVIG resistance in patients with KD (92, 93). For instance, a retrospective study of 1,490 KD patients identified GI involvement, prolonged fever, elevated alanine aminotransferase (ALT), PLT count, and C-reactive protein (CRP) as risk factors for CAL. Those with liver dysfunction had longer hospital stays, higher IVIG resistance and an increased incidence of CAL, and elevated CRP, suggesting that liver function may reflect the severity of systemic inflammation (18). Conversely, a study of 259 patients found no significant difference in CAL prevalence between those with normal and abnormal LFT, possibly due to a smaller sample size (94). Despite substantial evidence suggesting a potential link between gut permeability and liver dysfunction in KD, direct research is limited, representing a knowledge gap. Future studies should investigate whether increased gut permeability facilitates the migration of microbial products to the liver, triggering immune responses. Longitudinal studies could monitor gut permeability markers, such as ZO-1 and circulating sIgA, alongside LFT, such as ALT and as well as CRP levels, to identify patterns in KD progression. The potential relationship between increased gut permeability and liver dysfunction in KD is illustrated in Figures 2A, B .

Cardiovascular disease (CVD) impacts various organs, notably the intestinal tract, often implicated early in the disease process (95). In CVD, heightened gut permeability is linked to systemic inflammation, potentially due to translocation of bacterial elements into the bloodstream and disruptions in immune responses within the gut (96). A study by Lai et al. demonstrated that serum levels of the TJ protein ZO-1 were lower in KD patients compared to controls, with these levels correlating to the formation of CAL (73). This suggests a possible connection between compromised gut permeability and CAL in KD. In KD, increased gut permeability is accompanied by elevated levels of circulating sIgA and IgA deposition in vascular tissues, as seen in a mouse model of KD vasculitis. Addressing gut barrier dysfunction in the model corrected permeability, prevented IgA deposition, and improved cardiovascular health. Furthermore, after LCWE injection in KD mice, gut permeability increased rapidly, preceding coronary artery inflammation and abdominal aorta dilation. These findings indicate that a compromised gut barrier may initiate rather than result from vasculitis. Treatment with AT1001, a zonulin inhibitor, effectively restored the gut integrity and reduced cardiovascular lesions, highlighting the importance of early gut barrier disruption in the development of KD vasculitis and coronary artery aneurysms (70).

The disruption of the gut barrier not only affects local inflammation but also influences broader immune mechanisms, including those involving key cytokines like IL-33, which are crucial for immune regulation and inflammation. The IL-33/ST2 axis plays a significant role in this context (97). IL-33, a cytokine from the IL-1 family, acts as an “alarm signal” when cells are damaged, being released primarily from the nuclei of endothelial and epithelial cells (98). It interacts with the ST2 receptor, which has two forms: transmembrane ST2 (ST2L), a membrane-bound receptor that triggers inflammatory responses when IL-33 binds to it; and soluble ST2 (sST2), a soluble form that can block the effects of IL-33 by acting as a decoy. This axis, therefore, helps regulate immune responses and inflammation (99). In the gut, IL-33 promotes the proliferation and differentiation of enterocytes, enhancing mucosal renewal and regeneration. It plays a pivotal role in balancing the Th1/Th2 immune response and regulating intestinal immune homeostasis (99). However, if the epithelial barrier is compromised, IL-33 release can trigger immune responses that worsen inflammation (100). During the acute phase of KD, serum levels of IL-33 and sST2—a decoy receptor that binds circulating IL-33—are significantly elevated (101, 102). Moreover, a recent study by Okada et al. found that KD patients, particularly those with CAL, had significantly elevated levels of sST2 during the acute phase. The study further demonstrated that IL-33 stimulates human coronary artery endothelial cells (HCAECs) leading to an upregulation of ST2L, which is necessary for the extracellular effects of IL-33. This stimulation also resulted in elevated production of sST2, IL-6, IL-8, and monocyte chemoattractant protein-1. These changes occurred in a time- and concentration-dependent manner, highlighting a proinflammatory role of IL-33. These findings suggest that the IL-33/ST2 axis plays a significant role in the pathogenesis of KD, particularly in the development of vasculitis and CAL (16). However, direct evidence linking increased gut permeability to the onset of systemic vasculitis and CAL in KD patients is still lacking. Further studies should aim to identify the specific mechanisms by which increased gut permeability contributes to the development of systemic vasculitis and CAL in KD. Key areas of investigation might include tracking changes in gut permeability over the course of KD progression and exploring the involvement of specific immune pathways, such as the IL-33/ST2 axis, in mediating the link between gut barrier disruption and systemic vasculitis. This targeted research could help clarify how early disruptions in gut integrity contribute to vascular complications, potentially leading to new strategies for early intervention and improved management of KD-related vasculitis. The hypothesis linking increased gut permeability to vasculitis and CAL in KD is summarized in Figure 2C .

IVIG therapy, the standard treatment for KD, primarily aims to reduce systemic inflammation and prevent complications such as CAL (5, 27). While its exact mechanisms remain complex, IVIG is thought to work by modulating the immune system (72). According to Nadig et al., IVIG can influence both the innate and adaptive immune responses. It affects the innate immune system by modifying pathways like TLR pathways, controlling autophagy and apoptosis in the mononuclear phagocytic system, managing the formation of neutrophil extracellular traps, and adjusting dendritic cell activity. In the adaptive immune system, IVIG helps regulate T-cell differentiation, cytokine production, and the function of Treg cells (103). Emerging evidence points to a potential connection between gut barrier function and IVIG efficacy. A multicenter study by Fabi et al., involving over 300 KD patients from 13 pediatric centers, evaluated the relationship between GI symptoms and the response to IVIG therapy. The study found that KD patients presenting with initial GI symptoms had a higher likelihood of IVIG unresponsiveness and a greater risk of developing coronary aneurysms. These findings suggest that GI involvement, possibly linked to gut permeability, could significantly influence the effectiveness of IVIG treatment and impact disease progression (3). Lai et al. observed that KD patients with CAL exhibited reduced serum levels of the TJ protein ZO-1. This suggests a potential link between compromised gut barrier function and the development of CAL in KD. However, the study did not find significant differences in ZO-1 levels when comparing IVIG-responsive and non-responsive patients, likely due to the study’s limited sample size (73). These findings suggest that increased gut permeability might contribute to IVIG unresponsiveness, but further large-scale studies are needed to confirm this connection. While it is not definitively established that IVIG directly stabilizes gut permeability, it is hypothesized that by reducing systemic inflammation—which can disrupt the gut barrier—IVIG might have an indirect stabilizing effect. Supporting this idea, Saito et al. found that IVIG treatment correlated with improvements in intestinal vascular permeability and mucosal damage caused by toxins from Clostridium difficile (104). However, studies directly comparing the levels of gut permeability markers before and after IVIG treatment in KD patients are limited. Future research should focus on understanding the role of gut permeability in KD and its influence on IVIG efficacy. This includes conducting larger, multicenter studies to validate the link between gut barrier dysfunction and IVIG responsiveness. Tracking markers like ZO-1 before and after IVIG treatment could clarify their predictive value for treatment outcomes.

PLT count is a crucial biomarker for monitoring KD progression and plays a significant role in assessing disease severity and guiding treatment decisions. Elevated PLT counts have been linked to increased risks of CAL, IVIG non-responsiveness, and KD shock syndrome (KDSS) (105–110). Specifically, patients with PLT counts greater than 450 × 10⁹/L at admission are at a higher risk of developing CAL (107). Park et al. conducted a study evaluating PLT counts in 505 KD patients during the acute phase, revealing that thrombocytosis—elevated PLT counts—was associated with worse clinical outcomes. Specifically, higher PLT counts correlated with prolonged hospital stays, longer fever durations, and a greater risk of IVIG non-responsiveness and coronary artery disease (108). Conversely, patients with post-hospitalization PLT counts below the normal range (<150 × 10⁹/L) have an increased risk of developing CAL. A rapid rise in PLT counts within the first 5 days of illness indicates heightened cytokine activity, which may damage the coronary arteries and lead to early-phase CAL (107). PLT counts are reported to decrease more significantly in patients with severe KD compared to others in the initial days of the illness (109, 110). Moreover, IVIG non-responding patients with the lowest PLT counts post-hospitalization are at a significantly increased risk of developing CAL independently (107). Before IVIG treatment, increased PLT aggregation and activation are observed, indicating early endothelial damage in KD (111, 112). This aggregation can lead to thrombocytopenia, prompting marrow stromal cells to produce more thrombopoietin, which enhances thrombopoiesis (113). In severe KD patients, thrombocytopenia may signal widespread vascular endothelium damage, causing further PLT aggregation and an increase in thrombopoiesis. Consequently, newly formed megakaryocytes and PLT have higher levels of vascular endothelial growth factor (VEGF) compared to mature PLT. These activated PLT cluster and release VEGF at sites of endothelial injury, perpetuating a vicious cycle that drives vascular inflammation and damage, contributing to the progression of CAL in KD (114). Moreover, activated PLT form complexes with monocytes and neutrophils—known as monocyte–PLT aggregates (MPAs) and neutrophil–PLT aggregates (NPAs)—which amplify the inflammatory response and increase IL-1β production, exacerbating vascular inflammation (9).

While the precise connection between gut permeability and PLT activation in KD remains unreported, recent research by Kocatürk et al. investigated PLT behavior in a KD animal model. The study showed that PLT aggregation contributes significantly to cardiovascular inflammation, primarily through the formation of MPAs. The study found that increased PLT counts and higher levels of MPAs were closely associated with severe cardiovascular inflammation. Notably, interventions that lowered PLT counts or inhibited PLT function effectively reduced inflammation, underscoring the critical role of PLT activation in worsening cardiovascular damage in KD vasculitis. This suggests that targeting MPAs, which enhance IL-1β production, could be a promising therapeutic strategy (9). Although this study did not specifically address the relationship between PLT counts and gut permeability, previous research using the same animal model demonstrated that gut permeability, alongside IgA deposition, plays a role in immune-mediated cardiovascular inflammation. Targeted interventions that restored gut barrier integrity not only corrected permeability issues but also prevented IgA buildup, leading to significant improvements in cardiovascular health (70). These findings suggest that both gut permeability and PLT activation are crucial factors in the development of vasculitis and cardiovascular complications in KD. It is hypothesized that increased gut permeability may disrupt gut immunity balance and damage the GVB, impacting vascular endothelial cells. This damage could promote PLT aggregation and activation, initiating a systemic inflammatory response, vascular inflammation, and the development of aneurysms. Understanding the link between gut permeability and PLT activation in KD is a priority for future research. Exploring this connection could shed light on KD’s pathogenesis and lead to innovative treatments. The potential mechanisms linking increased gut permeability to PLT activation in KD are illustrated in Figure 3 .

As the complexities of KD continue to be unraveled, the GI tract’s significant role in its pathogenesis has become increasingly apparent. Emerging evidence linking increased gut permeability to PLT activation provides a novel avenue for understanding the pathogenesis of KD and its severe vascular complications, such as coronary artery aneurysms. This connection suggests that compromised gut barrier function may contribute to the systemic inflammation and vascular damage observed in KD. Future research should focus on delineating the exact mechanisms by which gut permeability contributes to KD pathogenesis. This could include longitudinal studies tracking changes in gut barrier integrity throughout the progression of KD and its responses to various treatments. Identifying specific pathways—such as alterations in TJ proteins, disruptions in microbial metabolites like SCFAs, and interactions between the gut microbiota and immune cells—will be crucial for a deeper understanding of how gut health influences systemic inflammation in KD. Interventions targeting the gut barrier offer promising strategies for reducing the severity of KD. Probiotics, prebiotics, and dietary modifications designed to restore gut microbiota balance could potentially reduce gut permeability, thereby decreasing systemic inflammatory responses and improving outcomes in KD patients. For example, probiotics like C. butyricum have shown potential in enhancing SCFAs production and reinforcing the gut barrier (1). Detailed evidence from these interventions can strengthen their applicability in KD management, potentially leading to more effective outcomes. A multidisciplinary approach is essential for a comprehensive understanding of KD. Gastroenterologists can lead efforts to optimize gut health through dietary and microbial interventions, while immunologists can explore immune pathways contributing to systemic inflammation. Cardiologists can assess the cardiovascular benefits of gut-targeted therapies. Collaborative clinical trials, integrated treatment guidelines, and shared research initiatives could pave the way for more holistic and effective KD management. The development of targeted therapies to strengthen the gut barrier or modulate the immune response at the gut level could also be transformative. Incorporating gut health into the routine clinical management of KD could lead to earlier diagnosis and more personalized treatment approaches. Understanding the relationship between the gut microbiota and KD may also help identify biomarkers for disease susceptibility and treatment efficacy. Ultimately, as research progresses, these insights are expected to provide a deeper understanding of the underlying mechanisms of KD, leading to improved clinical practices and better patient outcomes.