Bitter side of sweet: A stage-dependent immunometabolic model linking metabolic syndrome and inflammatory bowel disease

Abstract

The increasing prevalence of metabolic syndrome (MetS) among patients with inflammatory bowel disease (IBD) has prompted renewed interest in their poorly defined bidirectional relationship, underpinned by shared mechanisms such as epithelial barrier disruption, chronic low-grade inflammation, and microbial dysbiosis. In this review, we comprehensively synthesize current evidence on the relationship between MetS and IBD, highlighting their shared pathophysiological mechanisms. We further propose a biphasic model of the MetS-IBD interaction, supported by original immunological data obtained from patients with ulcerative colitis (UC) and concomitant MetS. Early-stage MetS appears to promote a regulatory immune phenotype characterized by increased interleukin-10 and galectin-3-related pathways, which is associated with attenuated UC, whereas advanced MetS appears to be associated with a pro-inflammatory phenotype, increased interleukin-6 and C-X-C motif chemokine ligand 8 signaling, cytotoxic immune-cell infiltration, mucosal damage, and more severe UC. This paradigm should be regarded as hypothesis-generating and requires validation in independent longitudinal cohorts. Nevertheless, it provides a translational framework for future biomarker development, metabolic stratification, and stage-adapted therapeutic research in patients with IBD and metabolic comorbidity.

Key Words: Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease; Metabolic syndrome; Immune dysregulation; Gut microbiota

Core Tip: This review explores the interplay between metabolic syndrome and inflammatory bowel disease through shared pathways and stage-specific immune alterations, presenting a conceptual model of their relationship, highlighting clinical and therapeutic implications, and outlining potentially new directions for future research.

INTRODUCTION

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is generally viewed as an immune-related condition, where the primary dysregulation of the mucosal immune system leads to excessive immunologic responses to normal microbiome in genetically susceptible individuals[1,2]. Metabolic syndrome (MetS), on the other hand, describes a cluster of different synergic health pathologies, which incorporates insulin resistance or diabetes, obesity, hyperlipidemia and arterial hypertension[3-5]. Although IBD and MetS have been observed as separate, recent studies suggest a possible interconnection through shared mechanisms, chronic inflammation, epithelial barrier impairment, and alterations of the microbiome[6,7]. The increasing number of IBD patients with metabolic disorders supports this link[8]. However, the MetS impact on IBD remains poorly understood, as most research has predominantly focused on how IBD influences metabolic processes rather than examining the reverse relationship.

In this review, we synthesize current evidence and propose a conceptual two-phase model to explain how MetS may influence the progression of IBD. By focusing on the overlap between metabolism and immune function, we highlight the importance of mechanisms such as epithelial barrier dysfunction and microbiome imbalance. We also propose a more personalized approach for IBD patients who are metabolically at risk[9,10]. Importantly, the immunometabolic model presented herein should be regarded as hypothesis-generating rather than a validated causal framework, and requires confirmation in independent, longitudinal cohort studies.

EPIDEMIOLOGICAL AND CLINICAL CONTEXT

IBD is characterized as a chronic disorder involving repeated episodes of intestinal inflammation and impaired gut barrier function, driven by improper immune responses to intestinal bacteria. Genetic analyses have identified over 240 risk-associated gene regions, which are linked with immune system regulation, epithelial integrity, and cellular renewal and regeneration processes[11-13]. Additionally, environmental factors like consumption of highly processed foods, smoking habits, and sedentary lifestyles play crucial roles in disease progression[14-17]. Despite advances in therapeutic approaches, many patients continue to face challenges in achieving sustained disease management[18].

At the same time, MetS has become a major health problem worldwide. As mentioned above, it is defined by correlated metabolic changes, including obesity, insulin resistance, elevated blood lipids and arterial hypertension[3-5]. In addition to its role in heart disease, MetS promotes chronic low-level inflammation through impaired intestinal barrier function, inappropriate hormone signaling from adipose tissue, and microbiome imbalance[3,19]. In patients with IBD, these systemic effects may exacerbate the activation of intestinal immunity. Recent epidemiological studies show that MetS is increasingly common in IBD, especially in UC. Meta-analyses by Shen et al[8] report a pooled MetS prevalence of 19.4% among IBD patients, with much higher rates in UC (38.2%) compared to 13.6% in CD. Janani et al[20], who noted a pooled prevalence of 21.8%, once more with a predominance in UC (32.7% vs 14.1%), validated these results. Older age, excess weight, and pre- and existing diabetes were the main risk factors. These findings challenge the usual image of IBD patients as underweight and highlight the need to recognize metabolic complications. Moreover, patients simultaneously affected by IBD and MetS are frequently excluded from clinical trials, resulting in limited therapeutic guidance for this subgroup. The typical Western diet, rich in saturated fats, refined sugars, and highly processed foods, likely serves as a common trigger for both IBD and MetS[21]. Additionally, the chronic inflammation characteristic of IBD itself may predispose individuals to develop MetS, primarily through prolonged exposure to proinflammatory cytokines, which interfere with insulin signaling, leading to insulin resistance, lipid abnormalities, and vascular endothelial dysfunction[20]. Other disease-specific factors, such as disturbances in gut microbiota (GM), prolonged use of corticosteroids, and tumor necrosis factor (TNF)-α inhibitors, may further exacerbate this metabolic dysregulation[22,23].

These intertwined mechanisms generate a distinctive inflammatory-metabolic profile in certain IBD patients, elevating their risk for metabolic and cardiovascular complications. Despite this complexity, further targeted investigations are necessary to fully explain the precise influence of MetS on IBD outcomes.

Impact of MetS on IBD: Current clinical evidence

An unresolved question is whether MetS independently influences the course and outcomes of IBD or, because of shared pathophysiological pathways, coexists with gut inflammation. Recent studies showed that MetS can alter IBD severity and lead to worse outcomes, although the significance of these findings is still to be elucidated. In a retrospective cohort of 376 patients with CD, Huang et al[24] demonstrated that patients with concomitant MetS exhibited significantly higher disease activity, reflected by increased simple endoscopic score for CD values (10 vs 7, P < 0.001) and higher CD activity index scores (294.3 vs 256.6, P < 0.001). Moreover, MetS was associated with an increased risk of disease-related complications [odds ratio (OR) = 8.65, 95% confidence interval (CI): 2.01-37.26] and a greater likelihood of requiring surgery or invasive procedures (OR = 2.64, 95%CI: 1.27-5.45). Importantly, the cumulative number of MetS components demonstrated a dose-dependent association with disease severity and adverse clinical outcomes, suggesting that increasing metabolic burden may contribute to a more aggressive disease phenotype. Similarly, Liu et al[25] analyzed 676 patients with IBD and reported significantly higher baseline disease activity among patients with concomitant MetS, accompanied by elevated inflammatory biomarkers, including C-reactive protein and erythrocyte sedimentation rate. During a one-year follow-up, patients with MetS demonstrated substantially lower rates of clinical remission (54.48% vs 82.49%) and mucosal healing (24.83% vs 41.05%). These associations remained significant after propensity score matching, indicating that MetS may negatively affect disease control and therapeutic outcomes. At first glance, these observations appear to differ from our previously published findings in treatment-naive patients with newly diagnosed UC[9,10]. However, several important methodological differences should be considered. The recently published cohorts primarily included patients with established disease, heterogeneous treatment exposure, and varying disease durations, whereas our studies focused exclusively on treatment-naive patients at diagnosis, thereby minimizing the confounding effects of long-standing inflammation and immunomodulatory therapy. Furthermore, the more recent studies primarily assessed clinical disease activity and long-term outcomes, whereas our investigations were designed to characterize immunological alterations associated with distinct metabolic states. Notably, our findings suggested that the impact of MetS may not be uniform but may vary with metabolic stage, providing a rationale for the stage-dependent immunometabolic model discussed in subsequent sections. Therefore, rather than representing contradictory observations, the available evidence may reflect different phases of a dynamic interaction between metabolic dysfunction and intestinal inflammation.

Differential impact of individual MetS components on IBD

MetS represents a combination of different metabolic components rather than a single uniform entity, and each of the components may impact IBD outcomes. Visceral adiposity can predict adverse outcomes in IBD better than body mass index alone, highlighting the significance of the distribution of adipose tissue over overall obesity. Moreover, expansion of mesenteric adipose tissue in CD has been connected to transmural inflammation, fibrosis, as well as stenotic complications[26,27]. Another important components of MetS that can alter gut inflammation are hyperglycemia and insulin resistance. Insulin resistance alters gut barrier integrity, increases intestinal permeability, impairs tissue repair, and promotes intestinal inflammation and oxidative stress. Furthermore, hyperglycemia directly impairs intestinal tight junctions (TJ), facilitating the translocation of microbes and, consequently, inflammation[28,29]. Through bile acid metabolism, lipid-mediated immune system regulation, and microbiota alterations, dyslipidemia may alter IBD activity. Low high-density lipoprotein cholesterol has been associated with adverse clinical outcomes in IBD, potentially reflecting loss of its anti-inflammatory and antioxidant properties[24,28,29]. Other components, such as arterial hypertension, are less studied but may cause endothelial dysfunction, alter intestinal microcirculation, and promote thrombosis and inflammation[29]. Importantly, recent evidence indicates that the cumulative metabolic burden may be more informative than any individual component[28,29]. Therefore, future studies should evaluate both individual MetS components and their combined effects when assessing the impact of MetS overall on IBD progression and treatment outcomes.

Impact of IBD on metabolic dysfunction and its components

The opposite direction of the MetS-IBD relationship also exists, as chronic intestinal inflammation may influence the development of MetS components. Danish cohort study, which included more than six million individuals, showed that IBD increases the risk of type 2 diabetes [standardized incidence ratio (SIR) = 1.54, 95%CI: 1.49-1.60], with similar risks observed in both UC and CD. Additionally, the risk of developing type 2 diabetes was highest during the first year after IBD diagnosis (SIR = 4.48, 95%CI: 4.16-4.83) and remained elevated for more than 20 years, implicating that the connection cannot be explained simply by corticosteroid exposure or healthcare utilization[30]. Moreover, IBD has been associated with insulin resistance, dyslipidemia, visceral adipose tissue (VAT) remodeling, and increased cardiovascular risk[28,29,31,32]. Importantly, active inflammation during periods of disease activity appears to play a key role in these observations[31]. IBD also induces characteristic changes in body composition. Although there is connection of IBD with malnutrition through history, recent cohorts demonstrate increasing rates of overweight and obesity in IBD, particularly in UC[28]. In CD, “creeping fat” is a characteristic form of visceral adiposity associated with transmural inflammation and fibrostenotic complications[26]. In addition, sarcopenic obesity may occur despite a normal body mass index, highlighting the limitations of conventional anthropometric measures in this population[28]. The role of IBD on lipid metabolism and profile appears especially complex. There is a reduction of circulating cholesterol during a period of active inflammation, but these changes coexist with increased cardiovascular risks, a phenomenon known as the “lipid paradox”. Furthermore, chronic meta-flammation impairs lipoprotein structure and function, promoting endothelial dysfunction and atherogenesis in spite of a favorable lipid profile[31-33]. Importantly, treatment can also influence the risk of developing MetS components. It is well known that corticosteroid usage may cause insulin resistance, arterial hypertension, altered lipid profile, and obesity. On the contrary, the anti-inflammatory effect of anti-TNF therapy has been associated with improvements in metabolic and cardiovascular health[31]. Collectively, these observations suggest that IBD may actively contribute to the development of metabolic dysfunction and individual MetS components, supporting a bidirectional relationship between intestinal inflammation and metabolic disease.

SHARED PATHWAYS: A TRIAD OF BARRIER, IMMUNE, AND MICROBIAL DYSFUNCTION

Intestinal barrier

Disruption of the intestinal barrier is a shared element in IBD and MetS, linking gut dysfunction to systemic inflammation and disease progression. In MetS, a high-fat diet (HFD) and insulin resistance lead to alterations in the GM, which increase intestinal permeability, allowing bacterial lipopolysaccharides (LPS) to enter the circulation and cause “metabolic endotoxemia”. This causes low-grade inflammation and worsens insulin resistance[34-36]. Similarly, the disruption of the intestinal barrier is a noteworthy contributing factor in the pathogenesis of IBD. Furthermore, a disrupted epithelial layer allows microbial antigens to penetrate the lamina propria, triggering both innate and adaptive immune responses, which in turn lead to mucosal inflammation and tissue damage[37]. At the subcellular level, proteins that form TJ, such as claudins, occludin, and zonula occludens, are essential for controlling paracellular permeability. In MetS, the impairment of claudin-1, claudin-4, and claudin-7 correlates with increased intestinal permeability and metabolic disturbance[34,38,39]. Moreover, the upregulation of pore-forming claudin-2 increases intestinal permeability in IBD, while decreased levels of claudins that enhance TJ (like claudin-4, claudin-5, and claudin-8) are associated with the compromise of the epithelial barrier in both entities of IBD[37,40,41]. Therefore, in both IBD and MetS, changes in claudin expression lead to increased gut permeability, allowing the entrance of microbial products that subsequently promote inflammation. Furthermore, a recent study in MetS has confirmed that hyperglycemia exacerbates intestinal barrier dysfunction by compromising TJ integrity, thereby establishing a further connection between the two conditions[42].

Apart from intercellular junctions, the mucus layer produced by goblet cells plays a vital role in the epithelial defense mechanism. The important gel-forming mucin, mucin 2 (MUC2), plays a significant role in creating a physical and biochemical barrier that separates the microbiota from the gut epithelium. Studies on MUC2-deficient mice demonstrate its protective role, as evidenced by the development of spontaneous colitis and increased susceptibility to dextran sulfate sodium (DSS) exposure[43]. On the contrary, a thicker mucus layer is present in CD, accompanied by increased MUC2 secretion. However, during chronic inflammation, its secretion becomes ineffective, which leads to poor mucus quality due to shortened glycan chains and changes in sulfation[44]. Furthermore, HFD and a diet rich in fructose decrease the expression and secretion of MUC2, resulting in a reduction in mucus thickness. These changes lead to gut dysbiosis, as well as impairment of the intestinal barrier’s integrity, underscoring the critical role of MUC2 in maintaining metabolic balance[45]. In addition, specialized epithelial cells located at the base of intestinal crypts, named Paneth cells, secrete antimicrobial peptides, including α-defensins and lysozyme, which help control microbial overgrowth. In CD, Paneth cell dysfunction leads to the production of misfolded defensins, thereby weakening antimicrobial defense, which worsens dysbiosis and causes mucosal damage[46,47]. Moreover, recent findings suggest that dietary factors, such as a Western-style diet, exert a more substantial influence on small-intestinal microbiota composition than defensins, which appear to play a fine-tuning role in protection against diet-induced metabolic dysfunction[48].

In sum, these findings highlight intestinal barrier dysfunction as a common characteristic of both MetS and IBD. Exploring how these mechanisms overlap may provide novel approaches to restore mucosal integrity and impede disease advancement in both metabolic and inflammatory contexts.

Immune system

Both conditions (MetS and IBD) share a common immunopathological feature, such as disturbed immune homeostasis, favoring a pro-inflammatory state. This inflammatory state is fundamentally driven by impaired intestinal barrier integrity, which further facilitates the penetration of microbial products into the lamina propria or adipose tissue, amplifying the immune response[49]. Therefore, obesity and insulin resistance are associated with chronic low-grade intestinal inflammation, accompanied by a proinflammatory shift of intestinal immune cells[50]. This immune activation is driven by interaction between microbial products and pattern recognition receptors on intestinal epithelial cells and immune cells, which promotes cytokine production and the recruitment and activation of macrophages and dendritic cells, consequently inducing T helper cell (Th) 1 and Th17 immune responses[51]. Similarly, an inadequate immune response toward commensal gut microorganisms significantly contributes to IBD immunopathogenesis. This robust immune response is regulated by proinflammatory cytokines, such as TNF-α, interleukin (IL)-1β, and IL-6, which coordinate crucial immunopathological processes. These include the infiltration of immune cells and damage to epithelial tissues promoted by TNF-α, as well as the enhancement of cytokine cascades and the recruitment of immune cells driven by IL-1β. At the same time, IL-6 leads the T cell response toward proinflammatory Th17 dominance and suppresses the function of regulatory T cells (Tregs)[52]. Additionally, macrophage polarization in both MetS and IBD is altered toward a proinflammatory macrophage type 1 (M1) phenotype, resulting in increased production of inflammatory mediators[53-55]. In line with this, insulin resistance and hyperinsulinemia interfere with macrophage type 2 (M2) macrophage function by attenuation of insulin receptor substrate-2 signaling[54], whereas in IBD, a proinflammatory microenvironment promotes M1 polarization at the expense of the M2 phenotype[55]. In addition, neutrophils plays a critical role in the pathogenesis of both diseases. Neutrophils are central player in active inflammation in IBD[56] and contribute to the development of obesity-related complications in MetS through their participation in chronic low-grade inflammation[57]. Furthermore, innate lymphoid cells (ILCs), predominantly group 1 ILC (ILC1) and group 3 ILC (ILC3), play a significant role in both IBD and MetS. Following these findings, ILC1s are expanded in the inflamed mucosa and produce interferon (IFN)-γ, contributing to local inflammation in IBD[58]. Moreover, in MetS, ILC1s residing in adipose tissue produce IFN-γ in response to IL-12, promoting proinflammatory macrophage activation and insulin resistance[59]. ILC3 cells have a dual role in IBD pathology; upon overactivation, they drive inflammation through IL-17A and IL-22 production, promoting neutrophil infiltration and epithelial injury. However, in certain settings, IL-22 can support also epithelial repair and barrier integrity[58]. In MetS, ILC3-derived IL-22 preserves gut permeability, reduces endotoxemia, and improves metabolic parameters[60]. During chronic intestinal inflammation, dysregulation of cluster of differentiation 4 (CD4)⁺ T cell subsets, particularly Th1, Th2, and Th17 cells- is central observed disorders. Therefore, CD is traditionally characterized by the dominance of Th1 and Th17 immune responses accompanied with increased production of IFN-γ and IL-17, whereas UC exhibits a Th2-dominant immune profile, with elevated IL-4 and IL-5 alongside non-classical Th17 activity[61-63]. In addition, Th17 cells represent common proinflammatory axis in both MetS and IBD. Exposure to HFD initiates Th17 polarization and suppresses Tregs, thereby disrupting the Th17/Treg equilibrium that is crucial for mucosal immune tolerance[50,64].

A similar imbalance is noted in IBD, whereas enhanced Th17 responses and impaired Tregs function synergistically contribute to intestinal inflammation[65,66]. Moreover, IFN-γ and IL-17 have been implicated that disrupted epithelial TJ, thereby exacerbating intestinal permeability and sustaining the inflammatory cascade[40,50]. The overlapping epithelial barrier and immune system alterations observed in MetS and IBD are summarized in Table 1.

Table 1 Shared pathophysiological mechanisms linking metabolic syndrome and inflammatory bowel disease.

	Shared feature	MetS	IBD
Epithelial barrier	Barrier dysfunction; increased intestinal permeability	LPS entry fuels systemic low-grade inflammation	Barrier loss enables microbial entry into the lamina propria, driving localized chronic mucosal inflammation
	TJ protein dysregulation	Dysregulated claudin-1, claudin-4, claudin-7 expression	Claudin-2 (increase); (decrease) claudin-4, claudin-5, claudin-8
	Mucus layer alterations (MUC2)	HFD and fructose impair Muc2 expression, secretion and mucus thickness	UC: MUC2 deficiency leads to spontaneous colitis and increased susceptibility to injury. CD: Mucus quality is impaired
	Paneth cell dysfunction and defensin loss	Protect against diet-induced metabolic dysfunction	Contributes to dysbiosis and barrier breakdown
Immune system	Macrophage polarization	M1 (increase): Promotes chronic adipose inflammation. M2 (decrease): Suppressed via IRS-2 inhibition by hyperinsulinemia	M1 (increase): Contributes to mucosal damage. M2 (decrease): Downregulated by inflammatory cytokine milieu
	Neutrophil involvement	Drives obesity-related complications	Hallmark of active mucosal inflammation
	ILC1s	Adipose-resident ILC1s produce IFN-γ promoting M1 macrophage activation and insulin resistance	ILC1 (increase) cells in the inflamed mucosa and produce IFN-γ
	ILC3s	ILC3 derived IL-22 improves barrier function	Dual role via IL-17A/IL-22 (pro-inflammatory or protective)
	Th1/Th2/Th17 imbalance	HFD promotes Th17 polarization and Treg suppression	CD: Th1/Th17; UC: Th2/Th17

MetS: Metabolic syndrome; IBD: Inflammatory bowel disease; TJ: Tight junction; MUC2: Mucin 2; ILC1s: Group 1 innate lymphoid cells; ILC3s: Group 3 innate lymphoid cells; Th1: T helper type 1 cells; Th2: T helper type 2 cells; Th17: T helper type 17 cells; HFD: High-fat diet; LPS: Lipopolysaccharide; IRS-2: Insulin receptor substrate 2; IL: Interleukin; IFN: Interferon; Treg: Regulatory T cells; UC: Ulcerative colitis; CD: Crohn’s disease.

GM

The GM represents a highly complex and dynamic ecosystem, consisting of viruses, fungi, protozoa, archaea, and predominantly bacteria, all coexisting in a finely balanced symbiosis with each other and the human host. It represents a critical component of human physiology, exerting direct or indirect influences on various host functions. Moreover, it interacts with extraintestinal organs, forming axes[67]. Key GM roles include host defense and development/modulation of the immunity, digestion, nutrition, and metabolism[68,69]. Disturbances in the delicate balance of this ecosystem are widely acknowledged to contribute to a range of pathological conditions. Among these, the role of an imbalanced microbiota (dysbiosis) is especially well-recognized in IBD, where it contributes to increased intestinal permeability and a dysregulated immune response. In detail, an imbalanced microbiota and inflammation form a bidirectional relationship, where dysbiosis triggers immune activation while chronic inflammation reshapes the microbiota, creating a self-perpetuating cycle in which GM could be either an initiator or a consequence[70].

Despite overlapping characteristics, CD and UC exhibit distinct microbial signatures. Reduced bacterial diversity and stability are hallmarks of both diseases, though more pronounced in CD. Both conditions show a depletion of beneficial bacteria, including Faecalibacterium prausnitzii (phylum Firmicutes, family Ruminococcaceae), Roseburia intestinalis (Firmicutes, Lachnospiraceae), Eubacterium rectale (Firmicutes, Lachnospiraceae), and Bifidobacterium longum (Actinobacteria, Bifidobacteriaceae). Conversely, pathogenic taxa such as Escherichia coli (Proteobacteria, Enterobacteriaceae), Ruminococcus gnavus (Firmicutes, Lachnospiraceae), Fusobacterium nucleatum (Fusobacteria, Fusobacteriaceae), and Bacteroides fragilis (Bacteroidetes, Bacteroidaceae) are enriched[71]. Distinct immune responses further differentiate CD and UC. CD patients demonstrate elevated antibodies against bacterial antigens like Escherichia coli other membrane porins and Bacteroides fragilis toxins, while UC patients exhibit broader, albeit less intense, reactivity, including notable responses to fungal antigens such as Candida albicans (Ascomycota, Saccharomycetaceae). Antimicrobial antibody responses in CD correlate with disease severity and include reactivity to proteins from Bacteroides vulgatus, Proteus mirabilis, Shigella flexneri, and Streptococcus pneumoniae. In UC, antibody responses are reduced against several Firmicutes, such as Peptostreptococcus micra and Staphylococcus aureus, and Proteobacteria, including Helicobacter pylori and Klebsiella oxytoca. Notably, adaptive immune responses to Lachnospiraceae flagellins are prominent in CD, but absent in UC[72]. Clooney et al[73] provided GM analysis in IBD patients across North America, Europe, and Asia, focusing on relationships between microbiota composition, geography, disease subtypes, and therapeutic interventions. Analysis revealed significant geographic variation in GM composition, even with the same disease subtypes. Disease activity strongly correlates with microbiota fluctuations, with remission bringing only partial recovery, rarely restoring pre-disease microbial composition[73]. Extraintestinal manifestations (EIMs) in IBD, such as arthritis and skin conditions, have also been linked to GM composition. Patients with EIMs display lower alpha diversity and an altered Bacteroidetes-to-Firmicutes ratio. Beneficial taxa such as Agathobacter (Firmicutes, Lachnospiraceae) and Blautia (Firmicutes, Lachnospiraceae) are depleted, while pro-inflammatory bacteria, including Ruminococcus gnavus and Eggerthella lenta (Actinobacteria, Eggerthellaceae), are enriched. Functional microbial analysis reveals reduced short-chain fatty acids (SCFA) production pathways, such as butyrate synthesis, and disrupted LPS biosynthesis in EIM-affected patients[74]. Lastly, inflammation-associated microbial shifts within the intestinal mucosa underscore localized dysbiosis in IBD. One of the key aspects of the Walker et al[75] study was the reduction in microbial diversity, as a hallmark of dysbiosis, in inflamed regions. These localized changes further reflect the nuanced interplay between GM and host immune responses in shaping IBD pathogenesis[75].

Emerging evidence underscores the significant role of fungal microbiota in the IBD pathogenesis, emphasizing disease-specific bacterial-fungal imbalances. Interactions between gut fungi, bacteria, and their metabolites are increasingly acknowledged, with bacterial diversity shifts influencing fungal overgrowth[76]. Notable fungal shifts in IBD include altered Basidiomycota/Ascomycota ratios, a decrease in Ascomycota phyla and Saccharomyces cerevisiae, and an increase in Candida species, especially Candida albicans and Candida parapsilosis, as well as Debaryomyces hansenii and Basidiomycota phyla. Additionally, elevated levels of anti-Saccharomyces cerevisiae antibodies serve as a well-established biomarker for CD, correlating with disease activity and preceding diagnosis[76-83]. Fungal-induced inflammation is mediated via dectin-1 receptor, which recognizes β-1,3-glucans and activates caspase recruitment domain-containing protein 9 (CARD9) -dependent signaling pathways, eliciting Th1 and Th17 immune responses[76]. Polymorphisms in the dectin-1 gene (CLEC7A) are associated with severe forms of UC, while CARD9 variants are linked to IBD susceptibility. Furthermore, Malassezia restricta (Basidiomycota, Malasseziaceae) has been associated with CARD9 mutations in CD, though findings regarding its role remain inconsistent[76,80,84-87].

Focusing on viruses, Epstein-Barr virus, cytomegalovirus, and human herpesvirus 6 are frequently detected in the colonic mucosa, where they influence IBD progression and impact treatment outcomes[88]. Recent study by Tian et al[89] reported significant alterations in the gut virome in IBD patients, identifying 139 differently abundant viral signatures. Their findings showed an increase in phages predicted to infect Escherichia, Klebsiella, Enterococcus, Streptococcus, and Veillonella species, alongside a reduction in phages targeting Prevotella, Ruminococcus, Bifidobacterium, and Blautia species. Notably, the study reported an enrichment of Anelloviridae in IBD patients. At the family level, Siphoviridae and Myoviridae were significantly increased, while crAss-like phages and Quimbyviridae were markedly depleted[89].

Finally, two studies of the same authors focused on characterization of the ileal microbiota in both damaged and healthy settings and evaluation of the correlated local or/systemic inflammatory markers comparing first-time surgery and relapse clinical conditions. In the report they defined the molecular immunity distribution within the ileal layers and evaluated the correlated microbiota in damage and surrounding healthy tissue comparing first surgery/relapse clinical conditions. We observed a distinct cytokines profile across the CD vs healthy ileal layers; and a different distribution of IFN-γ, P-selectin, IL-27 and IL-21 in first surgery vs relapse patients. Moreover, the phylum Tenericutes, the family Ruminococcaceae, and the genera Mesoplasma and Mycoplasma were significantly increased on damaged tissue. Notably, between relapse and first surgery, they documented significant microbiota differences regarding the class Bacteroidia, and the genera Prevotella, Flavobacterium, Tepidimonas and Escherichia/Shigella[90].

In the second study, the authors showed that the mucosal adherent microbiota was enriched in healthy compared to pathological mucosa. At the systemic level, a significant decrease of both circulating miR-155 and miR-223, as well as 2-methyl butyric, isobutyric, and hexanoic (caproic) acids was registered in relapse compared to the first surgery condition[91].

VISCERAL ADIPOSITY AS A MODULATOR OF INTESTINAL INFLAMMATION

MetS and IBD exhibit some critical similarities, including persistent low-grade inflammation, modified immunological responses, impaired adipokine signaling, and an elevated risk of cardiovascular consequences[92,93]. VAT is recognized as a significant contributor to the pathogenesis of MetS and is increasingly acknowledged as a source of systemic inflammation in both MetS and IBD[92,94]. VAT is marked by increased adipocytes and has aberrant adipokine production. It is significant that VAT is linked to reduced production of adiponectin, leptin, and other adipocytokines that are crucial in modulating both pro-inflammatory and anti-inflammatory signaling pathways[95]. In individuals with CD, reduced levels of adiponectin have been observed in both blood and mesenteric fat, suggesting that impaired anti-inflammatory signaling may contribute to the pathogenesis of CD[96]. In addition to changing the synthesis of adipokines, VAT also makes pro-inflammatory cytokines including monocyte chemoattractant protein-1, TNF-α, and IL-6. This brings in classically activated M1 macrophages and keeps the low-level inflammation going. M1 macrophages contribute to hepatic steatosis and lipid accumulation[92,94], hence exacerbating inflammatory responses. This persistent inflammation subsequently disturbs the homeostasis of adipose tissue and alters the secretion patterns of adipokines in both IBD and MetS. TNF-α, IL-6, and IFN-γ are examples of inflammatory mediators that further lower the production of lipoprotein lipase, which is an important enzyme in lipid metabolism. This makes dyslipidemia more likely to happen[96]. Numerous studies have demonstrated a correlation between IBD and a unique lipid profile marked by reduced total cholesterol and high-density lipoprotein (HDL) values. Because HDL has anti-inflammatory properties, a drop in its levels may not only mean that the disease continues to be active, but it additionally contributes to keeping intestinal inflammation going[97]. The latest research shows the essential role of adipose tissue to encourage intestinal inflammation in IBD, partially facilitated by immunomodulatory adipokines. Patients with CD and UC exhibit markedly increased circulating levels of pro-inflammatory adipokines, including resistin and visfatin, as compared to healthy controls[98,99]. In contrast, concentrations of adiponectin, leptin, and omentin-1 are generally decreased in IBD. The opposite association of these molecules with disease activity suggests they may serve an anti-inflammatory function in modulating intestinal inflammation[96,99,100].

STAGE-DEPENDENT IMMUNOMETABOLIC INTERACTION: A CONCEPTUAL MODEL SUPPORTED BY CLINICAL OBSERVATIONS

Despite growing recognition of the intersection between MetS and IBD, the immunological consequences of this comorbidity remain poorly defined. Notably, no prior clinical studies have systematically examined how different stages of MetS modulate immune function and mucosal inflammation in UC. Evidence from previously published studies suggests a stage-dependent biphasic model in which early metabolic disturbance is associated with attenuated inflammatory activity and regulatory immune polarization, while advanced metabolic dysfunction correlates with immune dysregulation and worsened disease severity. These findings introduce a potentially new conceptual framework for understanding immunometabolic reprogramming in UC and emphasize the need for metabolic stage- specific evaluation.

MetS attenuates UC through a galectin-3-IL-10 axis

In our previously published observational study[9] of 89 treatment-naive patients with newly diagnosed, confirmed UC, the authors explored the impact of coexisting MetS on disease severity and systemic and mucosal immune responses. The study suggested that MetS may be associated with a paradoxically protective immunomodulatory effect in UC. Patients who met criteria for MetS showed reduced eosinophilic and chronic infiltration on histopathology, as well as significantly lower clinical and endoscopic disease activity scores. Despite coexisting metabolic disturbances, these results were consistent across matched disease stages. Based on serum cytokine profiling, patients with MetS + UC had significantly higher levels of IL-10 and lower levels of IL-17, indicating a shift toward systemic immune tolerance. Moreover, this shift was indicated also by the decreased pro/anti-inflammatory cytokine ratios (TNF-α/IL-10, IL-6/IL-10, and IL-17/IL-10). In obesity, experimental studies showed that IL-10 acts through enhancing glucose uptake and insulin signaling with simultaneous reduction of macrophage infiltration and pro-inflammatory cytokine production in skeletal muscles, therefore preserving insulin sensitivity[101,102]. On the contrary, in the adipose tissue, IL-10 acts through suppression of thermogenesis and energy expenditure[103]. Importantly, human studies suggest that increased IL-10 expression in obesity and MetS may represent a compensatory anti-inflammatory response to chronic low-grade inflammation[104,105]. Thus, the elevated IL-10 levels observed in our MetS + UC cohort may reflect an immunoregulatory environment characteristic of MetS that subsequently modulates intestinal inflammation. Interestingly, this cytokine profile persisted across all matched clinical and histological stages of UC, suggesting that MetS may impose a stage-independent regulatory imprint.

Immunophenotyping of colonic mucosa further supported this tolerogenic state. Patients with MetS + UC displayed a higher proportion of CD4⁺ forkhead box protein P3 (FoxP3)⁺ Tregs and reduced CD8⁺ cytotoxic T cell infiltration. Moreover, IL-10-producing CD56⁺ natural killer (NK) cells and CD4⁺ T cells were enriched in the lamina propria. Additionally, fecal galectin-3 (Gal-3) levels were markedly elevated in MetS patients alongside increased frequencies of Gal-3⁺ natural killer T cells (NKT) and CD8⁺ FoxP3⁺ T cells in colonic tissue. Gal-3 has been implicated in both pro-inflammatory and anti-inflammatory pathways in IBD, depending on the cellular context and disease stage[106,107]. Beyond intestinal inflammation, Gal-3 is increasingly recognized as an important mediator of immunometabolic responses and has been associated with obesity, insulin resistance, metabolic dysfunction-associated steatotic liver disease, and cardiovascular complications[108-110]. Elevated Gal-3 levels in MetS may therefore represent an adaptive response to chronic metabolic inflammation, analogous to the compensatory increase in IL-10 observed in obesity-related conditions, pointing out to the potential association with regulatory immune phenotype in UC by MetS (Figure 1).

Figure 1 Proposed immunological features associated with a regulatory immune phenotype in ulcerative colitis patients with concomitant metabolic syndrome. The figure summarizes immunological observations reported in patients exhibiting metabolic characteristics consistent with an early-stage metabolic syndrome profile, including increased frequencies of regulatory T cells (Tregs) and elevated interleukin-10 production. Dendritic cells may sense microbial components through Toll-like receptor (TLR)-2 and TLR-4 signaling pathways and contribute to Treg differentiation, potentially supporting an anti-inflammatory immune environment. Increased representation of M2 macrophages and markers associated with epithelial repair have also been observed. In parallel, lower activity of T helper cell (Th) 1- and Th17-associated immune responses was identified in comparison with patients lacking these immunometabolic features. CVD: Cardiovascular disease; NAFLD: Non-alcoholic fatty liver disease; IL: Interleukin; Treg: Regulatory T cells; IDO: Indoleamine 2,3-dioxygenase; DC: Dendritic cell; TLR: Toll-like receptor; Th0: T helper type 0 cells; TNF: Tumor necrosis factor.

Late-stage MetS exacerbates UC severity through loss of regulatory balance

Building on the previously identified tolerogenic profile in UC patients with coexisting MetS, our subsequent study[10] stratified patients into four metabolic stages based on oral glucose tolerance test-derived glucose and insulin dynamics. Patients in the terminal (IV) stage of MetS, characterized by pathological glucose tolerance and normal/hypoinsulinemia, exhibited significantly more severe UC, evidenced by elevated Mayo endoscopic and clinical scores, along with intensified histological features such as chronic inflammatory infiltrates. These patients frequently presented with deep mucosal erosions, spontaneous bleeding, and architectural disruption, contrasting with milder findings in early-stage MetS. At the systemic level, stage IV MetS was associated with significantly elevated serum IL-6 and C-X-C motif chemokine ligand 8 (CXCL8), while levels of the galectin-1 (Gal-1) were significantly decreased, inversely correlating with glucose and insulin levels. Gal-1 is recognized as a multifunctional immunomodulatory molecule with predominantly anti-inflammatory effects[111]. However, in this study, a marked decline in Gal-1 levels in late-stage MetS coincided with UC severity, indicating a collapse of its regulatory influence. Notably, the ratios of Gal-1 to proinflammatory cytokines (Gal-1/TNF-α, Gal-1/IL-6, Gal-1/IL-17) were significantly lower in both serum and feces of late-stage MetS patients, suggesting a loss of regulatory dominance that previously correlated with milder disease. Although Gal-3 levels remained stable across stages, this imbalance between Gal-1 and proinflammatory cytokines may represent a tipping point in the immunological control of UC. Furthermore, mucosal immunophenotyping revealed a significant increase in CD56⁺ NK cells and CD8⁺ T cells in stage IV patients, which strongly correlated with disease severity. These cytotoxic populations are key mediators of epithelial damage in UC, reinforcing the notion that late-stage MetS fosters a more aggressive immune environment. In contrast, no significant differences were observed in the percentages of CD3⁺ CD56⁺ NKT cells, CD4⁺ T cells, CD19⁺ B cells, FoxP3⁺ Tregs, or in Gal-3 expression and cytokine production among the analyzed leukocyte populations across MetS stages. Taken together, these findings suggest a biphasic association between MetS and UC. Early-stage MetS is associated with an anti-inflammatory and tolerogenic immune phenotype characterized by elevated Gal-3 and IL-10 levels, reduced pro-/anti-inflammatory cytokine ratios, and less pronounced mucosal inflammation. In contrast, advanced MetS (stage IV) is associated with a loss of regulatory immune features and enhanced activation of pro-inflammatory pathways, including reduced Gal-1-mediated regulation, increased IL-6 and CXCL8 production, greater infiltration of cytotoxic immune cells, and more severe tissue injury (Figure 2). These observations highlight the importance of stage-specific immune profiling and therapeutic stratification in UC patients with MetS, as the immunological landscape associated with metabolic dysregulation appears to change substantially across disease progression.

Figure 2 Proposed immunological features associated with advanced metabolic dysfunction in ulcerative colitis. The figure summarizes immunological observations identified in ulcerative colitis patients with metabolic characteristics consistent with advanced or late-stage of metabolic syndrome. Impaired intestinal barrier integrity may be associated with increased activation of dendritic cells and M1-polarized macrophages, accompanied by enhanced T helper cell (Th) 1- and Th17-associated immune responses. These immune populations are linked to increased production of interferon-γ, interleukin-17, and other pro-inflammatory mediators, together with greater recruitment of innate immune cells. Concurrently, reduced regulatory immune activity and predominance of pro-inflammatory signaling pathways have been observed in association with increased inflammatory burden and epithelial injury. CVD: Cardiovascular disease; NAFLD: Non-alcoholic fatty liver disease; IL: Interleukin; TLR: Toll-like receptor; Th1: T helper type 1 cells; Th0: T helper type 0 cells; Th17: T helper type 17 cells; IFN: Interferon; TNF: Tumor necrosis factor.

Microbiome and metabolic correlates of the proposed immunometabolic stages

Emerging evidence suggests that distinct microbial and metabolite signatures may correspond to the two immunometabolic stages proposed in our model, offering a multidimensional perspective on how gut dysbiosis interacts with stage-dependent immune reprogramming in UC. In early-stage MetS, the relative preservation of SCFA-producing bacteria, including Faecalibacterium prausnitzii and Roseburia intestinalis, and higher butyrate availability may support mucosal IL-10 production and Gal-3-mediated tolerogenic signaling in dendritic cells and macrophages, thereby reinforcing the regulatory immune phenotype observed at this stage[71]. Butyrate is a well-established inducer of Treg differentiation and IL-10 secretion, and its mucosal availability may thus serve as a metabolic bridge between microbiota composition and the Gal-3/IL-10 tolerogenic axis. In contrast, advanced MetS is characterized by progressive depletion of protective commensals, overgrowth of LPS-producing taxa such as Escherichia coli and Bacteroides fragilis, and increased systemic endotoxemia[34,35]. This dysbiotic shift likely amplifies pro-inflammatory IL-6 and CXCL8 signaling, promotes M1 macrophage polarization, and contributes to the loss of Gal-1-mediated immune regulation observed in terminal-stage MetS. It must be acknowledged, however, that direct mechanistic evidence causally linking specific microbial signatures to Gal-3/IL-10 induction or Gal-1 depletion in the context of MetS-associated UC remains limited. These associations should therefore be regarded as hypothesis-generating, warranting dedicated prospective studies integrating longitudinal microbiome profiling, metabolomics, and mucosal immune phenotyping across MetS stages.

CLINICAL TRANSLATION AND THERAPEUTIC IMPLICATIONS

Stage-guided therapeutic strategies in metabolically comorbid IBD

Recent findings suggest the existence of immunometabolic transition in UC patients with concurrent MetS. Early stages appear to be associated by an IL-10-driven and Gal-3-rich tolerogenic profile, while advanced stages are associated with a proinflammatory state marked by diminished Gal-1 expression, increased IL-6 and CXCL8 levels, and increased infiltration of CD8⁺ and NK immune cells. These observations raise the possibility that integrating metabolic and immunological characteristics may improve patient stratification and provide additional insight into disease heterogeneity. Accurate metabolic stratification, attainable with oral glucose tolerance testing in combination with insulin profiling, may help identify distinct immunometabolic phenotypes associated with disease severity. We suggest the assessment of IL-10, IL-6, TNF-α, IL-17, CXCL8, Gal-1, and Gal-3 in both serum and stool, with calculated ratios such as Gal-1/IL-6, Gal-3/IL-17, and IL-10/IL-6. These composite markers may potentially show how effectively the immune and metabolic systems operate together and assist out how effectively a treatment will work. However, the clinical utility of these markers for prognosis, treatment selection, or therapeutic monitoring remains to be established in prospective studies. Notably, the absence of Gal-1 in advanced MetS indicates its dual function as a potential therapeutic target and a biomarker. In UC patients with advanced MetS, Gal-1 shows as a complex yet potential treatment possibility. Gal-1 has powerful anti-inflammatory and barrier-stabilizing effects in animal models of colitis[112]. However, its therapeutic application warrants caution given its pleiotropic and context-dependent roles: Elevated Gal-1 levels have been associated with insulin resistance and impaired glucose metabolism[113], and Gal-1 has been implicated in tumor progression and immune evasion in several cancer types, including promotion of an immunosuppressive tumor microenvironment through T cell apoptosis and Treg expansion[114]. These associations indicate that Gal-1-based interventions in patients with concurrent MetS and UC must be approached with careful patient stratification, excluding those with pre-existing metabolic dysfunction or oncological risk. In contrast, Gal-3 increases during the early stages of MetS, where it correlates with a tolerogenic immune profile, and displays context-dependent effects in IBD[106,107]. While its tolerogenic and mucosal-protective roles make it an attractive therapeutic candidate in early-stage disease, the adverse dimensions of Gal-3 biology must also be considered: Gal-3 has been implicated in the promotion of fibrosis across multiple organs, facilitation of tumor-promoting microenvironments through interaction with oncogenic signaling pathways, and pro-inflammatory macrophage activation during acute colitis[106]. Therefore, targeting Gal-3 requires meticulous patient stratification, particularly excluding patients with established fibrotic or neoplastic comorbidities, and precise timing of intervention to harness its regulatory effects while minimizing pro-fibrotic or pro-tumorigenic risks.

Targeting shared pathways: Barrier, microbiota, and immune modulation

UC and MetS share a number of pathophysiological axis, including disruption of epithelial barrier, microbial dysbiosis, and immunological polarization. This overlap makes it possible to use more than just traditional immunosuppression as a treatment. Agents that improve barrier integrity, like IL-22-based biologics[115,116], farnesoid X receptor agonists, insulin receptor signaling enhancers, and modulators of the urokinase-type plasminogen activator-urokinase-type plasminogen activator receptor axis, show promise in restoring mucosal homeostasis[117]. Microbial-based treatments such fecal microbiota transplantation, next-generation probiotics, prebiotics, and postbiotics may also change the gut-immune-metabolic interface[118]. These combined methods could help with inflammation in both the intestines and the whole body in those with UC and other metabolic problems. Targeting cytokines that are increased in both disorders, such as IL-6 and TNF-α, on the immunological front could have two benefits[119,120]. Anti-IL-6 treatments, including tocilizumab, are already used to treat rheumatoid arthritis. They have showed some potential in IBD trials[120] and should be studied in MetS-associated UC, especially in advanced stages when IL-6 levels are high.

Repurposing metabolic drugs for IBD

Recent findings open the door for the rational repurposing of metabolic drugs in UC. In addition to controlling glucose levels, MetS drugs such glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, semaglutide), metformin, and sodium-glucose co-transporter 2 (SGLT2) inhibitors also have anti-inflammatory properties. GLP-1 agonists reduce systemic inflammation by lowering levels of C-reactive protein and TNF-α[121], improve the integrity of the mucosa, and reduce inflammation in the intestines[122]. Experimental studies show that GLP-1 reduces DSS-induced colitis[123], whereas research indicates that GLP-1 analogs enhance outcomes in IBD patients with type 2 diabetes, particularly in those with obesity[124]. More recent clinical data indicate that GLP-1 receptor agonists are generally safe and well tolerated in patients with IBD and may be associated with reduced risks of hospitalization, corticosteroid use, and IBD-related surgery, although prospective randomized studies are still lacking[125-127].

In both in vitro and in vivo models, metformin has anti-inflammatory and antioxidant effects. It also enhances the integrity of the gut barrier and changes the microbiota in colitis models, which lowers intestinal inflammation[128]. Additionally, its administration in individuals with type 2 diabetes has been associated with a diminished chance of IBD developing[129].

SGLT2 inhibitors, currently used in the treatment of heart failure and chronic renal disease, demonstrate several kinds of immunomodulatory effects[130]. Recent experimental findings demonstrate that the SGLT-2 inhibitor empagliflozin significantly reduces DSS-induced colitis in murine models[131]. In addition, SGLT2 inhibitors inhibit M1 macrophage polarization and reduce IL-6-, TNF-α-, and monocyte chemoattractant protein-1-mediated inflammatory signaling[132-134]. Furthermore, a 2025 nationwide cohort study from Taiwan found that SGLT-2 inhibitor use was associated with a significantly reduced risk of incident IBD compared to dipeptidyl peptidase-4 inhibitors among patients with type 2 diabetes. Among 258355 patients, the incidence of IBD was substantially lower in the SGLT-2 inhibitor group (12.51 per 100000 person-years vs 35.83 per 100000 person-years), with an adjusted hazard ratio of 0.391 (95%CI: 0.237-0.645; P < 0.001). This association remained consistent across multiple sensitivity analyses and applied to both UC and CD subtypes[135].

These findings raise an interesting clinical question regarding the possible optimal timing of metabolic drug deployment across MetS stages. In early-stage MetS, where a tolerogenic immune profile predominates, GLP-1 receptor agonists and metformin may complement existing regulatory mechanisms, thought their effect on enhancing mucosal homeostasis, support barrier integrity, and prevent immunological escalation. In contrast, in terminal-stage MetS, where pro-inflammatory IL-6 and CXCL8 signaling dominates and Gal-1-mediated regulation is lost, metabolic agents alone are probably insufficient. At this stage, combination strategies incorporating anti-IL-6 therapy (tocilizumab, olokizumab), anti-TNF agents (infliximab, adalimumab), and SGLT2 inhibitors could be more appropriate, targeting both the inflammatory surge and the underlying metabolic dysfunction simultaneously. The proposed framework raises the possibility that the timing, dosing, and combination of these agents could be influenced by the patient's immunometabolic stage; however, further studies are required to determine the clinical utility of such an approach (Table 2).

Table 2 Hypothesized stage-specific immunometabolic biomarkers and therapeutic opportunities in metabolic syndrome-associated ulcerative colitis.

Target/mechanism	Proposed biomarker or therapy	Early-stage MetS (stage I-III)	Terminal-stage MetS (stage IV)
Gal-3	Candidate biomarker of regulatory immune activity	Elevated in our MetS + UC cohort; associated with the proposed tolerogenic phenotype	Less prominent; therapeutic relevance remains uncertain
Gal-1	Candidate biomarker and investigational target	Preserved expression	Reduced expression associated with the proposed pro-inflammatory stage; depleted candidate therapy; caution due to links with insulin resistance and cancer
IL-10	Candidate marker of regulatory immune responses	Elevated levels observed in MetS + UC; associated with immune regulation	Reduced relative contribution to the inflammatory profil
IL-6/CXCL8	Biomarker; therapeutic target	Generally not dominant inflammatory pathways	Increased levels associated with advanced-stage inflammation; rationale for investigating IL-6-directed therapies
TNF-α	Inflammatory biomarker; established therapeutic pathway	Monitoring may be informative	May contribute to inflammatory amplification; anti-TNF therapies remain relevant
Composite ratios (Gal-1/IL-6, Gal-3/IL-17, IL-10/IL-6)	Candidate staging biomarkers	Potential indicators of regulatory immune predominance	Potential indicators of inflammatory predominance
IL-22 pathway	Barrier-restoring strategy	Potential relevance for maintenance of epithelial integrity	Potential relevance for restoration of impaired barrier function
Microbiota-targeted therapy	FMT, next-gen probiotics, prebiotics, postbiotics	Preserve SCFA producers; support Gal-3/IL-10 axis	May help counter dysbiosis and endotoxin-associated inflammation
GLP-1 receptor agonists	Metabolic and immunomodulatory therapy	May be particularly relevant due to effects on metabolic homeostasis, barrier integrity, and low-grade inflammation	Potential adjunctive metabolic therapy; stage-specific efficacy unknown
Metformin	Metabolic and barrier-supportive therapy	Potentially relevant due to effects on microbiota and barrier function	Potential adjunctive metabolic therapy
SGLT2 inhibitors	Metabolic and immunomodulatory therapy	Limited stage-specific rationale currently available	Mechanistically attractive due to effects on IL-6 signaling and macrophage polarization; requires validation
FXR agonists/INSR enhancers/uPA-uPAR modulation	Mucosal homeostasis restoration	Potential modulators of metabolic and mucosal homeostasis	Potential adjunctive approaches requiring further study; combined with immunomodulators

MetS: Metabolic syndrome; Gal-1: Galectin-1; Gal-3: Galectin-3; IL: Interleukin; CXCL8: C-X-C motif chemokine ligand 8; TNF: Tumor necrosis factor; GLP-1: Glucagon-like peptide-1; SGLT2: Sodium-glucose co-transporter 2; FXR: Farnesoid X receptor; INSR: Insulin receptor; uPA/uPAR: Urokinase-type plasminogen activator and its receptor; FMT: Fecal microbiota transplantation; UC: Ulcerative colitis; SCFA: Short-chain fatty acids.

UNMET NEEDS, LIMITATIONS, AND FUTURE DIRECTIONS

In spite of the increasing recognition of the bidirectional relationship between IBD and MetS, an understanding of this relationship and its translational relevance is still lacking. Current clinical trial designs often exclude patients with metabolic comorbidities. As a result, the growing MetS patient population is underrepresented and the full potential impact of MetS on IBD progression, response to therapy, and long-term prognosis is not apparent. Additionally, MetS is composed of several different entities which can cause different immunological effect.

Although current evidence generally suggests a stronger association between MetS and UC than CD[8,20], the mechanisms underlying this difference remain incompletely understood. UC may be more susceptible to metabolic influences because of its colonic localization and continuous mucosal inflammation[20], whereas CD is frequently associated with small-bowel involvement, malabsorption, and distinct metabolic phenotypes[8,20,136]. Consequently, UC more often presents the age-related, inflammatory, colonic, treatment-related, and metabolic features that overlap with the classical MetS phenotype, whereas CD more frequently exhibits small-bowel, malabsorptive, or nonclassical metabolic patterns. However, this association should be regarded as a tendency rather than a universal rule, as findings remain heterogeneous across cohorts and certain metabolic traits, including obesity and metabolic-associated fatty liver disease, may be more strongly associated with CD in specific populations[137,138]. Additionally, disease-specific immune signatures in UC and CD may also contribute to the observed differences and should not be overlooked. Future prospective studies should determine whether individual MetS components differentially influence UC and CD, identify disease-specific immunometabolic pathways, and clarify whether metabolic interventions have distinct therapeutic implications across IBD subtypes.

Furthermore, the cross-sectional design of the foundational studies[9,10] precludes definitive conclusions regarding causal directionality. Reverse causality must be considered: Chronic intestinal inflammation in UC may itself promote MetS progression through prolonged glucocorticoid use, which induces visceral adiposity, insulin resistance, and dyslipidemia, as well as through increased intestinal permeability facilitating systemic endotoxemia, and persistent exposure to proinflammatory cytokines such as TNF-α and IL-6 that interfere with insulin signaling. The ideal validation approach would involve prospective cohort studies with baseline and follow-up monitoring of metabolic and immune dynamics in newly diagnosed, treatment-naive UC patients. It should be noted that the core data supporting the biphasic model were derived from 89 treatment-naive UC patients in the 2019 study[9], with a further stratified sub-cohort of stage IV MetS cases in the 2021 study[10]. These relatively small, single-center samples without independent validation sets limit the generalizability of the proposed model. This model should therefore be regarded as an exploratory finding requiring external validation in independent, multicenter cohorts with larger IBD populations. Although statistical effect measures such as Cohen’s d or 95%CIs were not recalculated in this narrative review, future validation studies should report standardized effect sizes and CIs to enable more robust quantification of the observed immunometabolic differences.

Longitudinal studies integrating metabolic profiling, immune phenotyping, and microbiome analysis are required to determine whether the proposed stage-dependent transitions occur consistently across patient populations. Proposed biomarkers such as Gal-1 and Gal-3 have context-depending roles and should be interpreted with cautious and confirmed in independent cohorts. Finally, current therapeutic implications remain largely speculative. Although several metabolic and immunomodulatory agents show promise in preclinical and early clinical settings, robust evidence supporting stage-specific treatment strategies in patients with coexisting MetS and IBD is lacking. Taken together, these limitations highlight the need for cautious interpretation of the proposed model and underscore its role as a hypothesis-generating framework rather than a clinically validated paradigm.

CONCLUSION

MetS is possibly not just a simple exacerbator of intestinal inflammation. It may function as a dynamic immune-metabolic modulator in IBD, potentially influencing its course in diverse ways. We suggest a two-phase model that highlights the potential of early stages of metabolic disturbances to drive immunosuppressive mechanisms, while advanced metabolic dysfunction is associated with exacerbation of local and systemic proinflammatory responses and subsequent mucosal damage. Based on these observations, we propose a biphasic conceptual framework describing potential stage-dependent interactions between MetS and IBD. While this model provides a plausible explanation for the heterogeneous relationship between metabolic dysfunction and intestinal inflammation, the current evidence remains largely associative and is based on a limited number of clinical and experimental studies. Therefore, the proposed immunometabolic stages and their therapeutic implications should be considered hypothesis-generating rather than definitive. Future longitudinal studies integrating clinical, immunological, microbiome, and metabolomic data will be required to validate this framework, clarify causal relationships, and determine whether immunometabolic stratification can improve patient characterization and guide therapeutic decision-making in IBD.