The integrative evaluation of pathophysiological and clinical relevance of biomarkers in inflammatory bowel disease: a narrative review

Introduction

Background

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic relapsing inflammatory disorder of the gastrointestinal tract (1-4). IBD is most prevalent in North America, Europe, and Oceania; however, the number of cases has risen rapidly in Asia, South America, and Africa (5). Although regional variations exist, sex differences in disease prevalence remain small (5,6). Despite therapeutic advances, a complete cure remains elusive, and IBD continues to impose substantial clinical and socioeconomic burden worldwide (7,8).

The pathogenesis of IBD involves complex interactions between genetic susceptibility, environmental triggers, intestinal microbiota alterations, and immune dysregulation (9,10). Genome-wide association studies have identified multiple susceptibility loci linked to innate and adaptive immune pathways, epithelial barrier functions, and microbial sensing (11,12). At the cellular level, intestinal inflammation is orchestrated by activated macrophages, neutrophils, and T lymphocytes (10,13-17). Macrophage-derived cytokines contribute to epithelial injury and inflammatory cascades (10,15). Neutrophil infiltration into the mucosa and lumen is a pathological hallmark of active disease and is associated with mucosal damage (16,17).

In UC, long-standing inflammation increases the risk of colorectal cancer, underscoring the need for accurate disease monitoring (18). These findings highlight the need for noninvasive biomarkers that reflect intestinal inflammation and support activity monitoring and therapy-response prediction.

Compared with recent biomarker reviews, our novelty lies in a unified framework that connects pathophysiological source/pathway, sample type/assay considerations, and clinical readiness across stool, blood, and urine biomarkers. Establishing the clinical utility and appropriate application of these biomarkers may enhance the precision of disease assessment and support less-invasive patient management.

Rationale and knowledge gap

Despite advances in endoscopy and histopathology, the clinical management of IBD relies heavily on invasive assessments and non-specific systemic inflammatory markers. Conventional indices, such as white blood cell and platelet counts, as well as the erythrocyte sedimentation rate (ESR), fluctuate in response to inflammation but lack disease specificity (19,20). Although widely used, serum C-reactive protein (CRP) reflects systemic rather than intestinal inflammation, and its correlation with endoscopic disease activity, particularly in UC, remains inconsistent (19-21).

These limitations underscore the need for non-invasive, organ-specific, and quantitatively reliable biomarkers that can accurately reflect intestinal inflammation, predict disease activity, and assess therapeutic responses. For example, the current European Crohn’s and Colitis Organization-European Society of Gastrointestinal and Abdominal Radiology (ECCO-ESGAR) guideline encourages using fecal biomarkers to monitor disease activity and avoid unnecessary endoscopic procedures (22). Although numerous promising candidates have been proposed, their diagnostic performance, optimal cutoff values, and clinical applicability remain incompletely defined. The reported sensitivity and specificity vary depending on the disease subtype, sample type, and assay methodology.

Accordingly, the systematic evaluation of emerging biomarkers is essential to better delineate their pathophysiological relevance, analytical characteristics, and potential roles in clinical practice. Addressing these gaps may facilitate the development of more accurate and less invasive monitoring strategies for both UC and CD patients.

Proposed criteria for an adequate biomarker in IBD

An adequate IBD biomarker should demonstrate clinical validity (clear use case and correlation with objective endpoints), analytical validity (standardized, reproducible measurement with defined cutoffs), and implementation feasibility (minimally invasive, practical, and adding value beyond CRP/ESR).

Objective

This review aimed to evaluate emerging biomarkers and candidate molecular factors associated with IBD, including fecal, urinary, and serum indicators. By summarizing their biological characteristics, analytical properties, cutoff values, and clinical applicability, this article seeks to clarify their pathophysiological relevance, diagnostic and prognostic potential, and limitations as noninvasive tools for assessing disease activity and therapeutic response in UC and CD. We present this article in accordance with the Narrative Review reporting checklist (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-69/rc).

Methods

Search strategies and results

A literature search was conducted for English-language articles through November 2025, using MEDLINE and Google Scholar. Eligible full-text articles were reviewed, and assay characteristics, cutoffs, and clinical applications were extracted.

The overall search strategy is presented in Table 1. As summarized in Table 2 and Figure 1, the following biomarkers were identified: S100A8/A9 (calprotectin), S100A12 (calgranulin C), leucine-rich alpha2 glycoprotein (LRG), prostaglandin E-major metabolite (PGE-MUM), neutrophil gelatinase–associated lipocalin (NGAL), oncostatin M (OSM), anti-integrin αvβ6 antibody, and perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA).

Figure 1 Overview of biomarker sources, sample types, and clinical roles in IBD. COX, cyclooxygenase; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; LRG, leucine-rich α2-glycoprotein; NGAL, neutrophil gelatinase–associated lipocalin; OSM, oncostatin M; p-ANCA, perinuclear anti-neutrophil cytoplasmic antibody; PGE₂, prostaglandin E₂; PGE-MUM, prostaglandin E-major urinary metabolite; UC, ulcerative colitis.

S100A8/A9 (calprotectin)

S100A8 and S100A9 are members of the S100 protein family that form the heterodimer S100A8/A9 (calprotectin), which is highly expressed in neutrophils, monocytes, and macrophages, and localizes primarily to the cytoplasm and cell membrane (23-25). Their expression markedly increases during acute inflammatory responses (24,25).

In IBD, intestinal inflammation promotes the excessive release of calprotectin from infiltrating neutrophils and macrophages, leading to elevated fecal concentrations (26-31). Fecal calprotectin shows a strong correlation with endoscopic activity and demonstrates a particularly high accuracy in evaluating disease severity in UC (28-33). It is also useful for distinguishing IBD from irritable bowel syndrome (IBS) (31). The reported cutoff values for detecting endoscopic activity vary considerably, typically ranging from 50 to 500 µg/g (30-32). Lower thresholds (50–80 µg/g) improve sensitivity and reduce the likelihood of missing active inflammation, whereas values of around 170 µg/g provide higher specificity (32,33).

However, fecal calprotectin may show limited elevation in isolated small intestinal diseases, as is commonly observed in CD (34,35). Recent studies have indicated that serum or plasma calprotectin may reflect UC activity (36,37), although its disease specificity is lower than that of stool calprotectin, suggesting that blood-based measurements may require combination with other biomarkers for optimal diagnostic performance. In addition, another established fecal marker is lactoferrin, an iron-binding glycoprotein released from activated neutrophils (38). In a comparative study, fecal lactoferrin was reported to be ~90% specific for identifying inflammation in active IBD and 100% specific for ruling out IBS (38).

S100A12 (calgranulin C)

S100A12 (calgranulin C) is a calcium-binding protein of the S100 family that is produced almost exclusively by neutrophils, with increasing concentrations in the intestinal mucosa and systemic circulation during inflammatory responses (27,39). Because it reflects localized intestinal inflammation more specifically than calprotectin, which can increase both intestinal and systemic inflammation, S100A12 has attracted interest as a stool-based biomarker (27,39).

Stool is considered an appropriate sample type for S100A12 measurement, and the protein demonstrates high stability, remaining unchanged for up to 7 days at room temperature, greater stability than that observed for calprotectin (40,41). Reported cutoff values for distinguishing IBD from non-IBD range from approximately 0.8–10 µg/g, with higher thresholds generally applied in pediatric populations (26,42). Notably, S100A12 shows excellent diagnostic performance for pediatric IBD, achieving a sensitivity of 96% and specificity of 92% (42). Taken together, the consistently high diagnostic performance reported in pediatric IBD underscores the clinical potential of fecal S100A12 as an emerging biomarker.

Despite these advantages, assays for S100A12 remain primarily in the research domain and standardized clinical reference values have not been established. In addition, S100A12 levels may be elevated in infectious enteritis, parasitic infections, and intestinal dysbiosis, which may reduce disease specificity in certain contexts (43).

Leucine-rich alpha2 glycoprotein (LRG)

LRG is a 50-kDa glycoprotein produced primarily by hepatocytes and myeloid immune cells (44-46). Serum LRG levels are closely correlated with endoscopic disease activity in IBD (47-49). Because LRG is induced not only by interleukin (IL)-6, but also by cytokines such as tumor necrosis factor (TNF)-α and IL-22, it is particularly useful for evaluating disease activity in patients whose CRP levels remain within the normal range (49,50).

The cutoff values for serum or plasma LRG associated with endoscopic activity generally range from 10 to 16 µg/mL (51-53). Concentrations of 10–13 µg/mL often distinguish remission from mild activity, whereas levels of 15–16 µg/mL are commonly used to identify active inflammation (51-53). Because LRG reflects inflammatory activity in both the small and large intestines and can be easily measured in the serum, it offers substantial practical utility (54).

However, LRG has limited disease specificity. Concentrations increase in a wide range of inflammatory, neoplastic, and metabolic conditions, and thus, may be influenced by comorbidities or underlying systemic inflammation (55-57). As an acute-phase reactant, LRG shares with CRP the limitation of being elevated in non-IBD inflammation; nevertheless, LRG may retain sensitivity in some patients with active IBD whose CRP remains within the normal range, supporting its role as a complementary marker to CRP (49,50,55-58).

Prostaglandin E-major metabolite (PGE-MUM)

PGE-MUM is the final metabolic product of prostaglandin E₂ (PGE₂), and its urinary excretion reflects total systemic PGE₂ production (59-61). Urinary PGE-MUM may serve as a non-invasive gauge of global inflammatory activity via systemic PGE₂ production. PGE₂ is synthesized by various cell types, including macrophages, intestinal epithelial cells, fibroblasts, endothelial cells, and neutrophils, and the inflammatory activity in IBD leads to increases in both PGE₂ and urinary PGE-MUM levels (59-64). As PGE-MUM measurement requires only a urine sample, it offers a practical advantage over stool or blood sampling. Multiple studies have demonstrated strong correlations between urinary PGE-MUM concentrations and endoscopic inflammation (62-64).

Urinary PGE-MUM is commonly expressed as µg/g creatinine (Cr) because creatinine correction helps to account for variability in urine concentration (64). Cutoff values of approximately 17–30 µg/g Cr have been proposed to indicate endoscopic activity (65-67).

However, PGE-MUM lacks intestinal specificity. As a marker of systemic PGE₂ production, it increases in a wide range of inflammatory diseases and infections (59,68,69). Environmental and physiological factors, including smoking, obesity, and aging, can also elevate urinary PGE-MUM levels (70,71). Although creatinine correction reduces hydration-related variability, it is also influenced by the muscle mass and renal function. Consequently, both creatinine-corrected values (µg/g Cr) and absolute concentrations (ng/mL) are used in clinical research (59,71,72). While fecal calprotectin and CRP are explicitly endorsed in ECCO-ESGAR guideline as primary non-invasive markers for monitoring IBD activity, PGE-MUM is not specifically recommended and should therefore be regarded as an investigational biomarker at present (22).

Neutrophil gelatinase-associated lipocalin (NGAL)

NGAL (also known as lipocalin-2) is a 25-kDa protein involved in iron transport and immune regulation (73,74). It is abundantly stored in neutrophil secondary granules but is also expressed in macrophages, intestinal epithelial cells, hepatocytes, and distal renal tubules (75,76). Although NGAL is traditionally used as a biomarker of kidney injury, it has recently gained attention in the context of IBD (77,78). Several studies have suggested that fecal NGAL reflects intestinal inflammation and shows diagnostic performance comparable to, and potentially complementary with, fecal calprotectin (79,80).

Compared to calprotectin, NGAL measurement remains less standardized across biological samples. Reported serum NGAL cutoff values include 42.1 ng/mL for distinguishing active from inactive IBD and 43.6 ng/mL for differentiating active disease from remission in UC (81). A higher cutoff of 196.9 ng/mL has been proposed to differentiate IBD from IBS (82). However, urinary and fecal NGAL measurements are not yet standardized in routine practice, which limits its immediate clinical applicability.

Because serum and urinary NGAL levels markedly increase under conditions of renal impairment, their utility for assessing IBD activity is limited in patients with kidney dysfunction (77,78). Furthermore, exploratory studies have examined matrix metalloproteinase (MMP)-9/NGAL complexes as additional biomarkers with potential diagnostic relevance (83).

OSM

OSM is a cytokine of the IL-6 family that is predominantly produced by neutrophils, macrophages, and T cells (84). OSM contributes to intestinal epithelial barrier disruption and enhances the expression of inflammatory cytokines such as IL-6, IL-1β, and TNF-α (84,85). In IBD, high OSM expression in the intestinal mucosa has been associated with poor response to anti-TNF therapy, positioning OSM as both a potential therapeutic target and a promising diagnostic biomarker (85).

Serum OSM cutoff values proposed for predicting response to anti-TNF treatment include 168.7 pg/mL for CD and 233.6 pg/mL for UC (85). For distinguishing IBD from non-IBD, lower thresholds, such as approximately 78.5 pg/mL have also been reported (86). In UC, OSM levels decrease with clinical and endoscopic remission and correlate strongly with Mayo score and fecal calprotectin levels (86,87). Although OSM is often highlighted as UC-associated because it tracks UC activity, elevated OSM has also been reported in active CD; however, OSM may remain high even in remission, limiting its utility for CD activity monitoring (85-88). Accordingly, OSM is likely more informative as a prognostic biomarker for therapeutic response (e.g., anti-TNF non-response) than as an activity marker, particularly in CD.

However, OSM lacks disease specificity, as elevations are observed in numerous inflammatory, fibrotic, and neoplastic conditions (84,89). This limits its utility as a standalone marker and highlights the need for complementary biomarker approaches.

Anti-integrin αvβ6 antibody

Integrin αvβ6 is an epithelial-specific heterodimer that is absent in normal intestinal epithelium and is induced only during epithelial repair (90,91). It plays a crucial role in activating transforming growth factor (TGF)-β, which exhibits anti-inflammatory and immunosuppressive properties but also contributes to fibrosis (92,93). In UC, circulating immunoglobulin G (IgG) autoantibodies against integrin αvβ6 have been identified as a serum biomarker, and these autoantibodies bind αvβ6 and may modulate αvβ6-related signaling, including TGF-β activation (92,93).

Recent studies have reported frequent detection of this autoantibody in UC, including a nationwide multicenter validation study, supporting its robustness as a novel serological biomarker (94,95). Proposed cutoff values of 1.64 and 1.68 U/mL have yielded sensitivities of 87.7–87.9% and specificities of 82.0–86.8% for distinguishing UC from non-UC controls (94,95). Although positivity can be observed in a minority of CD patients (particularly those with colonic involvement), anti-αvβ6 autoantibodies are generally far less frequent in CD and may therefore serve as a supportive serological discriminator favoring UC over CD (94,95). To date, no validated cutoff values for CD have been established. As αvβ6 expression is upregulated early during epithelial injury, this autoantibody serves as a UC-specific marker that may support early disease detection (94-96).

However, antibody titers tend to remain chronically elevated and do not reliably reflect short-term changes in the inflammatory activity (95,96). In addition, mild positivity has been reported in some autoimmune liver diseases and fibrotic disorders, although potential false positives have not been fully characterized (97,98).

p-ANCA

p-ANCA, while a longstanding serological marker in UC, is discussed here as an immunological indicator that may support IBD subtype classification. Based on the characteristic immunofluorescence staining patterns, ANCA is classified into cytoplasmic ANCA (c-ANCA) and p-ANCA (99,100). c-ANCA predominantly targets proteinase-3 and is commonly associated with polyarteritis nodosa (99,100).

In contrast, p-ANCA typically recognizes myeloperoxidase, whereas atypical p-ANCA directed against antigens such as elastase, lactoferrin, or cathepsin G is particularly prevalent in patients with UC (101,102). Atypical p-ANCA is also frequently detected in individuals with coexisting primary sclerosing cholangitis and UC (103).

A universal cutoff for atypical p-ANCA in UC has not been established because of substantial variability in assay methodologies, including indirect immunofluorescence and antigen-specific enzyme-linked immunosorbent assays and chemiluminescent enzyme immunoassay assay, as well as differences in antigen targets (104). Clinically, p-ANCA is reported to be positive in approximately 40–70% of patients with UC but is much less frequent in CD, supporting its use as a serological aid for differentiating UC from CD (101-104). However, because of limited sensitivity, heterogeneous antigen targets, and poor reflection of short-term disease activity, p-ANCA is mainly of diagnostic value rather than a marker for routine disease monitoring (101-104).

Limitations

Several limitations associated with the present study warrant mention. First, despite efforts to comprehensively summarize the current evidence, the available studies remain highly heterogeneous in study design, patient characteristics, disease subtypes, assay methodologies, and sample handling practices, which can hinder direct comparisons and limit the feasibility of meta-level interpretations. Many biomarkers, including fecal calprotectin, serum LRG, and urinary PGE-MUM, still lack standardized measurement protocols and clinically validated cutoffs, contributing to variability in reported diagnostic performance. Current literature is dominated by data from adult populations. Pediatric and elderly patients are underrepresented despite likely differences in the immune function and microbiome composition.

Most of the included studies were cross-sectional or single-center investigations, with relatively small sample sizes. Large prospective multicenter studies remain limited, and few have evaluated longitudinal changes in biomarker levels during remission, relapse, or therapeutic intervention. Consequently, the long-term predictive value, stability, and reproducibility of these biomarkers remain uncertain.

Conclusions

The search for reliable, noninvasive biomarkers for IBD has progressed over the past decade, driven by the need for more precise tools to support diagnoses, disease monitoring, and therapeutic decision-making. Conventional systemic markers such as CRP and ESR are clinically useful, yet they lack intestinal specificity. In contrast, the emerging biomarkers reviewed in this article demonstrate stronger associations with mucosal and histological inflammation and offer deeper insights into the dynamic immunological processes underlying IBD.

Given the multifactorial nature of IBD, no single biomarker can comprehensively reflect disease activity or reliably predict treatment outcome. In addition, underexplored endocrine factors—such as gastrointestinal hormones (e.g., gastrin)—may offer adjunct information beyond inflammatory pathways; recent evidence suggests that fasting serum gastrin levels can differ between UC, CD, and controls (105). A multi-marker approach that integrates molecular, immunological, and microbiome-derived indicators is likely to improve diagnostic accuracy and prognostic capability. Omics and artificial intelligence may support early detection and personalized care. Elucidating the mechanistic roles of individual biomarkers is crucial for successful clinical translation.

In summary, although notable progress has been made in identifying promising biomarkers of intestinal inflammation, important challenges remain, including assay heterogeneity, a lack of standardization, and limited clinical validation. Future research should prioritize robust, standardized multi-marker panels that integrate biochemical, genetic, and microbial signals, consistent with treat-to-target frameworks that advocate combined objective assessments, such as Selecting Therapeutic Targets in Inflammatory Bowel Disease II (STRIDE-II) and ECCO-ESGAR guideline (22,106). Such approaches have the potential to refine disease stratification, guide therapeutic decisions, and advance our understanding of IBD pathophysiology.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-69/rc

Peer Review File: Available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-69/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-2025-1-69/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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