Beyond inflammation control: Rethinking fatigue as a multidimensional target in Crohn’s disease management

Abstract

Fatigue is among the most disabling and least understood symptoms in patients with Crohn’s disease (CD), frequently persisting despite adequate pharmacological control of intestinal inflammation. In this editorial, we comment on the recent study by Morais et al published in the World Journal of Gastroenterology, which provides new evidence on psychological and hematological determinants of fatigue in CD. Traditionally viewed as a secondary manifestation of active disease or anemia, fatigue is increasingly recognized as a complex, multidimensional problem. Recent observational evidence highlights that fatigue in treated CD patients is strongly associated with psychological burden - including depression, anxiety, stress, and insomnia - as well as markers of immune imbalance, rather than classic nutritional deficiencies alone. These findings challenge the inflammation-centric paradigm that often dominates clinical decision-making in inflammatory bowel disease. Importantly, the coexistence of psychological distress and subtle hematological alterations suggests a bidirectional interaction between the brain, immune system, and gut that may perpetuate fatigue independently of overt disease activity. From a gastroenterology perspective, this has practical implications: Optimizing fatigue management in CD requires moving beyond escalation of anti-inflammatory therapy toward integrated assessment strategies that incorporate mental health, lifestyle factors, and immune profiles. Recognizing fatigue as a distinct therapeutic target may improve quality of life and patient-reported outcomes, underscoring the need for multidisciplinary approaches in the long-term management of CD.

Key Words: Crohn’s disease; Fatigue; Psychological distress; Gut-brain axis; Immune imbalance; Quality of life

Core Tip: Fatigue in Crohn’s disease persists in a substantial proportion of patients despite adequate control of intestinal inflammation and is increasingly recognized as a multidimensional clinical problem. Accumulating evidence suggests that psychological distress, sleep disturbance, and neuroimmune dysregulation play a central role in the pathogenesis and maintenance of fatigue, often outweighing traditional contributors such as anemia or biochemical disease activity. These editorial challenges the inflammation-centric paradigm and highlights fatigue as a distinct therapeutic target. Integrating mental health assessment, lifestyle factors, and emerging gut-brain axis mechanisms into routine care may substantially improve patient-reported outcomes and long-term quality of life in Crohn’s disease.

This editorial refers to "Psychological and hematological factors associated with fatigue in patients with Crohn's disease receiving pharmacological treatment" by Morais et al, 2026; https://doi.org/10.3748/wjg.v32.i5.115673.

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INTRODUCTION

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract characterized by a relapsing-remitting course and a broad spectrum of systemic manifestations[1,2]. Beyond intestinal inflammation, patients frequently experience symptoms that profoundly impair daily functioning and health-related quality of life, among which fatigue is one of the most prevalent and disabling[3,4]. Epidemiological studies indicate that nearly half of patients with inflammatory bowel disease report clinically significant fatigue, and notably, fatigue often persists even during periods of clinical and biochemical remission[5,6].

Traditionally, fatigue in CD has been interpreted as a secondary consequence of active inflammation, anemia, or nutritional deficiencies alone. Consequently, clinical management has largely focused on intensifying anti-inflammatory therapy or correcting hematological abnormalities[7]. However, accumulating evidence challenges this unidimensional view. Multiple observational and mechanistic studies demonstrate that fatigue severity correlates only weakly with objective markers of disease activity and often remains refractory to optimized pharmacological control[8,9]. This disconnect suggests that fatigue in CD represents more than a passive byproduct of intestinal inflammation.

Recent research has reframed fatigue as a complex, multidimensional phenomenon involving physical, cognitive, emotional, and behavioral domains[10,11]. Within this multidimensional framework, fatigue in CD can be conceptualized across interconnected biological, psychological, and behavioral domains. Psychological factors - particularly depression, anxiety, stress, and sleep disturbance - have emerged as dominant contributors, frequently mediating the relationship between disease activity and fatigue[12,13]. Recent observational evidence further supports this multidimensional profile, demonstrating that fatigue in pharmacologically treated patients with CD is independently associated with combined psychological distress (depression, anxiety, stress, and insomnia), sedentary lifestyle, and subtle hematological alterations, rather than inflammatory activity alone[14]. In parallel, growing attention has been directed toward the gut-brain axis and neuroimmune mechanisms, representing key biological pathways through which immune signaling, central nervous system processing, and peripheral inflammation interact, with neuroimaging and microbiome-based studies providing biological plausibility for central nervous system involvement in fatigue pathophysiology[15-17].

From a clinical perspective, these insights have important implications. Persisting fatigue not only diminishes quality of life but also contributes to reduced work productivity, impaired social participation, and increased psychological burden, including among patients with well-controlled disease activity[18,19]. Yet, fatigue remains under-recognized and undertreated in routine gastroenterology practice. As an editorial, this article aims to synthesize emerging evidence and stimulate clinical reflection on fatigue as a multidimensional and under-recognized therapeutic target in CD, rather than to provide a systematic or comprehensive review. As an editorial, this article comments on the recent study by Morais et al[14] published in the World Journal of Gastroenterology, critically evaluates its findings within the broader literature, and synthesizes emerging evidence on fatigue as a multidimensional target in CD management, critically appraise its underlying mechanisms, and discuss emerging assessment and intervention strategies that extend beyond inflammation control (Figure 1).

Figure 1 Conceptual framework of multidimensional fatigue in Crohn’s disease. CRP: C-reactive protein.

FATIGUE AS A MULTIDIMENSIONAL SYMPTOM IN CD

Limitations of the inflammation-centric paradigm

While active inflammation and anemia undoubtedly contribute to fatigue in CD, their explanatory power is limited. Several studies have demonstrated that fatigue frequently persists despite mucosal healing and normalized inflammatory biomarkers[9,20]. Structural modeling and path analyses further reveal that the direct effect of disease activity on fatigue is modest and often mediated through psychological variables rather than acting independently[12,21]. These findings underscore the inadequacy of relying solely on inflammatory indices to explain or manage fatigue.

Psychological burden and behavioral factors

Among non-inflammatory contributors, depression consistently emerges as the strongest predictor of fatigue severity in CD, often surpassing self-reported disease activity[14,22]. Anxiety, stress, insomnia, and maladaptive coping behaviors - such as all-or-nothing activity patterns and catastrophic thinking - also play important roles in fatigue persistence and progression[23,24]. Qualitative studies highlight that patients frequently perceive fatigue as overwhelming, unpredictable, and poorly validated by clinicians, further exacerbating emotional distress and functional impairment[18,25].

Neuroimmune and gut-brain axis mechanisms

Emerging evidence suggests that fatigue in CD may be driven by dysregulation within the gut-brain axis. Neuroimaging studies have identified alterations in brain morphology and sensorimotor regions associated with fatigue severity, even in patients in remission[10]. Concurrently, immunological and microbiome research has implicated chronic low-grade inflammation, cytokine signaling, and microbial metabolites in modulating central fatigue pathways[16,17,26]. These findings support a bidirectional model in which immune activity, psychological stress, and neural processing interact to perpetuate fatigue independently of overt intestinal inflammation.

Notably, the recent study by Morais et al[14] further reinforces this perspective by showing that fatigue in pharmacologically treated CD patients is more strongly associated with psychological distress and hematological alterations than with inflammatory activity itself. However, as a cross-sectional analysis, the study cannot establish causal relationships, underscoring the need for longitudinal and mechanistic investigations.

ASSESSMENT AND MANAGEMENT IMPLICATIONS

Challenges in fatigue assessment

Despite widespread use of validated fatigue instruments such as Functional Assessment of Chronic Illness Therapy-Fatigue, Multidimensional Fatigue Inventory, and Patient Reported Outcome Measurement Information System scales, there remains no universally accepted, CD-specific fatigue assessment tool[11]. The heterogeneity of measurement approaches limits comparability across studies and complicates clinical implementation. From a pragmatic clinical perspective, persistent fatigue in patients with CD - particularly during clinical or biochemical remission - should prompt targeted screening for common and potentially modifiable contributors, including psychological distress (e.g., depression or anxiety), sleep disturbance, and residual or recurrent hematological abnormalities such as anemia. For gastroenterologists, incorporating fatigue assessment into routine CD follow-up represents an essential extension of disease monitoring beyond inflammatory activity alone. Integrating patient-reported outcomes with psychological screening and objective disease markers may provide a more comprehensive and clinically meaningful assessment framework (Table 1).

Table 1 Rethinking fatigue in Crohn’s disease: Multidimensional contributors beyond inflammation.

Domain	Representative factors	Evidence summary	Clinical implications
Inflammatory	Residual inflammation; cytokine signaling	Weak and inconsistent association with fatigue severity in remission	Inflammation control alone is insufficient for fatigue resolution
Psychological	Depression; anxiety; stress; insomnia	Strongest and most consistent predictors across observational studies	Routine screening and integration of psychological interventions are essential
Behavioral	Physical inactivity; maladaptive coping; sleep disturbance	Contributes to persistence and fluctuation of fatigue symptoms	Lifestyle modification and behavioral therapy should be incorporated
Hematological	Anemia; subclinical hematological alterations	Contributory but does not fully explain fatigue burden	Correction of abnormalities should be combined with broader assessment
Neuroimmune (gut-brain axis)	Microbiome alterations; neuroinflammation; CNS changes	Emerging mechanistic evidence linking immune signaling to central fatigue	Potential target for future mechanistic and therapeutic studies

CNS: Central nervous system.

Toward integrated, multidisciplinary management

Intervention studies increasingly support psychological therapies - particularly cognitive-behavioral therapy and mindfulness-based cognitive therapy - as effective strategies for reducing fatigue and improving quality of life[27,28]. From a multidisciplinary perspective, these approaches represent key contributions from psychiatry and psychology, addressing maladaptive coping patterns, mood disturbances, and fatigue-related cognitive burden. Lifestyle interventions addressing sleep, physical activity, and stress management further complement pharmacological treatment[29]. Such strategies often involve collaboration with primary care physicians, sleep specialists, physiatrists, and allied health professionals, emphasizing non-pharmacological optimization alongside standard gastroenterological care. Within this framework, gastroenterologists play a central coordinating role by excluding ongoing inflammatory activity and reversible organic contributors, while other disciplines contribute targeted symptom-focused interventions, collectively addressing fatigue through complementary rather than drug-specific approaches. Importantly, patient preference studies indicate strong acceptance of psychologically informed and digitally delivered interventions, suggesting feasible pathways for integration into routine care[30,31].

CONCLUSION

Fatigue in CD represents a prevalent, disabling, and multifactorial symptom that cannot be adequately explained or managed through inflammation control alone. A growing body of evidence supports a multidimensional conceptualization in which psychological distress, behavioral factors, and neuroimmune mechanisms play central and interrelated roles. Recognizing fatigue as a distinct therapeutic target has important clinical implications, calling for routine assessment beyond disease activity indices and for integrated, multidisciplinary management strategies. As a concise and conceptually focused editorial, this article aims to provide an accessible introduction to fatigue as a multidimensional therapeutic target for clinicians involved in CD care. Future research should prioritize standardized fatigue measurement, longitudinal studies elucidating causal pathways, and adequately powered intervention trials. Ultimately, rethinking fatigue within a biopsychosocial framework offers a critical opportunity to improve patient-centered outcomes and long-term quality of life in CD.