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

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.