Molecular mechanisms of inflammatory bowel diseases and associated fatigue

Up to 80% of patients with inflammatory bowel disease (IBD) experience fatigue during active disease, and approximately half remain fatigued despite being in remission. Patients frequently identify fatigue as their most disabling symptom, yet established factors such as active inflammation, iron deficiency, sleep disturbances, and depression explain only half of the variation in fatigue severity. Why fatigue persists in the absence of overt inflammation remains unknown, and objective biomarkers are lacking.
This thesis investigated molecular mechanisms underlying fatigue in IBD using epigenomics, transcriptomics, metabolomics, autonomic physiology, and inflammasome biology. A key finding is that fatigue is not a uniform biological phenomenon but differs according to disease subtype (Crohn's disease versus ulcerative colitis) and disease activity (active disease versus remission). Combining these patient groups in research may dilute biological signals and obscure underlying mechanisms.
DNA methylation and mRNA expression profiles in peripheral blood differed markedly between disease subtype and activity. In patients with Crohn's disease in remission and severe fatigue, metabolomics revealed disturbed tryptophan metabolism, characterized by decreased kynurenine and increased serotonin levels, suggesting disease-specific mechanisms with kynurenine pathway metabolites as candidate biomarkers. A meta-analysis showed consistent upregulation of NLRP3 and IL1B in intestinal tissue from patients with IBD, highlighting the inflammasome as a promising target for future research. Finally, a pilot study using a wearable monitoring patch found that single heart rate variability measurements are insufficient to detect fatigue, emphasizing the need for longitudinal within-patient monitoring.
These findings provide a foundation for more targeted treatments and support stratifying patients by disease subtype and activity in future fatigue research.