Background: Fatigue is common in patients with inflammatory bowel disease (IBD: Crohn's disease (CD), ulcerative colitis (UC)) with profound impairment of health-related quality of life. While active disease and nutritional deficiencies contribute to fatigue in some patients, up to 40% of patients with quiescent IBD report significant fatigue in the absence of overt causes. We examined whether subclinical inflammation or metabolomic abnormalities contribute to fatigue in a prospective cohort.
Methods: This prospective study enrolled patients with quiescent CD and UC defined as clinical remission and a colonoscopy within 1 year which demonstrated no active disease. Fatigue was assessed using the Multidimensional Fatigue Inventory (MFI) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores. A FACIT-F score <43 indicated significant fatigue. Serum samples from each parent were analyzed for a panel of 25 inflammatory cytokines and targeted metabolomics.
Results: Our study included 87 IBD (58 CD, 29 UC) patients in remission with a mean age of 40 years and disease duration of 13.6 years. The mean MFI was significantly higher (56 vs. 34) and FACIT lower (31 vs. 48) in patients with significant fatigue (p<0.0001). Those with significant fatigue reported lower SIBDQ scores (50 vs. 63) and greater anxiety (53 vs 43), depression (49 vs 43) and disturbed sleep t-scores (50 vs 43) compared to those without (p<0.001). There were no differences in disease related characteristics, demographics, or medication use between the two groups. Analysis of the log-transformed cytokine levels demonstrated significantly lower G-CSF (p=0.02), GM-CSF (p=0.003) (Fig. 1), and lymphotoxin α (p=0.069) in patients with fatigue. On metabolomic profiling, 15 metabolites were significantly different between those with and without fatigue (4 down-regulated, 11 up-regulated) (Table 1).
Key differences were identified in three pathways – pyrimidine metabolism, branched chain amino acid biosynthesis (valine, leucine, isoleucine), and glyoxylate and dicarboxylate metabolism.
Conclusions: Fatigue in IBD patients in remission is not due to a subclinical pro-inflammatory state. Rather, more complex immune dysregulation and metabolomic abnormalities contribute to this disabling symptom and could be therapeutic targets.