Systemic antibody responses against bacterial and viral antigens associate with fatigue in patients with inflammatory bowel disease.

Fatigue is common and debilitating in inflammatory bowel disease (IBD), but its etiology remains unclear. Phage-display immunoprecipitation sequencing (PhIP-Seq) was used to profile systemic antibodies against 344,000 rationally selected peptide antigens in 327 patients with IBD, assessing associations with fatigue severity across quartiles and in a remission sub-cohort. No individual antibody remained significant after multiple testing correction. However, aggregation-based analyses identified recurring differences involving Epstein-Barr virus (EBV), influenza virus, and Staphylococcus antigens. Higher fatigue was associated with lower responses to EBV early antigen protein D (EA-D) and higher responses to EBV nuclear antigens (EBNA-1, EBNA-3), as well as influenza M1/M2 proteins and Staphylococcus clumping factor B. These patterns were not statistically robust and may reflect random variation or disease-/exposure-related factors. Given broader evidence linking EBV-related immune responses to immune-mediated diseases, these observations warrant further investigation. Overall, this study illustrates challenges of linking high-dimensional immune data to complex clinical symptoms.