Serum thiol redox-related alterations in asymptomatic first-degree relatives are associated with future Crohn's disease

BACKGROUND: Increased oxidative stress is well documented in patients with Crohn's disease (CD). However, it remains unclear whether early redox-related alterations occur prior to diagnosis and whether they are correlated with early alterations in inflammatory responses. AIMS: We examined whether the serum cysteine sulfinic acid to cysteine ratio, as a redox-related marker indicative of sustained oxidative conditions, is associated with future CD risk and correlated with gut and systemic inflammation, proteomic, and metabolomic profiles. METHODS: In the Genetic, Environmental, and Microbial (GEM) Project, 79 healthy first-degree relatives (FDRs) who later developed CD (Pre-CD) were identified and matched by age, sex, geographic location, and time of recruitment with 311 FDRs who remained disease-free. Conditional logistic regression assessed the association between redox biomarkers and future CD risk. Partial Spearman correlation assessed correlations between the cysteine sulfinic acid to cysteine ratio and C-reactive protein (CRP), fecal calprotectin (FCP), serum metabolites (Metabolon®), and serum proteomic profiles (Olink®). RESULTS: An elevated serum cysteine sulfinic acid to cysteine ratio was positively associated with the risk of developing CD (odds ratio = 2.06, 95% CI: 1.42-3.00, p = 0.00015) and showed a positive correlation with CRP (coefficient = 0.296; p = 3.04e-09) and FCP (coefficient = 0.123; p = 0.0198) levels. A total of 295 metabolites and 201 proteins were correlated with the cysteine sulfinic acid to cysteine ratio. CONCLUSION: This study provides new evidence that redox-related alterations are present during the preclinical phase prior to CD onset.