Abstract Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by recurrent mucosal inflammation and oxidative stress-driven tissue injury, partly driven by dysregulated oxidative, nitrosative, and sulfur-based signaling pathways. However, the interplay of the electron exchange processes in relation to clinical and biochemical disease activity is not well understood. This exploratory study aimed to characterize systemic redox alterations in UC by profiling thiol-, sulfide-, and nitric oxide-related pathways in patients with active and quiescent UC, and healthy controls (HCs). Methods Plasma samples were obtained from 24 patients with UC (12 quiescent UC, 12 active disease) participating in a large IBD-cohort and from 12 age- and sex-matched HCs from a large population-based cohort study. The thiol redox redox metabolome was quantified using a validated ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) platform, enabling simultaneous nanomolar- level detection of reduced and oxidized glutathione, cysteine, homocysteine, and sulfide. Principal component analysis (PCA) was applied to identify data-driven biomarker patterns. Results Active UC showed significant disruptions across multiple redox-related metabolites compared with quiescent UC and HCs. Notably, the GSH/GSSG and Cys/CySS ratios were elevated in both quiescent and active UC compared to HCs and homocysteine levels were increased in active UC (Fig. 1A-C). ROC analyses demonstrated robust discrimination between quiescent and active UC, with the GSH/GSSG ratio achieving the highest accuracy (AUC=0.878) (Fig 1D-F). PCA revealed clear separation among HCs, quiescent, and active UC with four components explaining 49.1% of the cumulative variance (Fig. 2A-E). PC1 was dominated by high positive loadings of GSSG, GSH (free and protein-bound), and CysGly (total), reflecting an oxidative shift in redox equilibrium characterized by enhanced glutathione production and a more reduced extracellular redox state. In contrast, PC2 was primary driven by negative loadings of both free thiol and total form of GluCys. Conclusion This explorative study demonstrates that UC is characterized by systemic redox alterations distinct from classical ‘oxidative stress’ signatures. The coordinated alterations in glutathione-, cysteine-, and sulfur-related pathways indicate specific shifts in electron fluxes between major thiol and nitrosative systems, possibly reflecting a loss of redox homeostatic control in UC. These findings suggest that tissue oxidative stress in UC is accompanied by a marked shift in extracellular redox state towards enhanced reduction, indicative of an imbalance in redox equilibrium that extends beyond localized mucosal inflammation. Conflict of interest: Mr. Geertsema, Sem: No conflict of interest Minnion, Magdalena: No conflict of interest Bulthuis, Marian L. C.: No conflict of interest Reinders-Luinge, Marjan: No conflict of interest Dijkstra, Gerard: Grant: Royal DSM Personal Fees: Consultancy fee from Astra-Zeneca and Speakers fee from Abbvie Faber, Klaas-Nico: K.N.F received research grants from Janssen Pharmaceuticals, outside the submitted work. Feelisch, Martin: No conflict of interest Bourgonje, Arno R.: A.R.B. received speaker’s fees from AbbVie and Ferring, outside the submitted work.
Geertsema et al. (Thu,) studied this question.