Biomarker signatures in pathophysiology and therapeutic interventions in inflammatory bowel diseases:a multimodal approach

Inflammatory bowel disease (IBD) is a term mainly used to describe two diseases: Crohn’s disease (CD) and ulcerative colitis (UC). These are complex diseases of the gastrointestinal tract, characterised by a relapse-remitting disease course. Hence, IBD is difficult to predict and to adequately treat. Since IBD is a complex, heterogeneous and unpredictable disease, there is an urgent need for biomarkers, which are objectively measured parameters of (ab)normal biological processes or -systems, which may help to (early) diagnose and classify IBD, to assess disease activity and disease complications, and to accurately predict how a patients’ disease course will develop and/or how a patient will respond to a particular treatment. The findings presented in this thesis represent a number of newly identified biomarkers for multiple disease outcomes in patients with IBD. These outcomes included, but were not limited to, diagnosis and classification (Part I), disease activity and complications (Part II and III), and modulation by and prediction of treatment effects (Part IV). This thesis adopted a multimodal approach by exploring biomarkers from different biological perspectives and by performing laboratory-, clinical- and computational research (and combinations thereof). We demonstrated that immune system components (Part I), inflammation, permeability and fibrosis (Part II), and oxidative stress (Part III) provide excellent resources for biomarker discovery and application. The work presented in this thesis sheds light on the establishment of a “systems biology” approach, studying the interplay between multiple disease processes to establish personalised medicine for patients with IBD, thereby improving outcomes of patients with IBD

Clinical Value of Multiomics-Based Biomarker Signatures in Inflammatory Bowel Diseases:Challenges and Opportunities

Inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are complex and heterogeneous diseases characterized by a multifactorial etiology, therefore demanding a multimodal approach to disentangle the main pathophysiological components driving disease onset and progression. Adoption of a systems biology approach is increasingly advocated with the advent of multi-omics profiling technologies, aiming to improve disease classification, to identify disease biomarkers and to accelerate drug discovery for patients with IBD. However, clinical translation of multi-omics-derived biomarker signatures is lagging behind, since there are several obstacles that need to be addressed in order to realize clinically useful signatures. Multi-omics integration and IBD-specific identification of molecular networks, standardization and clearly defined outcomes, strategies to tackle cohort heterogeneity, and external validation of multi-omics-based signatures are critical aspects. While striving for personalized medicine in IBD, careful consideration of these aspects is however needed to adequately match biomarker targets (e.g. the gut microbiome, immunity or oxidative stress) with their corresponding utilities (e.g. early disease detection, endoscopic and clinical outcome). Theory-driven disease classifications and predictions are still governing clinical practice, while this could be improved by adopting an unbiased, data-driven approach relying on molecular data structures integrated with patient and disease characteristics. In the foreseeable future, the main challenge will lie in the complexity and impracticality of implementing multi-omics-based signatures into clinical practice. Still, this could be achieved by developing easy-to-use, robust and cost-effective tools incorporating omics-derived predictive signatures and through the design and execution of prospective, longitudinal, biomarker-stratified clinical trials

Clinical implications of vitamin B₁₂ as redox-active cofactor

Vitamin B12 is a redox-active compound containing a cobalt atom that cycles between oxidation states. Superoxide scavenging induces its oxidation, disabling activation of the enzymes methionine synthase and methylmalonyl-CoA mutase, disrupting gene expression and energy production. High-dosed vitamin B12 may be clinically used to reduce oxidative stress and preserve cofactor functions

Plasma Citrate Levels Are Associated with an Increased Risk of Cardiovascular Mortality in Patients with Type 2 Diabetes (Zodiac-64)

Circulating citrate may represent a proxy of mitochondrial dysfunction which plays a role in the development of vascular complications in type 2 diabetes (T2D). Here, we determined the associations between plasma citrate levels and cardiovascular (CV) mortality in T2D patients. In this prospective cohort study, 601 patients were included who participated in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC). Plasma citrate levels were measured by nuclear magnetic resonance spectroscopy. Cox proportional hazards regression models were used to evaluate the associations between plasma citrate and the risk of CV mortality. Over a median follow-up of 11.4 years, 119 (19.8%) of the 601 patients died from a CV cause. In multivariable Cox proportional hazards regression models, adjusting for conventional risk factors, plasma citrate was associated with an increased risk of CV mortality (the hazard ratio (HR) per 1-SD increment was 1.19 (95%CI: 1.00–1.40), p = 0.048). This association was prominent in males (n = 49 with CV mortality) (HR 1.52 (95%CI: 1.14–2.03), p = 0.005), but not in females (n = 70 with CV mortality) (HR 1.11 (95%CI: 0.90–1.37), p = 0.319) (age-adjusted Pinteraction = 0.044). In conclusion, higher plasma citrate levels are associated with an increased risk of CV mortality in patients with established T2D. Future studies are warranted to unravel the potential role of citrate-related pathways in the pathogenesis of T2D-related vascular complications