Inflammatory bowel disease (IBD) is associated with the production of reactive species that target cysteine redox switches in proteins, thereby affecting gene regulation, DNA damage, ion transport, ...intermediary metabolism, and mitochondrial function. Precursors of reactive species are derived from organic and inorganic compounds and their cofactors, including amino acids, vitamins, oxygen, nitrite, and sulfate. Nutrition and the gut microbiome fuel this process to a significant extent. The production of reactive species in IBD is reflected by a reduction in systemic free thiols, the major components of the antioxidant machinery. Systemic free thiols are amenable to nutritional or therapeutic intervention. This opens up future avenues for therapeutic modulation of redox status in IBD.
Oxidative stress is a key feature of Inflammatory Bowel Disease (IBD). However, there is still insufficient understanding of the redox architecture that defines the pathogenic mechanisms that link oxidative stress to IBD.In addition to reactive oxygen species (ROS), there are reactive nitrogen species (RNS) and reactive sulfur species (RSS). Interactions among themselves and with downstream biological targets are defined by the recently introduced concept of the ‘Reactive Species Interactome’ (RSI).The RSI is mainly fueled by nutritional components, emphasizing the importance of studying the effects of nutritional modulation on redox signaling processes in IBD.Whereas cellular cysteine free thiols (-SH) are the major biological constituents of the RSI that fulfill important redox switch functions, free thiols in plasma/serum are a central readout of the whole-body redox status.Redox metabolomics, in conjunction with other multi-omics technologies, may be a promising approach to improve our understanding of the pathophysiology of IBD.
The human gut microbiota has now been associated with drug responses and efficacy, while chemical compounds present in these drugs can also impact the gut bacteria. However, drug-microbe interactions ...are still understudied in the clinical context, where polypharmacy and comorbidities co-occur. Here, we report relations between commonly used drugs and the gut microbiome. We performed metagenomics sequencing of faecal samples from a population cohort and two gastrointestinal disease cohorts. Differences between users and non-users were analysed per cohort, followed by a meta-analysis. While 19 of 41 drugs are found to be associated with microbial features, when controlling for the use of multiple medications, proton-pump inhibitors, metformin, antibiotics and laxatives show the strongest associations with the microbiome. We here provide evidence for extensive changes in taxonomy, metabolic potential and resistome in relation to commonly used drugs. This paves the way for future studies and has implications for current microbiome studies by demonstrating the need to correct for multiple drug use.
Inflammatory bowel diseases (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), are intimately associated with inflammation and overproduction of reactive oxygen species (ROS). ...Temporal and inter-individual variabilities in disease activity and response to therapy pose significant challenges to diagnosis and patient care. Discovery and validation of truly integrative biomarkers would benefit from embracing redox metabolomics approaches with prioritization of central regulatory hubs. We here make a case for applying a personalized redox medicine approach that aims to selectively inhibit pathological overproduction and/or altered expression of specific enzymatic sources of ROS without compromising physiological function. To this end, improved ‘clinical-omics integration’ may help to better understand which particular redox signaling pathways are disrupted in what patient. Pharmacological interventions capable of activating endogenous antioxidant defense systems may represent viable therapeutic options to restore local/systemic redox status, with HIF-1α and NRF2 holding particular promise in this context. Achieving the implementation of clinically meaningful mechanism-based biomarkers requires development of easy-to-use, robust and cost-effective tools for secure diagnosis and monitoring of treatment efficacy. Ultimately, matching redox-directed pharmacological interventions to individual patient phenotypes using predictive biomarkers may offer new opportunities to break the therapeutic ceiling in IBD.
The microbiota of the gut has many crucial functions in human health. Dysbiosis of the microbiota has been correlated to a large and still increasing number of diseases. Recent studies have mostly ...focused on analyzing the associations between disease and an aberrant microbiota composition. Functional studies using (in vitro) gut models are required to investigate the precise interactions that occur between specific bacteria (or bacterial mixtures) and gut epithelial cells. As most gut bacteria are obligate or facultative anaerobes, studying their effect on oxygen-requiring human gut epithelial cells is technically challenging. Still, several (anaerobic) bacterial-epithelial co-culture systems have recently been developed that mimic host-microbe interactions occurring in the human gut, including 1) the Transwell “apical anaerobic model of the intestinal epithelial barrier”, 2) the Host-Microbiota Interaction (HMI) module, 3) the “Human oxygen-Bacteria anaerobic” (HoxBan) system, 4) the human gut-on-a-chip and 5) the HuMiX model. This review discusses the role of gut microbiota in health and disease and gives an overview of the characteristics and applications of these novel host-microbe co-culture systems.
•Gut microbiota play an essential role in human health.•Anaerobic bacteria form the major part of the gut microbiota.•The oxygen-sensitivity of anaerobes hinders interaction studies with oxygen-requiring epithelial cells.•Host-anaerobe interaction models enable detailed study of this interplay.•The gut microbiome is an attractive target to modify to improve human health.
Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis, metabolic dysregulation, and neutrophilic inflammation. In this study, we hypothesized that systemic levels of ...plasma calprotectin, as a biomarker of neutrophilic inflammation, may be associated with suspected MAFLD. Plasma calprotectin levels were measured in subjects (n = 5446) participating in the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort study. Suspected MAFLD was defined by the fatty liver index (FLI ≥ 60) and hepatic steatosis index (HSI ≥ 36) as proxies. Plasma calprotectin levels were significantly higher in subjects with FLI ≥ 60 (0.57 IQR: 0.42−0.79 mg/L, n = 1592) (p < 0.001) compared to subjects with FLI < 60 (0.46 0.34−0.65 mg/L, n = 3854). Multivariable logistic regression analyses revealed that plasma calprotectin levels were significantly associated with suspected MAFLD (FLI ≥ 60), even after adjustment for potential confounding factors, including current smoking, alcohol consumption, hypertension, diabetes, cardiovascular diseases, insulin resistance (HOMA-IR), hs-CRP, eGFR, and total cholesterol levels (OR 1.19 95% CI: 1.06−1.33, p = 0.003). Interaction analyses revealed significant effect modifications for the association between plasma calprotectin and suspected MAFLD by BMI (p < 0.001) and hypertension (p = 0.003), with the strongest associations in subjects with normal BMI and without hypertension. Prospectively, plasma calprotectin levels were significantly associated with all-cause mortality after adjustment for potential confounding factors, particularly in subjects without suspected MAFLD (FLI < 60) (hazard ratio (HR) per doubling: 1.34 (1.05−1.72), p < 0.05). In conclusion, higher plasma calprotectin levels are associated with suspected MAFLD and with the risk of all-cause mortality, the latter especially in subjects without suspected MAFLD.
Adequate functioning of the intestinal barrier is required in order to repel invading pathogens while tolerating commensal microbiota and self-antigens. Inflammatory bowel diseases (IBDs), ...encompassing Crohn's disease (CD) and ulcerative colitis (UC), are characterized by disrupted intestinal barrier integrity, resulting in excessive passage of luminal antigens and the activation of aberrant immune responses against otherwise unexposed antigens. A comprehensive overview of the exact antigens associated with IBD is still lacking, but recent innovative antibody profiling technologies have enabled systematic characterization of humoral immunity in health and disease. Here, we review established serological antibodies and novel high-throughput methods, such as protein arrays, phage-display immunoprecipitation sequencing (PhIP-Seq), and B cell receptor sequencing (BCRseq), and provide an outlook on their applications in disease diagnostics, therapeutic interventions, and opportunities for prevention in IBD.
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