Complement-Mediated Immune Dysregulation and Endothelial Injury in Microbial Burden Cardiometabolic Patients

Abstract

Cardiometabolic disease is increasingly being viewed as a chronic immunometabolic syndrome that is associated with endothelial dysfunction. There is evidence that complement activation and microbial translocation are involved in driving vascular injury; however, how the two relate to each other has not been well characterized. To determine serum, complement activation studies in cardiometabolic patients and to analyze their interrelation with endothelial injury, as well as assist in the setting of the role of the microbial burden in complement-mediated vascular damage. A prospective case-control study was carried out on 120 cardiometabolic patients and 60 age- and sex-matched healthy controls. The classical and alternative component activity was assessed by CH50 and AH50 assays, and C3, C5 and C3/C5 activation products (C3a, C5a, C5b-9) were measured using ELISA. Endothelial injury was assessed by soluble VCAM-1, ICAM-1, vWF and circulating endothelial microparticles. Microbial burden was quantified by using serum concentrations of LPS, LBP and bacterial DNA cycle-threshold responses. Correlations, regression models and ROC analyses were conducted. Cardiometabolic patients had significantly higher complement proteins/activation fragments, CH50/AH50 activity and markedly higher endothelial injury markers (p < 0.001). Stimulated levels of LPS, LBP and bacterial DNA, thus suggesting chronic microbial translocation, were also significantly higher. Complement activation fragments were strongly associated with endothelial injury markers and an area under the receiver operator characteristic curve (ROC) analysis of good predictive performance was observed for C5a and C5b-9 (AUC >= 0.89). Therefore, there is a mechanistic immune-metabolic-vascular axis that is supported by chronic complement activation and microbial burden that promotes endothelial dysfunction in cardiometabolic disease. Complement biomarkers have potential benefit in early vascular risk stratification and can be used for future therapeutic approach in dealing with complement pathways or gut-derived microbial translocation.