C-reactive Protein: An Inflammatory Biomarker and a Predictor of Neurodegenerative Disease in Patients With Inflammatory Bowel Disease?

Abstract

Inflammatory bowel disease (IBD) refers to two chronic conditions of the digestive tract: ulcerative colitis (UC) and Crohn’s disease (CD), representing a progressive inflammatory process that mainly occurs in the gut, with frequent extra-intestinal manifestations. Even if remission is periodically obtained for some patients, the histological activity and digestive symptoms may continue, maintaining a persistent systemic inflammation that could induce further extra-intestinal complications and contribute to the development of neurodegenerative disease. C-reactive protein (CRP) is an acute-phase reactant that is widely accepted as a dominant serum biomarker in IBD. CRP consequently activates the complement cascade, supports the release of pro-inflammatory cytokines, and the clearance of microbial pathogens. All these processes facilitate further processes, including atherosclerosis and hypercoagulability, alteration of the intestinal microbiota, and the increased permeability of the intestinal barrier for neurotoxic substances produced by gut microorganisms, due to the presence of a high level of lipopolysaccharides. For IBD, the connection between intestinal inflammation and central nervous system inflammation could be explained through the activity of the vagus nerve, a carrier of cytokines, CRP, and toxic materials to the brain, potentially inducing vascular lesions and damage of the glial vascular unit, with further risk for degeneration within the central nervous system. CRP is a key marker for IBD pathogenesis and is able to dissociate into its monomeric form, mCRP, on contact with activated cell and tissue components via the systemic circulation. We hypothesize that the chronic inflammatory process within IBD could initiate neuroinflammation and neurodegeneration, and therefore, further investigation of the significance of chronically raised plasma of CRP and mCRP in patients with IBD is warranted, as it may represent a critical predictive factor associated with a later neurodegenerative risk. Any future initiative aimed at pharmacologic modulation of CRP (e.g., blocking CRP-mCRP dissociation), could represent a new therapeutic approach protecting against intestinal inflammation and concomitantly reducing the risk of neuroinflammation, neurodegeneration, and cognitive decline.

Monomeric C-Reactive Protein Potential Utilization in the Histological Assessment of Inflammatory Bowel Disease (IBD) Patients

“…The limitations of this study include, as a first factor, the size of the patient groups. Having the theoretical correlation between CRP-mCRP-intestinal mucosal inflammation-IBD as a starting point [3], we tested the hypothesis of the existence of mCRP in intestinal samples from CD and UC patients starting with 20 subjects. The positive results obtained until now impose a future extension of the study for a larger cohort.…”

“…The pathogenic mechanism in IBD has chronic inflammation as a main actor. The local and general overexpression of C-reactive protein (CRP), inflammatory cytokines, and adherent molecules contribute to vascular endothelial dysfunction, impaired fibrinolysis, activation of the coagulation cascade, and an abnormal platelet function, resulting in increased arterial and venous thrombosis with consequences at the level of intestinal mucosa [3,4]. The local inflammation alters the intestinal microbiota and the intestinal barrier, allowing toxic substances (and even inflammatory factors) produced by intestinal microorganisms to enter the circulatory system and induce extraintestinal complications [5].…”

“…CRP is an acute-phase reactant that is widely accepted as a dominant serum biomarker in IBD trials [11]. Studies revealed that CRP could efficiently prognosticate patients in the active phase of IBD and, concomitantly, evaluate the efficiency of treatment through repeated measurement of this protein, but with limited accuracy in patients with lower activity [3]. When CRP meets activated cell and tissue components via the systemic circulation, the insoluble monomer of the native molecule: monomeric CRP (mCRP) is irreversibly produced in situ.…”