Dottorato in TECNOLOGIE BIOMEDICHE INNOVATIVE IN MEDICINA CLINICA

Titolo della tesi: New non-invasive serum markers for inflammatory bowel disease: lipocalin-2, brain-derived neurotrophic factor, and nerve growth factor in children with newly diagnosed ulcerative colitis.

Background Neurotrophins (NTs), including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), regulate immune functions in inflammatory and autoimmune diseases. Lipocalin-2 (LCN-2) is a pleiotropic mediator of various inflammatory processes. Aim In this prospective cross-sectional pilot study, primary objective was to determine serum levels of NGF, BDNF and LCN-2 in a cohort of newly diagnosed ulcerative colitis (UC) children (aged 6-18 years) and to compare them with healthy controls. Serum levels of LCN-2 were also measured in a mouse model of DSS-Induced Colitis. Methods Blood withdrawal was carried out at the diagnosis of UC. As a control group, we analyzed the serum of age and sex matched, healthy controls. Serum NGF, BDNF and LCN-2 were measured by enzyme-linked immunosorbent assay, following the supplier instructions. Results Thirty-two cases and 38 healthy controls were consecutively enrolled. Mean BDNF serum levels were significantly lower in cases then in controls (24,6 ± 8 ng/mL vs 31,1 ± 13 ng/mL, p = 0,019), while serum levels of LCN-2 were significantly higher (279,9 ± 152 ng/mL vs 66,2 ± 55 ng/mL, p < 0,001). In mouse model of DSS-induced colitis, serum levels of LCN-2 were increased when compared to healthy control mice (78,8 ± 20,6 ng/mL vs 27,2 ± 3,9 ng/mL, p < 0,0001). No difference between the two groups was found for the NGF serum concentration. Among UC children, higher LCN-2 levels were measured in pancolitis (363,7± 155,2 ng/mL) compared to proctitis, left-sided and extensive colitis (184,9 ± 74,65 ng/mL, p = 0,0003). An inverse correlation was observed between LCN-2 and albumin levels at the diagnosis by the Spearman coefficient correlation (r = −0,455, p = 0,03) and a direct correlation was observed between LCN-2 and C-reactive protein at the diagnosis (r = 0,44, p = 0,05). Conclusions We demonstrated a modulation of serum BDNF and LCN-2 in children with UC. In particular, LCN-2 has been confirmed to be a good marker of both the extent and severity of the disease. If confirmed by larger studies, these biomarkers might collaborate to the expansion of the armamentarium for testing and monitoring pediatric inflammatory bowel disease in the upcoming precision medicine era.