Background:Sparicotylosis is an endemic parasitic disease across the Mediterranean Sea caused by the polyopisthocotylean monogenean Sparicotyle chrysophrii, which affects the gills of gilthead sea bream (GSB; Sparus aurata). Current disease-management, mitigation and treatment strategies are scarce against sparicotylosis. In order to successfully develop more efficient therapeutic strategies against this disease, understanding which molecular mechanisms and metabolic pathways are altered in the host is critical. This study aims to elucidate how S. chrysophrii infection modulates GSB physiological status and to identify the main altered biological processes through plasma proteomics.Methods:Experimental infections were conducted in a recirculating aquaculture system (RAS), exposing naïve recipient GSB (R; 70 g; N= 50) to effluent water from S. chrysophrii-infected GSB. An additional tank with unexposed naïve fish (C; 70 g; N=50) was maintained in parallel, with open water flow disconnected from the RAS. Haematological and infection parameters from sampled C and R fish were registered for 10 weeks. Plasma samples from R fish were categorised into 3 different groups according to their infection intensity in the right-sided gill arches: low, medium and high (L: 1-25; M: 26-50; H: >50 worms, respectively). Five plasma samples of each category were selected, in addition to five C samples and underwent a SWATH-MS proteome analysis. Additional assays on haemoglobin, cholesterol and the lytic activity of the alternative complement pathway were performed to validate the proteome analysis findings.Results:The discriminant analysis of the plasma protein abundance revealed a clear separation into 3 groups (H, M/L and C). A pathway analysis was performed with the differentially quantified proteins, indicating that the parasitic infection mainly affected pathways related to haemostasis, the immune system and lipid metabolism and transport.Twenty-two proteins significantly correlated with the infection intensity, highlighting apolipoproteins, globins and complement c3. Validation assays in blood and plasma (haemoglobin, cholesterol and lytic activity of alternative complement pathway) confirmed these correlations.Conclusions:Sparicotylosis profoundly alters the haemostasis, the innate immune system and the lipid metabolism and transport in GSB. This study gives a crucial global overview of the pathogenesis of sparicotylosis and highlights new targets for further research.