Rational & Objectives. There is an urgent need to find reliable early biomarkers of the cardiometabolic syndrome (CardMetS) allowing intervention before irreversible damage develops while assessing the efficacy of nutritional prevention. Oxylipins could be relevant candidate biomarkers thanks to their involvement in the homeostatic regulation of various process related to the cardiometabolic status and the consistent link reported between diet, oxylipins and cardiometabolic dysregulations. Moreover, the oxylipin profiling could provide a mechanistic signature at the metabolite level allowing a better stratification of patients at risk of cardiometabolic diseases (CVD and diabetes).

Our main objective in the OXYGENATE project was to uncover and validate the oxylipin signatures reflecting the cardiometabolic status or its early transition towards the CardMetS. To achieve this goal, we proposed a multidisciplinary project involving experts in lipidomics, nutrition and epidemiology and combining the comprehensive and quantitative lipidomic profiling of circulating oxylipins and the use of different biobanks from large prospective cohorts and different whole-diet interventions.

Overall achievements. The OXYGENATE project started with the optimization of the MS-based targeted lipidomic profiling of oxylipins. The optimized method developed allows a comprehensive profiling of all types of oxylipins including the free and the esterified forms. The method has been validated through a round robin test involving 5 different laboratories worldwide and allowing to determine for each oxylipin (i) intra- and inter-day variabilities and (ii) consensus values and their respective dispersion. The OXYGENATE consortium also provided a detailed SOP for sample storage and preparation including quantitative and qualitative data regarding oxylipin stability. Using this original method, we have generated the oxylipin profiles of over 1000 participants involved in various independent studies (cross-sectional and longitudinal observational studies and intervention studies) performed in four different populations (Polish, French, Danish and American). So far, the cross-sectional studies nested in the Polish branch of the PURE cohort and the French Nutrinet-Santé cohort lead to the identification of a signature of 23 oxylipins coined OxyScore. This score is highly discriminant of CardMetS and has high performances of classification and replicability. Moreover, the identified oxylipins provide a unique mechanistic signature of MetS that may enhance the prediction of cardiometabolic diseases risk. Complementary cross-sectional studies nested in the same cohorts have been performed to investigate the links between the OxyScore and diet. Moreover, to further validate the OxyScore, we have tested its ability to monitor the changes of cardiometabolic health in response to diet using the biocollection collected in two independent studies (the Danish SHOPUS study and the American iMAPS study).

Expected impacts. On completion, the OXYGENATE project has (i) provided an internationally validated method of comprehensive oxylipins profiling (ii) generated the 1^st large diet- and health-related oxylipins database, (iii) identified and validated the oxylipins reflecting the cardiometabolic status and the quality of dietary patterns (biostatistics under progress) (iv) provided a proof-of-concept of the ability of oxylipins to monitor the effect of diet on the cardiometabolic status (biostatistics under progress). It is expected that the oxylipins identified and validated will allow a better detection and management of the cardiometabolic diseases.

In the framework of the JPI-Oxygenate project we have:

1.          Standardized and validated a MS-based method for the quantitative analysis of over 130 oxylipins including all species found in the free form and esterified into complex circulating lipids.


2.           Showed that total plasma oxylipins (sum of free and esterified) are stable regarding delays during plasma generation and long-term storage at −80°C.


3.         Showed that our MS-based method for the quantitative analysis of total oxylipins in plasma has a low technical variability and allow reliable, reproducible and comparable oxylipin concentrations in independent laboratories.


4.           Identified an oxylipin signature of cardiometabolic syndrome having high performances of classification and replicability.


5.         Showed that the oxylipin signature of cardiometabolic syndrome provides a unique mechanistic phenotyping informing on crucial molecular pathways that may help identify patients at high risk of cardiometabolic diseases.