Exploratory Double Blind Placebo Controlled Study Investigating the Regulation of Proresolving Mediators and White Blood Cell Responses by Fish Oil Supplements in Healthy Volunteers

Rationale for the study The relationship between omega-3 essential fatty acid supplementation, and specifically fish oil supplementation, and SPM production in humans is very poorly understood. Given that the body produces SPM from omega-3 essential fatty acids to regulate inflammation and also to repair damaged tissues, it is critical to gain further insights on how the body utilizes dietary supplementation of omega-3 fatty acids from fish oils for SPM formation. With the availability of a mass spectrometry based platform developed by the investigators the scientific community is now in a unique position to better understand the biology of fish oil supplementation by monitoring the levels of SPM in plasma. This understanding may in turn shed light into the beneficial actions of omega-3 supplementation. It may also provide new leads for the control of excessive inflammation, as found in chronic inflammatory disorders, via dietary supplementation to exploit the body's own defense systems.

Rationale for choice of doses Given that in a study using a different fish oil source and formulation the investigators found that 1 g of essential fatty acids gave a mild but significant increase in plasma SPM levels (25) the investigators chose the lowest dose in the study to be of 1.5g. with the other two doses being within the European Food Safety Authority's Tolerable Upper Intake Level for supplements containing both EPA and DHA. Given that this limit is of 5 g and previous study with both healthy volunteers and patients demonstrated that doses up to 4 g are well tolerated (22-24), the investigators chose the remaining 2 doses to be 3.0 g and 4.5 g. In addition, this supplement was awarded a Generally Recognized as Safe Status (see appendix 1) in the for a dose of up to 5 g. Similar doses of the emulsion from of the fish oil supplement are also being used in an ongoing clinical study in the USA (ClinicalTrials.gov Identifier: NCT02719665) measuring different outcomes to those being investigated in the present study.

Aim of research The aim of this research is to investigate whether fish oil supplementation increases the peripheral blood levels of SPM and whether fish oil supplementation also regulates peripheral white blood cell responses (including neutrophils, monocytes and platelets) to inflammatory stimuli.

Original hypothesis Given that fish oils are rich in omega-3 essential fatty acids that are precursors in the biosynthesis of SPM the hypothesis underlying the present study is: Fish oil supplementation increase peripheral blood levels of SPM precursors that may be converted to bioactive mediators which in turn will regulate white blood cell responses.