Dietary Intervention with Cottonseed and Olive Oil Differentially Affect the Circulating Lipidome and Immunoregulatory Compounds—A Randomized Clinical Trial

<b>Background/Objectives</b>: Cottonseed oil (CSO) is a dietary oil especially high in the n-6 polyunsaturated fatty acid (PUFA), linoleic acid (FA 18:2), which is a precursor for many pro-inflammatory eicosanoids. Curiously, diets rich in CSO have not been shown to cause increases in inflammatory markers or other negative health outcomes in humans. To rigorously test this, we have compared the health impact of a diet rich in CSO to olive oil (OO), which is generally considered to be a healthy oil. <b>Methods</b>: Specifically, this study examines circulating metabolite and lipid profiles during a 4-week dietary intervention with CSO or OO on 47 healthy adults. Untargeted metabolomics, targeted bulk lipidomics, and targeted lipid mediator analyses were conducted on fasting plasma samples taken pre- and post-dietary intervention. <b>Results</b>: A high degree of similarity was observed in the global metabolomic profiles of CSO and OO participants, indicating that CSO may elicit metabolic responses comparable to those of OO, potentially supporting similar effects on metabolic health markers. Targeted bulk lipidomics revealed changes in acyl chain composition reflective of the dominant fatty acid consumed-either 18:2 in CSO or 18:1 in OO. Immunoregulatory lipids 15-deoxy-PGJ2 and prostaglandin F2 alpha (PGF2a) were both higher in abundance in high-CSO diets, demonstrating differential effects of CSO and OO on immunoregulatory compounds. A correlative network analysis revealed two clusters arising from the dietary intervention as drivers of the dietary and immune responses. <b>Conclusions</b>: This study shows that CSO and OO differentially impact the circulating lipidome and immunoregulatory compounds in healthy adults.