Supplementation with GPR120 (Ffar4) ligand omega-3 does not improve survival in murine sepsis models

Sepsis is a condition marked by physiologic dysregulation secondary to infection and is influenced by the nutritional state. Despite several preclinical studies and clinical trials examining nutrition and supplements in sepsis, there are no clear guidelines. Omega-3 fatty acids are polyunsaturated fatty acids with anti-inflammatory properties, represented mainly by alpha-linolenic (ALA, C18:3), eicosapentaenoic (EPA, C20:5), and docosahexaenoic (DHA, C22:6). Since sepsis is characterized with high levels of inflammation and subsequent organ dysfunction, we hypothesized that omega-3 ingestion would improve sepsis survival by attenuating inflammation via activation of GPR120 in immune cells. Here, we aimed to experimentally explore the role of omega-3 and the receptor that mediates their anti-inflammatory functions, GPR120, during sepsis. To evaluate GPR120 functionality, acute inflammation was induced via lipopolysaccharide (LPS) treatment in Raw 264.7 cells, 3T3-L1 cells, bone marrow-derived macrophages, and primary adipocytes. To evaluate the impact of omega-3 in sepsis, C57BL/6J mice were supplemented with omega-3 before LPS administration or cecal ligation and puncture (CLP) surgery. GPR120 mRNA expression decreased during inflammation. Unexpectedly, omega-3 supplementation preceding CLP worsened sepsis survival in mice. In addition, omega-3 did not affect inflammatory markers such as TNFα, IL1β, IL10, and IL6. Overall, our findings that omega-3 do not influence inflammation or improve survival in sepsis are surprising, given that omega-3 supplementation is recommended for the prevention of cardiovascular diseases due to its anti-inflammatory properties. The negative impact of omega-3 supplementation on survival in the CLP model raises caution for future clinical studies involving sepsis.<b>NEW & NOTEWORTHY</b> This study uncovers worsening in survival in mice models pretreated with omega-3 supplementation. We demonstrated decreased <i>Ffar4</i> receptor expression in macrophages and adipocytes when challenged with acute and chronic sepsis models in vitro and in vivo. This study offers insight into the role of omega-3 supplementation in the context of sepsis, highlighting concerns and underscoring the need for further investigation.