Gut Microbiota Modulate Adipose Eicosanoid Metabolism: Potential Roles of the Lipoxygenase Pathway

Numerous studies support that gut microbiota regulate adipose inflammation and function, thereby influencing the development of obesity, diabetes, and associated metabolic disorders; however, the underlying mechanisms remain not fully elucidated. While previous studies on microbiota-adipose interactions have primarily focused on how gut microbiota modulate adipose protein-based mediators, the role of lipid mediators (LMs), lipid-based signaling molecules crucial for adipose homeostasis, remains unclear. In this study, we used high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted lipidomics, which can quantify over 100 LMs, to compare LM profiles in adipose tissues from germ-free (GF) and conventionally raised (specific pathogen-free, SPF) mice. We found that 5- and 12/15-lipoxygenase (LOX)-derived LMs were among the most significantly altered metabolites in conventionally raised mice compared to GF controls. Mechanistically, the effects of the gut microbiota are associated with two potential pathways: (1) downregulating transcriptional expression of 5- and 12/15-LOX in adipose tissue, and (2) lowering circulating levels of 5- and 12/15-LOX-derived metabolites. Given the potent biological activities of LOX-derived LMs, these findings may suggest a novel mechanism by which gut microbiota modulate adipose function and influence disease development.