EpOMEs Compromise Colonic Homeostasis Through Microbiome Dysbiosis and Inflammatory Activation

Linoleic acid-derived epoxyoctadecenoic acids (EpOMEs) have been implicated in inflammatory and metabolic diseases, yet their direct effects on colonic homeostasis under normal physiological conditions remain unclear. In this study, we investigated whether EpOMEs exposure alters colonic crypt structure, immune activation, and gut microbiome composition in C57BL/6 mice. We found that EpOMEs administration shortened colonic crypt length and reduced the expression of antimicrobial peptide genes, including Defb1 and Reg3g, indicating impaired epithelial architecture and weakened antimicrobial defense. EpOMEs also promoted macrophage accumulation in the colon and elevated expression of pro-inflammatory cytokines. Furthermore, 16S rRNA gene sequencing revealed that EpOMEs exposure altered gut microbial composition, characterized by reduced microbial diversity, depletion of potentially beneficial taxa including Muribaculaceae and Akkermansia, and enrichment of inflammation-associated Romboutsia. Together, these findings demonstrate that EpOMEs exposure is associated with impaired epithelial structure, enhanced macrophage-associated inflammatory responses, and gut microbiome dysbiosis. This study could provide new insight into how linoleic acid-derived lipid mediators may contribute to the early stages of gut dysfunction and increase susceptibility to associated inflammatory disorders.