Oxidized Linoleic Acid Interacts With Gut Microbiota to Promote Colitis and Colorectal Cancer

Abstract

Background: Emerging human studies support that a high intake of linoleic acid (LA), which is an essential fatty acid and the most abundant polyunsaturated fatty acid (PUFA) in human diet, is associated with increased risks of developing inflammatory bowel disease (IBD). As a PUFA, LA is highly prone to oxidation; to date, it remains unknown whether the observed IBD-enhancing effect of dietary LA is caused by LA itself (un-oxidized LA) or oxidized LA. Answering this question will help us to identify the exact risk factor of IBD and to develop targeted strategies to reduce the risks of IBD; in addition, the obtained information could have important implications for optimizing dietary recommendations. Results: Here we show that oxidized LA, rather than LA itself, exacerbates colitis and colorectal tumorigenesis, via gut microbiota- and microbial receptor Toll-like receptor 4 (TLR4)-dependent mechanisms. Administration of a diet containing oxidized LA, at low human-consumption levels, increases the severity of colitis and exaggerates the development of colorectal tumorigenesis in mice. In addition, oxidized LA alters gut microbiota and fails to promote colitis in antibiotic-treated mice. Finally, oxidized LA activates TLR4 signaling in vivo and fails to promote colitis in Tlr4-/- mice. Conclusions: Overall, these results support that oxidized LA could be a risk factor of IBD and associated diseases, highlighting the need to develop novel strategies to further control oxidation of dietary LA and potentially update policies regulating the levels of oxidized LA in food products.