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DIETARY AND ENVIRONMENTAL RISK FACTORS OF COLONIC INFLAMMATION AND COLON CANCER

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Abstract
The consumption of linoleic acid (LA, 18:2 ω-6) has risen dramatically in recent decades. However, the impact of excess intake of dietary LA on human health is not well understood. Here we show that a high dietary intake of LA exaggerates the development of colon tumorigenesis in mice, in part via the formation of epoxyoctadecenoic acids (EpOMEs) which are metabolites of LA produced by cytochrome P450 (CYP) monooxygenases. We find that dietary treatment with an LA-rich diet exaggerates azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumorigenesis in mice, with increased tumor number and tumor size, and higher infiltration of immune cells in colon. Among all the metabolites of LA, LC-MS/MS profiling shows that 9,10- and 12,13-EpOME are the most dramatically changed eicosanoid metabolites in colon by the LA-rich diet induced colon tumorigenesis. Furthermore, the colon tumorigenesis-enhancing effect of the LA-rich diet is abolished by the genetic ablation of Cyp2c monooxygenases. Moreover, systemic infusion with 12,13-EpOME, but not 12,13-DiHOME (metabolite of 12,13-EpOME via soluble epoxide hydrolase), exaggerates AOM/DSS-induced colon tumorigenesis in mice. Together, our results support that a high intake of dietary LA could cause adverse effects on colon cancer through the CYP/EpOME eicosanoid pathway. The gastrointestinal tract is a major route of entry for toxic environmental chemicals involved in the etiology of numerous human diseases. Here weestablish that a specific reaction catalyzed by the intestinal microbiota produces thegut toxicity of triclosan (TCS), a ubiquitous pollutant in the environment. Using a range of in vitro, ex vivo, and in vivo approaches, we pinpoint the specific microbial enzymes involved and define the molecular motifs required to metabolically activate TCS in the gut. Furthermore, targeted inhibition of these bacterial enzymes abolishes the colitis-enhancing and microbiota-altering effects of TCS, establishing the essential roles of specific microbial proteins in TCS toxicity. Our results support the conclusion that commensal microbes drive the intestinal toxicity of TCS and suggest that microbial enzymes may serve as therapeutic targets to alleviate colitis.
Type
campusfive
dissertation
Date
2021
Publisher
License
License
http://creativecommons.org/licenses/by/4.0/