FADS1-arachidonic acid axis enhances arachidonic acid metabolism by altering intestinal microecology in colorectal cancer

Chunjie Xu, Lei Gu, Lipeng Hu, Chunhui Jiang, Qing Li, Longci Sun, Hong Zhou, Ye Liu, Hanbing Xue (), Jun Li (), Zhigang Zhang (), Xueli Zhang () and Qing Xu ()
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Chunjie Xu: Shanghai Jiao Tong University
Lei Gu: Shanghai Jiao Tong University
Lipeng Hu: Shanghai Jiao Tong University
Chunhui Jiang: Shanghai Jiao Tong University
Qing Li: Shanghai Jiao Tong University
Longci Sun: Shanghai Jiao Tong University
Hong Zhou: Shanghai Jiao Tong University
Ye Liu: Shanghai Jiao Tong University
Hanbing Xue: Shanghai Jiao Tong University
Jun Li: Shanghai Jiao Tong University
Zhigang Zhang: Shanghai Jiao Tong University
Xueli Zhang: Shanghai Jiao Tong University
Qing Xu: Shanghai Jiao Tong University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Colonocyte metabolism shapes the microbiome. Metabolites are the main mediators of information exchange between intestine and microbial communities. Arachidonic acid (AA) is an essential polyunsaturated fatty acid and its role in colorectal cancer (CRC) remains unexplored. In this study, we show that AA feeding promotes tumor growth in AOM/DSS and intestinal specific Apc−/− mice via modulating the intestinal microecology of increased gram-negative bacteria. Delta-5 desaturase (FADS1), a rate-limiting enzyme, is upregulated in CRC and effectively mediates AA synthesis. Functionally, FADS1 regulates CRC tumor growth via high AA microenvironment-induced enriched gram-negative microbes. Elimination of gram-negative microbe abolishes FADS1 effect. Mechanistically, gram-negative microbes activate TLR4/MYD88 pathway in CRC cells that contributes FADS1-AA axis to metabolize to prostaglandin E2 (PGE2). Cumulatively, we report a potential cancer-promoting mechanism of FADS1-AA axis in CRC that converts raising synthesized AA to PGE2 via modulating the intestinal microecology of gram-negative.

Date: 2023
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DOI: 10.1038/s41467-023-37590-x

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