Multi-Omic Analysis of Transgenic Animal Models Uncovers the Tissue Omega-6/Omega-3 Fatty Acid Imbalance as a Critical Risk Factor for Chronic Disease

An unbalanced increase in dietary omega-6 polyunsaturated fatty acids (PUFA) and decrease in omega-3 PUFA in our foods coincides with the global rise in preventable chronic diseases. However, whether omega-6 (n-6) and omega-3 (n-3) PUFA oppositely contribute to the development of chronic disease remains controversial. Clarification of this issue is extremely challenging due to confounding factors of diet. By utilizing unique transgenic mouse models, which can eliminate the confounding factors of diet, in combination with multi-omics technologies, here we show that mice with varying n-6/n-3 PUFA ratios resulted in distinct gut microbiome, fecal and serum metabolites, and susceptibilities to cancer and certain metabolic disorders. FAT-2 transgenic mice with elevated n-6 PUFA levels and the highest n-6/n-3 PUFA ratios showed the most unfavorable metabolic conditions and the highest liver cancer rate. These adverse health outcomes were largely prevented in FAT-1 and FAT-1+2 mice, which can convert n-6 PUFA to n-3 PUFA and have a balanced n-6/n-3 PUFA ratio. Our multi-omics study of host-microbiota interactions therefore demonstrates that n-6 PUFA may be harmful in excess, and highlights the importance of n-3 PUFA and a balanced tissue n-6/n-3 PUFA ratio in lowering the risk for chronic diseases.

Deposited data; The data for main figure 1 panels (except for 1d, e, g, h and i), V4 16S rRNA gene sequencing with the Illumina MiSeq platform.OTU tables, raw data, taxonomy, FASTA files, KEGG and KO pathways and abundance data collected using PICRUSt software and metadata for 16S rRNA gene sequence analysis performed by Secondgenome microbioe profiling company (EPAN15-0231).Global fecal and serum metabolome data (MGPT-01-15VW) (OrigScale, ScaledImpData, biochemical name and pathway IDs) performed by Metabolon Inc (https://www.metabolon.com/).