Multi-Omic Analyses of Dietary Fatty Acid-Microbe-Host Interactions Reveal Metaorganismal Lipid Metabolic Crosstalk Impacting Cardiometabolic Disease

SUMMARY Following a meal, our gut microbiome and human cells collaborate via metaorganismal metabolic circuits to produce diverse nutrient metabolites that systemically circulate to influence health and disease. Although there are now several examples of bacterial fiber-, amino acid-, and micronutrient-derived metabolites impacting cardiometabolic disease, very little is known in regards to how diet-microbe-host interactions impact lipid homeostasis. Here we address this by defining dietary fatty acid substrate availability in germ-free versus conventionally-raised mice coupled to deep multi-omic metabolic phenotyping. Our data demonstrate that the effects of dietary saturated (SFA), monounsaturated (MUFA), and polyunsaturated fatty acids (PUFA) on the host lipidome, transcriptome, proteome and metabolome are uniquely impacted by resident microbiota. Also, the hepatic levels of both pro-inflammatory and pro-resolving lipid mediators are strongly influenced by dietary fatty acid-microbe interactions. This study presents a unique resource to the nutrition and metabolism research community to advance our understanding of metaorganismal lipid metabolism. Competing Interest Statement Kohey Kitao is CEO of Noster Inc., which provides microbiome-associated lipid metabolite reference standards and analytical protocols used in this study. Co-authors (Adarsh Sandhu, Chiaki Tomimoto, Kowa Tsuji and Yasunori Yonejima) are employees of Noster Inc. and contributed to the development of analytical reference standards and LC-MS/MS quantification protocols for microbiome-associated lipid metabolites used in this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.