The gut microbiota promotes hepatic fatty acid desaturation and elongation in mice

Alida Kindt,Sabine Schweizer,Dominic Helm,Bernhard Küster,Alexandra Ganzha,Gabriele Hörmannsperger,Thomas Clavel,Gerhard Liebisch,Rosalie Morisset,Hongsup Yoon,Dirk Haller,Hannelore Daniel,Daniela Kolmeder,Jan Krumsiek,Alexander Sigruener,Josef Ecker,Till Strowig,Claudine Seeliger,Sabrina Krautbauer

doi:10.1038/s41467-018-05767-4

Abstract

Interactions between the gut microbial ecosystem and host lipid homeostasis are highly relevant to host physiology and metabolic diseases. We present a comprehensive multi-omics view of the effect of intestinal microbial colonization on hepatic lipid metabolism, integrating transcriptomic, proteomic, phosphoproteomic, and lipidomic analyses of liver and plasma samples from germfree and specific pathogen-free mice. Microbes induce monounsaturated fatty acid generation by stearoyl-CoA desaturase 1 and polyunsaturated fatty acid elongation by fatty acid elongase 5, leading to significant alterations in glycerophospholipid acyl-chain profiles. A composite classification score calculated from the observed alterations in fatty acid profiles in germfree mice clearly differentiates antibiotic-treated mice from untreated controls with high sensitivity. Mechanistic investigations reveal that acetate originating from gut microbial degradation of dietary fiber serves as precursor for hepatic synthesis of C16 and C18 fatty acids and their related glycerophospholipid species that are also released into the circulation.

Highlights

Interactions between the gut microbial ecosystem and host lipid homeostasis are highly relevant to host physiology and metabolic diseases
Using in vivo stable isotope labeling experiments and dietary intervention strategies we showed that the short chain fatty acid (SCFA) acetate (FA 2:0) originating from gut microbial degradation of dietary fiber is a precursor for hepatic synthesis of long chain fatty acids and glycerophospholipids containing these fatty acids
Pathway enrichment analysis revealed a number of metabolic pathways significantly enriched in germfree mice (GF) mice, including those involved in drug metabolism, in agreement with a previous study[17], and lipid metabolism (4 of 10 pathways; Fig. 1b)

Summary

Introduction

Interactions between the gut microbial ecosystem and host lipid homeostasis are highly relevant to host physiology and metabolic diseases. We present a comprehensive multiomics view of the effect of intestinal microbial colonization on hepatic lipid metabolism, integrating transcriptomic, proteomic, phosphoproteomic, and lipidomic analyses of liver and plasma samples from germfree and specific pathogen-free mice. Membranes undergoing rapid morphological changes contain high levels of poly-unsaturated fatty acids (PUFA), whereas membranes with biosynthetic functions are dominated by monounsaturated FA (MUFA)[6,7] Numerous cellular processes, such as cell growth, cell differentiation, and organelle generation, require cellular de novo FA synthesis for cell membrane generation[8,9]. Integrated and pathwaydriven analysis identified that the gut microbiota triggers MUFA generation and PUFA elongation, leading to significant alterations in the acyl-chain profile of glycerophospholipids, including phosphatidylcholine (PC), -ethanolamine (PE), -inositol (PI), and PEbased plasmalogens (PE P). Using in vivo stable isotope labeling experiments and dietary intervention strategies we showed that the short chain fatty acid (SCFA) acetate (FA 2:0) originating from gut microbial degradation of dietary fiber is a precursor for hepatic synthesis of long chain fatty acids and glycerophospholipids containing these fatty acids

Objectives

Methods

Results

Conclusion