Gut microbiome lipid metabolism and its impact on host physiology

Abstract

Metabolites produced by commensal gut microbes impact host health through their recognition by the immune system and their influence on numerous metabolic pathways. Notably, the gut microbiota can both transform and synthesize lipids as well as break down dietary lipids to generate secondary metabolites with host modulatory properties. Although lipids have largely been consigned to structural roles, particularly in cell membranes, recent research has led to an increased appreciation of their signaling activities, with potential impacts on host health and physiology. This review focuses on studies that highlight the functions of bioactive lipids in mammalian physiology, with a special emphasis on immunity and metabolism.

Keywords: PUFAs; autoimmune disease; bacteria; cholesterol; diet; inflammation; innate immunity; lipids; metabolism; microbiome; phospholipids; sphingolipids.

Figure 1:. Membrane lipids biosynthesized by the gut microbiome and their known host signaling functions.

An overview of the diversity of membrane lipids known to be biosynthesized by the gut microbiome, which includes sphingolipids, saccharolipids, plasmalogens, cardiolipins, sterol lipids, phospholipids, sulfonolipids, and prenol lipids. Representative structures of each lipid are shown in the inner ring (beige) and putative host functions for each lipids are in the outer ring (blue). Functions with little experimental evidence are shown in a faded blue color in the outer ring.

Figure 2:. Biotransformation of dietary lipids by microbiome enzymes

Examples of dietary lipids substrates utilized by gut bacteria and enzymatically converted. These are examples where the enzyme class, species and resulting biotransformed product are known and many more are likely to exist. The host signaling function of the microbiome-transformed lipid product is listed, with references given throughout the manuscript text for each example.

Figure 3:. The function of gut microbiome enzymes responding to dietary lipids are a key step to explain the variation in risk for metabolic syndrome and autoimmunity across human populations.

Metabolic syndrome and autoimmunity are diseases of more recent occurrence, and are seen at much higher levels in human populations eating an industrialized and processed food rich diet. This is compared to an ancestral diet which was common among hunter gatherer populations most of human history. Ingestion of dietary lipids are essential for human health and have a large role in all aspects of mammalian biology, and this lipid profiling we ingest has rapidly been changing through industrialization. As the incidence of these disease rise dramatically, it is clear there is variation from human to human on their risk profile for developing systemic inflammation and metabolic dysfunction. This variation in susceptibility for disease is multifactorial and can be explained by 3 main variables as summarized here in this figure; 1) Variation in diet consumed, 2) Variation in metagenomic output by the microbiome and 3) variation in activity and function of metabolism genes from each individual’s genome. Ultimately the outcome of these 3 variables results in; 4) the variation of risk for metabolic syndrome and autoimmunity. The percentage of each of these variables contributing risk is unknown. Human genetic risk explains some variance, however there is a large environmental component to risk of these conditions. The connection between dietary lipid input, and metagenomic output of the microbiome interacting with genetics are crucial, understudied variances in risk for onset of metabolic syndrome and autoimmunity. Systematic inflammation, once initiated, can influence every variable in the process, including what humans crave (e.g. leptin signaling), inflammation-induced ecological shift in microbiome function and epigenetic changes in host gene expression (e.g. stress related), as visually shown here by the arrows.