Genetic and microbiome influence on lipid metabolism and dyslipidemia

Abstract

Disruption in the metabolism of lipids is broadly classified under dyslipidemia and relates to the concentration of lipids in the blood. Dyslipidemia is a predictor of cardio-metabolic disease including obesity. Traditionally, the large interindividual variation has been related to genetic factors and diet. Genome-wide association studies have identified over 150 loci related to abnormal lipid levels, explaining ~40% of the total variation. Part of the unexplained variance has been attributed to environmental factors including diet, but the extent of the dietary contribution remains unquantified. Furthermore, other factors are likely to influence lipid metabolism including the gut microbiome, which plays an important role in the digestion of different dietary components including fats and polysaccharides. Here we describe the contributing role of host genetics and the gut microbiome to dyslipidemia and discuss the potential therapeutic implications of advances in understanding the gut microbiome to the treatment of dyslipidemia.

Keywords: diet; dyslipidemia; genetic; gut microbiome; lipid metabolism.

Fig. 1.

Circos plot of genes associated to lipid levels through published genome-wide association studies (GWASes). The Circos plot displays the genes that have been reported in GWASes with a significance threshold of 10⁻⁸. The name of the gene is color coded according to the lipid trait most predominantly associated to it: blue (triglycerides), red (HDL), green (LDL), or orange (total cholesterol).

Fig. 2.

Schematic drawing of diet/gut microbiome/lipid interaction metabolism. Different pathways have been proposed for the influence of diet/gut microbiome interaction on lipid levels. Experimentally, gut microbiome has been shown to modify both dietary components and metabolic precursors producing secondary metabolites. In postprandial state, macronutrients from dietary intake [polyunsaturated fat (PUFA), dietary fiber, and carnitine from red meat] enter the digestion process; at the same time as bile acids are released into the gut from the gall bladder (1). In the gut, microbial enzymes produce short chain fatty acids (SCFAs), conjugated linoleic acid (CLA), trimethylamine N-oxide (TMAO), and secondary bile acids (BAs) from dietary fiber, PUFA, carnitine, and bile acids, respectively (2). Because of cross-feeding (i.e., the process whereby some microbial metabolites can modulate gut microbial composition), CLA production increases SCFA producers, indirectly affecting the overall SCFA production. The secondary metabolites produced in the gut exert their systemic effects in different parts of the body. The metabolites affecting lipid metabolism have their receptors mostly in the liver, triggering metabolic signaling cascades (3). SFCAs and CLA interact with peroxisome proliferator-activated receptors (PPARs) leading to higher HDL levels, higher triglyceride (TG) and VLDL clearance, and higher lipolysis. Interaction of secondary bile acids with FXR receptors correlates to higher HDL and lipolysis and lower VLDL levels. The effects of TMAO in lipid levels are mainly due to HDL lowering disrupting lipid metabolism homeostasis.

Fig. 3.

Examples of recent association studies between lipid-related traits and gut microbiome in murine models.* TG, triglycerides; HDL, HDL cholesterol; LDL,  LDL cholesterol; TC,  total cholesterol; CONV-R, conventionally raised; CONV-D,  conventionalized; GF, germfree;↑, high; ↓, low. *Circulating lipid levels unless otherwise specified.

Fig. 4.

Examples of recent association studies between lipid-related traits and gut microbiome in humans. TG, triglycerides; HDL, HDL cholesterol; LDL, LDL cholesterol; TC, total cholesterol; ↑,  high; ↓, low; spp, subspecies; T2D, Type 2 diabetes.