The Gut Microbiome Contributes to a Substantial Proportion of the Variation in Blood Lipids

Abstract

Rationale: Evidence suggests that the gut microbiome is involved in the development of cardiovascular disease, with the host-microbe interaction regulating immune and metabolic pathways. However, there was no firm evidence for associations between microbiota and metabolic risk factors for cardiovascular disease from large-scale studies in humans. In particular, there was no strong evidence for association between cardiovascular disease and aberrant blood lipid levels.

Objectives: To identify intestinal bacteria taxa, whose proportions correlate with body mass index and lipid levels, and to determine whether lipid variance can be explained by microbiota relative to age, sex, and host genetics.

Methods and results: We studied 893 subjects from the Life-Lines-DEEP population cohort. After correcting for age and sex, we identified 34 bacterial taxa associated with body mass index and blood lipids; most are novel associations. Cross-validation analysis revealed that microbiota explain 4.5% of the variance in body mass index, 6% in triglycerides, and 4% in high-density lipoproteins, independent of age, sex, and genetic risk factors. A novel risk model, including the gut microbiome explained ≤ 25.9% of high-density lipoprotein variance, significantly outperforming the risk model without microbiome. Strikingly, the microbiome had little effect on low-density lipoproteins or total cholesterol.

Conclusions: Our studies suggest that the gut microbiome may play an important role in the variation in body mass index and blood lipid levels, independent of age, sex, and host genetics. Our findings support the potential of therapies altering the gut microbiome to control body mass, triglycerides, and high-density lipoproteins.

Keywords: HDL; body mass index; cardiovascular diseases; lipids; lipoproteins; metabolism.

Figure 1.

The richness of the gut microbiome. The microbial richness associated with age and sex. The bar plot shows the distribution of individuals binned to different groups of richness. The black and gray colors indicate the proportion of men and women in each group, and the dark gray line indicates the correlation between the average age and richness, whereas the light gray shadow indicates the SD of the age per richness bin. OTU indicates operational taxonomy unit.

Figure 2.

The effect of taxonomies on body mass index (BMI) and lipids. The effects of 34 taxonomies associated with BMI, triglycerides (TG), and high-density lipoprotein (HDL) are shown as Z scores. Red sectors indicate positive associations and blue negative associations. Brighter colors indicate that the association was significant at false discovery rate (FDR) 0.05 level. Dashed circles indicate the scale of Z values from 1 to 5.

Figure 3.

The contribution of the gut microbiome to body mass index (BMI) and lipids. A, The variation explained by gut microbes at different levels of significance. B, The variation explained by different risk models, including age, sex, genetic risk, and microbial risk. The significance of microbial contribution is indicated as the P value of the ANOVA test that compared the performance of the risk models r₂ and r₃. HDL indicates high-density lipoprotein; LDL, low-density lipoprotein; TC, total cholesterol; and TG, triglycerides.