Targeting the gut microbiome: potential for managing atherogenic dyslipidaemia?

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8 October 2015

This report shows that the gut microbiome may play a key role influencing variability in plasma triglycerides (TG) and high-density lipoproteins (HDL), and may therefore represent a novel target in cardiovascular disease prevention.

Fu J, Bonder MJ, Cenit MC et al. The gut microbiome contributes to a substantial proportion of the variation in blood lipids. Circ Res 2015; DOI: 10.1161/CIRCRESAHA.115.306807

STUDY SUMMARY

Objective:

To investigate 1) which gut bacteria were associated with body mass index (BMI) and blood lipids, and 2) how much of the variation in blood lipids could be explained by the gut microbiome.

Study design:

Analysis from the LifeLines-DEEP population cohort, a sub-cohort of the LifeLines cohort general population study.

Study population:

893 human subjects in the LifeLines-DEEP population cohort, 380 men and 513 women, mean age 44.6 years (range 18-80 years). Blood lipids and BMI in this cohort are summarised in Table 1.

Table 1. Characteristics of cohort

Parameter	Mean ±standard deviation
BMI, kg/m²	25.2±4.1
Total cholesterol (TC), mmol/L	5.08±1.01
LDL cholesterol, mmol/L	3.19±0.93
TG, mmol/L	1.15±0.92
HDL cholesterol, mmol/L	1.54±0.42

LDL low-density lipoprotein

Primary variable:

Lipid parameters: TG, HDL-C, LDL cholesterol (LDL-C), TC and BMI

Secondary variable:

Microbiome data

Methods:

The selection of bacterial sequences (referred to as operational taxonomic units, OTUs) was performed using the QIIME reference optimal picking. Data for OTUs present in at least 1% of the population were analysed.

A two-part model was used to investigate the association of the OTUs with the lipid traits and BMI. Briefly, this model incorporated a binomial analysis that tested for the association of detecting a microbe (represented by an OTU) with a trait, followed by quantitative analysis of the association between the lipid level and the abundance of bacteria, in subjects where that microbe was present. Permutation tests were used to control the false discovery rate (FDR), set at 0.05.

Cross-validation analysis was used to estimate the proportion of variance in BMI and blood lipids that could be explained by the gut microbiome. Three different risk models were used to investigate whether the gut microbiome contributed significantly to variation in BMI and blood lipids, independent of age, gender and genetics.

Main results:

After adjusting for age and gender, 34 bacterial taxa were associated with BMI and blood lipids; 23 with TG, 4 with HDL, and 1 with LDL; most of these were novel.
Cross-validation analysis showed that the gut microbiota explained 4.5% of the variance in BMI, 6% in TG, and 4% in HDL, independent of age, gender and genetic risk factors.
Even when BMI was also included as a risk factor, the microbiome made a significant contribution to TG and HDL.

Authors’ conclusion:

These studies suggest that the gut microbiome may play an important role in the variation in BMI and blood lipid levels, independent of age, gender and host genetics. Our findings support the potential of therapies altering the gut microbiome to control BMI, TG and HDL cholesterol.

COMMENT

The findings from this study implicate bacterial diversity in the gut microbiome with variation in blood lipids, specifically levels of TG and HDL cholesterol. Importantly, the microbiota explained 6% of the variation in TG, and 4% in HDL cholesterol, and this association remained significant even in models adjusting for BMI, age, gender and genetics. The study has a number of strengths which reinforce the importance of these findings: the size of the cohort, the characteristics of the cohort (wide age range with comprehensive data to exclude subjects with concomitant antibiotic and/or lipid-lowering treatment), and the statistical modelling employed in the analysis.

These results provide support for proposals suggesting that the gut microbiome may represent a potential contributor to residual cardiovascular risk (1-3), especially given evidence of a link with TG and HDL. Indeed, studies support a role for dietary intervention in modifying the gut microbiome, and potentially, the individual’s cardiovascular risk (4). Further investigation in clinical trials is merited.

References

1. Spence D. Effects of the intestinal microbiome on constituents of red meat and egg yolks: a new window opens on nutrition and cardiovascular disease. Can J Cardiol 2014;30:150-1.

2. Tang WHW, Wang Z, Levison BS et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:1575–84.

3. Karlsson FH, Fåk F, Nookaew I et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat Commun 2012;3:1245.

4. David LA, Maurice CF, Carmody RN et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 2014;505-63.

Key words

Gut microbiome, lipids, triglycerides, HDL, cardiovascular disease