Metabolomic analysis sheds light on gut microbes' role in cardiovascular disease risk

In a recent eBioMedicine study, researchers explored the effect of gut bacteria on non-high-density lipoprotein cholesterol (non-HDL-c) variations.

Study: Gut microbial metabolism is linked to variations in circulating non-high density lipoprotein cholesterol. Image Credit: Alpha Tauri 3D Graphics/Shutterstock.comStudy: Gut microbial metabolism is linked to variations in circulating non-high density lipoprotein cholesterol. Image Credit: Alpha Tauri 3D Graphics/


Non-HDL-c is a primary risk factor for cardiovascular disease and a possible target for lipid-lowering drugs. The gut microbiota influences host metabolism, although its involvement in non-HDL-c variance remains unclear.

Non-HDL-c targeting accounts for residual hazards for atherosclerotic cardiovascular diseases (ASCVDs), including proatherogenic lipoprotein molecules comprising apolipoprotein B.

Developing new treatment techniques for lowering non-high-density lipoprotein-cholesterol levels might help reduce the worldwide burden of ASCVD.

The gut microbiome has a crucial role in host metabolic pathways and immunological homeostasis, with data pointing to a pathogenic function in metabolizing lipids.

About the study

In the present study, researchers investigated whether and how microbial metabolism causes variance in non-HDL-c.

The researchers included non-pregnant individuals with no significant disabilities and no malignancies, thyroid conditions, cirrhosis, biliary chronic or acute viral hepatitis, chronic kidney disease, or inflammatory illness.

They excluded individuals who were currently receiving hyperlipidemia medication, those who had taken antibiotics within the preceding three months, and those with a history of gastrectomy, infectious illness, or coronary artery disease. As a consequence, 1,361 community residents comprised the study population.

The researchers obtained blood samples from individuals and used enzymatic techniques to quantify total cholesterol (TC), total triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c).

They determined non-high-density lipoprotein levels by subtracting HDL-c from total cholesterol. They also isolated host deoxyribonucleic acid (DNA) for genotyping and stool samples for metagenomic investigation. 

The team used fecal metagenomics and Mendelian randomization (MR) to examine microbes and metabolic capabilities and their relationships with non-high-density lipoprotein cholesterol.

They then used linear regressions and the least-absolute shrinkage and selection operator (LASSO) to account for known cardiovascular risk variables such as age, gender, weight, drinking, smoking, and food.

Furthermore, the researchers used integrative analysis using plasma metabolomics to identify the primary chemicals that relate microbial metabolism to non-high-density lipoprotein cholesterol changes.

They used two-direction Mendelian randomization (MR) to investigate the causal relationships between selected microbes and metabolites and non-high-density lipoprotein cholesterol.


The median participant age was 50 years, and 55% were women. Individuals with elevated non-high-density lipoprotein cholesterol levels showed a higher likelihood of being older males with worse lipid concentrations and higher rates of metabolic diseases.

Lower Eubacterium rectale and higher Clostridium CAG_299 levels were related to non-high-density lipoprotein cholesterol levels.

The gut microbial analysis revealed 23 species significantly correlated with non-high-density lipoprotein cholesterol, eight of which were from the Bacteroidetes and Firmicutes phyla.

After controlling for possible variables, five species remained significantly linked with non-high-density lipoprotein, including many short-chain fatty acids (SCFA)-producing bacteria such as Eubacterium rectale, Faecalibacterium prausnitzii, and Prevotella disiens, followed by Clostridium sp. CAG_299 and Parabacteroides goldsteinii.

Clostridium sp. CAG_299 and E. rectale were related to non-high-density lipoprotein cholesterol in three MR approaches, indicating that they may act as important regulators of non-high-density lipoprotein-cholesterol.

After accounting for demographics, lifestyle, and metabolic comorbidities, 16 metabolic pathways, including the tricarboxylic acid (TCA) cycle, sugar acid degradation, and vitamin biosynthesis, were significantly linked with non-high-density lipoprotein-cholesterol levels.

Cinnamoylglycine levels were significantly lower in those with high non-high-density-type lipoprotein cholesterol levels, and they were adversely associated with atherogenic lipids, HOMA-IR analysis, and CAG_299.

L-cystine was considerably higher in participants with elevated non-high-density lipoprotein levels and was associated with lower TC, LDL-c, waist circumference, fasting blood glucose, and E. rectale.

The researchers identified N-methyltryptamine and 3-indolepropionic acid as the primary microbial effectors of non-high-density lipoprotein-cholesterol variance.

Decreased 2-oxoglutarate levels impeded the L-tryptophan breakdown XIII routes, decreasing 3-indolepropionic acid production. In contrast, a decrease in the quantity of oxaloacetate reduced L-aspartate production, resulting in a slowed metabolic cascade.

Both N-methyltryptamine and 3-indolepropionic acid had an inverse relationship between CAG_299 and many ASCVD risk variables, including proatherogenic lipids and insulin resistance.


The study found that the gut microbiome influences non-HDLc levels, with N-methyltryptamine and 3-indolepropionic acid as major effectors.

Addressing the gut microbiota may increase ASCVD preventive effectiveness. E. rectale reduces non-high-density lipoprotein, and CAG_299 increases them while favorably impacting LDL-c, TC, and waist circumference.

Individuals with high non-high-density lipoprotein cholesterol levels had lower amounts of 3-indolepropionic acid, which inhibits microbial reductive tricarboxylic acid cycle capabilities.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.


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