Project results: Gut microbiota, cardiovascular disease and the role of HDL

The most common underlying cause of cardiovascular disease (CVD) is atherosclerosis, a condition that develops when cholesterol-rich plaques build up in the artery wall. High density lipoproteins (HDL) cholesterol, through activity of the main protein component apoA-I, can reduce the risk of CVD by removing excess cholesterol from atherosclerotic plaque. At the same time, several studies highlighted a link between gut microbiota and atherosclerosis development. It has not been investigated before whether apoA-I/HDL can also modulate gut microbiota composition and notably, that an apoA-I/HDL imbalance can drive atherosclerosis development.

Over the past 4 years (2018 – 2022) the OCTOPUS (A sound microbiota in a sound body through the apolipoprotein A-I and HDL: from mouse models to human project) project has studied how apoA-I/HDL levels can influence atherosclerosis development by modulating gut microbiota composition. The project brought together researchers from academia from Italy, France and Germany and a researcher from a private company, in a multidisciplinary team covering various areas of expertise covering pharmacology, biomolecular sciences, microbiology, enzymology, nutrition, metabolomics and bioanalytics.


Overall, the OCTOPUS project was aimed at investigating the unexplored cross-talk between dyslipidemia (the imbalance of lipids), apoA-I/HDL levels and gut microbiota in the development of atherosclerosis. The project also investigated the effects of dietary choline in cardiovascular disease and the role of HDL in this context. Choline is an essential nutrient, with several physiological roles, ranging from contribution to cell structure to neurotransmitter synthesis. On the other side, choline is precursor of TMAO, a molecule with a recognized role in atherosclerosis development.

The study used both mouse models with different apoA-I-HDL levels and two human cohorts with varying HDL levels. In addition, microbiota from mice and humans with different levels of apoA-I/HDL were transplanted in atherosclerosis-prone germ-free mice to asses to what extent low apoA-I/HDL levels make the gut microbiota harmful for atherosclerosis development. 


The findings revealed new connections between HDL and a choline and its metabolite TMAO in the development of atherosclerosis. Although the OCTOPUS project confirms that apoA-I/HDL are protective towards the development of atherosclerosis in the animal model, it also demonstrates that the presence of HDL is mandatory for the detrimental effects of TMAO to occur. Taking this project result as a starting point, future research is needed to assess whether TMAO can impair the athero-protective effect of HDL or whether the interaction between the two molecules is more articulated and HDL also act as transporter of TMAO in the bloodstream.

Although no individual bacterial species have been identified/isolated that may impact on atherosclerosis development through a modulation of dietary choline metabolization, this project demonstrates with some consistency that varying levels of HDL, both in humans and mice, do not make the gut microbiota more or less pro-atherogenic.

Overall, the projects main conclusions justify increasing attention towards the dietary intake of choline, the precursor of the pro-atherogenic molecule TMAO. Not an easy challenge, considering that choline is an essential nutrient and is contained in a considerable number of foods that include meats, fish, shellfish, eggs and dairy products.

More results can be found here.

In total, 11 projects were funded within the HDHL-INTIMIC cofunded call. All results will be shared on our website. Stay tuned! See ‘more information’ below for already published project results.