The main objectives and expected results of the OCTOPUS project are the following:

- to determine, in genetically modified mouse models, to what extent different levels of apoA-I/HDL modulate gut microbiota composition, intestinal homeostasis/immunity, plasma metabolome and atherosclerosis development.

- to determine whether apoA-I/HDL levels can modulate gut microbiota composition and plasma metabolome in human cohorts, and to identify possible correlations between microbiota composition and metabolic parameters.

- to conduct SNPs analyses to highlight polymorphisms in genes involved in the microbiota-host cross-talk which could influence apoA-I/HDL levels.

- to disseminate to the general public, scientific community, and stakeholders the scientific questions, aims, initiatives and results of the project.

Expected impacts. Extensive laboratory research in the past decade has helped to unravel some of the biological and genetic bases of atherosclerosis; in addition, improved treatments have reduced the number of deaths from atherosclerosis-related diseases in high-income countries. Despite this progress, atherosclerosis remains a common health problem. People dying from cardiovascular diseases will expand to reach 23.3 million by 2030 and over 80% of these deaths will take place in low- and middle-income countries. This project is aimed at investigating the so far unexplored cross-talk between dyslipidemia, apoA-I/HDL levels and gut microbiota in the pathophysiology of atherosclerosis. The expected findings will possibly help in unravelling new mechanisms involved in plaque development and in promoting the search for new therapeutic targets/approaches.

The results obtained will potentially open a completely new scenario and shed a light on an aspect of apoA-I/HDL biology never investigated before. The scientific benefits deriving from the project are fourfold and may yield novel insights for treating cardiovascular disease by: i) demonstrating whether apoA-I/HDL influences atherosclerosis development by modulating the presence of TMAO-producing (or other) bacteria in the gut; ii) clarifying how apoA-I/HDL modulates gut microbiota composition by regulating intestinal homeostasis and immunity/inflammation; iii) highlighting polymorphisms in genes involved in the microbiota-host cross-talk which could influence apoA-I/HDL levels; iv) identifying metabolic biomarkers of dysbiosis associated to cardiovascular disease.

These outcomes will potentially translate into benefits for stakeholders (companies/enterprises, physicians, patients). Specifically, the identification of novel beneficial bacterial species able to impact on atherosclerosis development will spur companies/enterprises to produce new prebiotic/probiotic formulations directed at the huge market of dyslipidemic/cardiovascular patients. These formulations will provide physicians with new tools, acting synergistically with existing personalized dietary approaches or pharmacological treatments. Similarly, the identification of endogenous or microbially-derived biomarkers will draw companies/enterprises to invest in the production of diagnostic kits potentially helping in the stratification and management of patients according to their cardiovascular risk.