The Hidden Conductor: HDL-Gut Microbiome Interplay in the Pathophysiology of Inflammatory-Based Diseases.

High-density lipoprotein (HDL) is a cholesterol transporter that plays a well-defined role in reverse cholesterol transport. In addition, HDL shows anti-inflammatory and immunomodulatory functions mainly due to its ability to decrease the cholesterol content in lipid rafts, thus strongly influencing the membrane fluidity and the right localization/functionality of membrane-associated proteins (i.e., receptors/ligands) and their signal transduction pathways. Diverse experimental and clinical studies support the existence of a dynamic and complex relationship between HDL functionality and the gut microbiome (GM), with relevant implications for the pathophysiology of many widespread inflammatory-based diseases, such as cardiovascular disease (CVD), inflammatory bowel disease (IBD), neurodegenerative disorders (NDDs) and cancer. Host factors (age, genes, dietary and lifestyle habits, medications) or environmental conditions may strongly negatively affect both the HDL system and the GM composition and function, promoting chronic low-grade inflammatory conditions that may exacerbate susceptibility to these human pathologies. Therefore, it can be hypothesized that the HDL-GM relationship may represent a novel therapeutic target to decrease the burden of these inflammatory-based pathologies. This review summarizes current data about the role of HDL and GM in the pathogenesis of CVD, IBD, NDDs and cancer, as well as findings that support the HDL-GM interplay as a crucial factor in the development of these relevant illnesses. Finally, we discuss the shortcomings of this relationship delineating the future directions to address them.