Targeting Cardiovascular Disease with Microbiota-derived Bioactive Compounds

forthcoming

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, although advancements in glucose-lowering, weight-reducing, and lipid-lowering therapies. Emerging evidence suggests that the gut microbiome and its metabolites are critically involved in the pathogenesis of various metabolic disorders contributing to CVDs, including obesity and type 2 diabetes, and also play a direct role in CVD development. Conversely, other reported microbiome-derived compounds appear to be beneficial for the host, exhibiting antioxidant and anti-inflammatory properties. This project aims to explore the therapeutic potential of microbiota-derived polyphenols in modulating the immune system to prevent and treat CVDs. Specifically, this proposal seeks to identify polyphenolic metabolites associated with a reduced risk of atherosclerosis development and to assess their immunomodulatory and protective effects in murine models. Aim 1 will involve bioinformatic analyses of a large human cohort with comprehensive microbiome and metabolome data to identify polyphenolic candidates associated with a lower risk of atherosclerosis. Aim 2 will explore the capacity of these polyphenols to induce long-term anti-inflammatory phenotypes through epigenetic and transcriptomic reprogramming in human and murine innate immune cells (trained immunity). The therapeutic efficacy of these polyphenols will be further evaluated in murine models of atherosclerosis and chronic inflammation, with a focus on elucidating the underlying molecular mechanisms. The methodologies employed will include advanced bioinformatics, in vitro immune cell assays, and in vivo murine studies, including microbiota and metabolome profiling. This interdisciplinary approach, combining human clinical data with mechanistic studies in mice, is expected to provide new insights into the role of microbiota-derived polyphenols in CVD prevention and treatment, potentially leading to novel therapeutic interventions.