Gut microbiome-blood cholesterol crosstalk: towards personalized strategies for dyslipidemia

Hypercholesterolemia is a major risk factor for cardiovascular diseases, influenced by both genetic predisposition and multifactorial acquired factors, including diet, lifestyle, obesity, type 2 diabetes, and gut microbiota dysbiosis. Accumulating evidence suggests that the gut microbiome plays a causal role in cholesterol metabolism through multiple complementary mechanisms, including bile acid transformation, modulation of hepatic and intestinal receptors (FXR, TGR5), production of short-chain fatty acids (SCFAs) that inhibit hepatic cholesterol synthesis and microbiol conversion of cholesterol into poorly absorbed coprostanol. Host genetic, dietary habits, and lifestyle shape gut microbiol composition, contributing to interindividual variability in lipid profiles and responses to lipid-lowering interventions.Dietary interventions, including polyphenols, phytosterols, L-theanine, and probiotics, can beneficially modulate gut microbial composition, enrich SCFA-producing taxa, and improve cholesterol homeostasis. Pharmacological agents, including statins and berberine, also interact with the gut microbiome, underscoring the bidirectional nature of host-microbiome-drug interactions. Human, animal and in vitro studies collectively support the importance of baseline microbial composition, host genetics, and lifestyle in determining treatment response.This review synthesizes current knowledge on gut microbiome alterations in hypercholesterolemia, their causal role in cholesterol metabolism, and the influence of host and environmental factors on interindividual variability in therapeutic responses. It further discusses dietary and pharmacological strategies targeting the gut microbiome to modulate lipid metabolism. A better understanding these complex interactions may enable the development of personalized, microbiome-based strategies for the prevention and management of hypercholesterolemia.