Dietary Timing Modulates Bile Acid Metabolism and TGR5 Activation to Influence Atherosclerotic Progression

Feeding patterns are emerging as critical regulators of cardiometabolic health; however, their impact on atherosclerotic cardiovascular disease (ASCVD) remains incompletely understood. Here, we demonstrate that feeding during the active phase (i.e., the dark/nighttime phase, when mice are active), either <em>ad libitum</em> (unrestricted access) or restricted to the nighttime (limited to the dark phase), confers significant protection against atherosclerosis in <em>Apoe^⁻/⁻</em> mice, compared to misaligned feeding during the inactive phase (restricted to the light phase). Multi–omics integration revealed that this atheroprotective effect is mediated by gut microbiota–driven modulation of bile acid (BA) metabolism, particularly involving taurolithocholic acid (TLCA), a potent agonist of the G protein–coupled bile acid receptor TGR5. Daytime feeding disrupted the relative abundance of BA–transforming taxa (e.g., <em>Dubosiella</em>, <em>Clostridium</em>) and downregulated key microbial genes (<em>baiA</em>, <em>baiB</em>, <em>cbh</em>, <em>hdhA</em>, and <em>AMACR</em>), leading to reduced TLCA biosynthesis. Despite unaltered hepatic expression of <em>BAAT</em>, <em>FXR</em>, and <em>CYP7A1</em>, compensatory upregulation of <em>CYP7B1</em> was insufficient to restore TLCA levels. Consequently, impaired vascular TGR5 signaling promoted endothelial inflammation and reduced cholesterol efflux by downregulating <em>ABCA1</em> expression, thereby facilitating plaque formation. These findings identify the microbiota–BA–TGR5 axis as a critical mediator of feeding rhythm–linked atheroprotection and underscore the therapeutic potential of chrono–nutrition in ASCVD prevention.