Cholesterol-metabolizing eubacterium ramulus bacteria mitigate vascular senescence and atherosclerosis

Background Atherosclerotic cardiovascular diseases (ASCVD) remain the leading cause of death in ageing populations, accounting for >40% of global mortality. Atherosclerosis is exacerbated by classical risk factors including hypercholesterolemia, which promotes vascular endothelial senescence and dysfunction. While current cholesterol-lowering drugs effectively reduce total/LDL cholesterol, they often fail to fully prevent vascular ageing and ASCVD and have limited impact on absorption of dietary cholesterol in the intestine, underscoring the need for innovative complementary strategies synergizing their efficacy. Purpose Here, we identify specific gut bacteria that modulate intestinal cholesterol metabolism and reduce its absorption, mitigating the progression of atherosclerosis. Methods To address the knowledge gap in gut microbiota-cholesterol metabolism crosstalk, we performed high-throughput multi-omics (fecal shotgun metagenomics and plasma LC-MS/MS lipidomics) in the TwinsUK Aging Cohort (n=2,953) and Aging Heart Zurich Cohort (ASCVD patients; n=187), coupled with in vitro bacterial studies, bacterial colonization, and histopathological analyses in atherosclerosis-prone Ldlr-/- mice. Results Our metagenomic and plasma lipidomic analyses identified a lower abundance of ismA+ bacteria, including Eubacterium ramulus, in aged ASCVD patients and Ldlr-/- mice fed a western diet. Their abundance was negatively correlated with plasma and fecal cholesterol levels, and they actively converted cholesterol into cholestenone and coprostanol—less absorbable forms of cholesterol, both in vivo and in vitro. Impoetantly, our in vivo colonization with E. ramulus significantly reduced plasma cholesterol levels and attenuated aortic lesion area (%) in Ldlr-/- mice fed a western diet for 8 weeks. These effects were associated with a marked reduction in endothelial senescence phenotype, including downregulated cell-cycle arrest marker p16INK4a, SASP component IL-6, DNA damage response (γ-H2A.X), and reduced SA-β-gal activity in aortic and endothelial cells. Conclusions This study introduces characterizes E. ramulus as potential cholesterol-metabolizing probiotic with the potential of mitigating atherosclerosis. These findings suggest a novel microbiome-based strategy for vascular health in aging.