Gut ismA-expressing bacteria mitigate atherosclerosis by modulating cholesterol metabolism

Background The global aging population faces an increasing burden of atherosclerosis, exacerbated by hypercholesterolemia, which promotes vascular endothelial senescence and dysfunction. While current cholesterol-lowering drugs, such as statins, effectively reduce total/LDL cholesterol, they often fail to fully prevent or reverse atherosclerosis and have limited impact on absorption of dietary cholesterol in the intestine, underscoring the need for innovative strategies targeting this pathway. Purpose Here, we identify specific gut bacteria that break down cholesterol and reduce its intestinal absorption, mitigating the progression of atherosclerosis. Methods To address the knowledge gap in gut bacteria cholesterol lowering and mitigating atherosclerosis, we performed high-throughput multi-omics (fecal shotgun metagenomics and plasma LC-MS/MS lipidomics) in the TwinsUK Aging Cohort (n=952) and Aging Heart Zurich Cohort (ASCVD patients; n=105), coupled with in vitro bacterial studies, bacterial colonization, and histopathological analyses in ApoE-KO mice. Results Our metagenomic and plasma lipidomic analyses identified a lower abundance of ismA-encoding bacterial species in aged ASCVD patients. These bacteria, including Oscillibacter ruminantium, Oscillibacter sp. PC13, Oscillibacter sp. NSJ62, and Eubacterium pyruvativorans, convert cholesterol into cholestenone and coprostanol—less absorbable forms of cholesterol. Their abundance was negatively correlated with plasma and fecal cholesterol levels. As proof of concept, in vitro studies confirmed the causal role of these bacteria in cholesterol degradation. Accordingly, our in vivo colonization with Oscillibacter sp. PC13 and Eubacterium pyruvativorans significantly reduced plasma and fecal cholesterol levels and attenuated atherosclerotic lesions in aortas of ApoE-KO mice fed a 4-wk high-fat diet. These effects were associated with a marked reduction in endothelial senescence phenotypes, including decreased expression of cell-cycle arrest markers (p16INK4a, p19INK4d), SASP components (IL-6, VCAM-1), lysosomal alterations (SA-β-gal activity), and DNA damage response (γ-H2A.X) in aortic intimal endothelial cells. Conclusions This study introduces ismA-encoding bacteria as potential cholesterol-lowering probiotics with the capacity to attenuate atherosclerosis, presenting a novel microbiome-based approach for cardiovascular health in aging.