Influence of gut microbiota on atherosclerosis

Cardiovascular diseases (CVD) are recognized as a leading cause of death globally. Atherosclerosis, a key component of many CVDs, is a condition where plaque material builds up inside the arteries, leading to their narrowing and altered blood flow. Traditional risk factors for atherosclerosis include obesity, diabetes, and inflammation. Despite the availability of treatments targeting these risk factors, a significant disease burden remains, highlighting the urgent need for additional treatment strategies. Therefore, non-traditional drivers of atherogenesis, such as the gut microbiota (part 1 of this thesis) and cellular senescence (part 2 of this thesis), have gained attention.

Using preclinical mouse models, the following has been observed in this study by Tessa Yntema:

1. Different dietary components have distinct effects on the oral and fecal microbiota, with dietary fat altering bile acid (BA) metabolism, playing a pivotal role in obesity and its comorbidities.
2. Commensal gut bacteria protect against atherosclerosis, potentially through the production of short-chain fatty acids and secondary BAs.
3. A hydrophobic (human) BA pool leads to smaller atherosclerotic lesions in female mice, probably by targeting lipid metabolism rather than inflammation.

Next, we validated two different models for studying senescence in atherosclerosis. In atherosclerosis-prone p16tdTom mice, we observed p16-positive cells in heart lesions upon feeding with a Western-type diet. Additionally, we demonstrated that senolytic treatment on cultured human plaque slices leads to a reduction in senescence and inflammatory markers. This supports the potency of ex vivo human plaque slices as a valuable tool for evaluating novel therapeutics targeting atherosclerosis.