Understanding the Relationship Between Cerebrovascular Disease and the Gut Microbiome

Abstract

While traditional vascular risk factors (eg, hypertension, dyslipidemia, tobacco use) account for 20% of the explained variance in carotid atherosclerosis, they remain a prominent focus for primary and secondary ischemic stroke prevention strategies. Among other potential contributors to atheroma formation and cerebrovascular disease, the gut microbiome has become increasingly implicated as a mediator of vascular risk. The foods we eat, coupled with our physiology and exposures (eg, antibiotics, supplements), directly contribute to atherosclerotic disease in complex ways that are mediated by gastrointestinal flora and metabolic by‐products. Proliferation of “pathogenic” gut microbes such as Enterobacteriaceae and Streptococcus spp, decrement of “commensal” species such as Akkermansia spp and the biodiversity of gut flora are directly related to an individual's dietary intake and exposure history. Each of these components of the gut microbiome correlate with the development or progression of many conditions including atherosclerosis. Moreover, the metabolism of certain substrates found in animal products (notably l ‐carnitine and choline) and of refined sugars by these microorganisms leads to buildup of circulating metabolites with known links to atherogenesis, platelet activation, atrial fibrillation, and other adverse vascular outcomes. Several of these toxic metabolites, including trimethylamine and trimethylamine N‐oxide, have been extensively studied in cardiovascular and cerebrovascular disease. Trimethylamine and trimethylamine N‐oxide represent not only biomarkers of gut dysbiosis and cardiovascular risk, but they are increasingly recognized as therapeutic targets for novel interventions in atherosclerotic vascular disease. The individualized targeting of one's microbiome, and perhaps more generalized targeting of toxic microbial metabolites, has the potential to revolutionize the treatment of vascular disease. In this review, we summarize the latest evidence illustrating the impact of the microbiome on cerebrovascular disease and highlight the potential applications of this information on individualized and global scales.