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Page 2 of 18 Stuivenberg et al. Microbiome Res Rep 2025;4:11 https://dx.doi.org/10.20517/mrr.2024.22

factors such as age, sex, diabetes, blood pressure, and smoking are thought to account for most cases. Many
readers may be surprised that a probiotic could be leveraged to improve atherosclerosis outcomes. However,
as shown in Table 1, traditional risk factors account for only a small proportion of atherosclerosis, and toxic
[1]
metabolites formed by the gut microbiota emerged as strong predictors of atherosclerosis severity ,
measured as carotid total plaque area (TPA) .
[2]
There is increasing evidence to support the role of gut microbiota in both the progression and prevention of
atherosclerosis. Jie et al. showed that the gut microbiota of atherosclerosis patients distinguished them from
[3]
healthy controls and could predict atherosclerosis risk . Microbial metabolites produced in the
gastrointestinal tract, such as trimethylamine N-oxide (TMAO) and the short-chain fatty acid (SCFA)
[4]
propionate , have been linked to atherosclerosis severity and protection, respectively. Lactobacillus
[5]
rhamnosus is enriched in stable atherosclerotic plaques, suggesting it may have a role in regulating plaque
stability . Together, these findings highlight the ability of resident microbes to influence plaque growth and
[6]
stability.

Orally delivered probiotics are an effective way of altering the metabolic flux of the gut microbiota to
influence patient outcomes, because the distribution of metabolites produced by the network of gut
microbes will change. For established risk factors of atherosclerosis, probiotics could help equilibrate lipid
metabolism, vascular function, and macrophage polarization, which would benefit patients. Thus, probiotics
have promise in managing the newly emerging risk factors of atherosclerosis by altering gut microbiota
[7,8]
composition and clearing harmful gut-derived uremic toxins (GDUTs) [9-11] . The aim of this perspective is
to assess whether probiotics may improve atherosclerosis, with a focus on emerging risk factors. We also
provide recommendations on how to identify novel probiotic candidates.

EXTREMES OF ATHEROSCLEROSIS HIGHLIGHT THE IMPORTANCE OF THE GUT
MICROBIOTA
Carotid plaque burden is strongly associated with cardiovascular risk [12,13] . Among patients in whom TPA
and levels of traditional risk factors have been measured, three phenotypes can be distinguished: Explained
atherosclerosis, in which plaque burden is explained by traditional risk factors; Unexplained atherosclerosis,
wherein atherosclerosis is severe despite little risk; and Protected individuals, who have high levels of
traditional risk factors, but little or no carotid plaque. Figure 1 shows the distribution of these phenotypes
among 316 of 3,056 patients who attended the Stroke Prevention & Atherosclerosis Research Centre,
Robarts Research Institute, London, Canada.

In that study, metabolic products of the gut microbiota that typically accumulate in individuals with renal
failure, GDUTs, were assayed in plasma by ultra-performance liquid chromatography coupled to
quadrupole time-of-flight mass spectrometry. Plasma levels of TMAO, p-cresyl sulfate, p-cresyl glucuronide,
and phenylacetylglutamine were significantly lower among patients with the protected phenotype, and
higher in those with the unexplained phenotype, despite no significant differences in renal function or in
dietary intake of nutrient precursors of GDUT. As shown in Table 1, both TMAO and p-cresyl sulfate were
significant predictors of TPA in a model that excluded diabetes, sex and systolic blood pressure, i.e., these
intestinal metabolites were stronger predictors of TPA than those three traditional risk factors. While our
study did not show a significant effect on TPA by other GDUTs, such as indoxyl sulfate, some have been
implicated to promote atherosclerosis, and will be discussed later in the review.