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Page 10 of 18 Stuivenberg et al. Microbiome Res Rep 2025;4:11 https://dx.doi.org/10.20517/mrr.2024.22

some cases, care should be taken to ensure that the beneficial properties are maintained when delivered
alongside other strains.

When considering individual strains, both Bifidobacterium breve and Bifidobacterium longum can reduce
toxin burden and enhance SCFA production [47-51] , both of which would be beneficial to atherosclerosis
patients. While the mechanism of toxin clearance is often unknown, both B. breve and B. longum have been
[10]
shown to clear p-cresol directly from bacteriological growth media and a colonic environment [52,53] . Taken
together, these studies suggest that oral supplementation of B. breve or B. longum could offer protection
against gut microbiota metabolites relevant to atherosclerosis. These studies also point toward the
importance of proper strain selection. In the future, there should be an emphasis on testing individual
probiotic strains for the desired function, whether toxin clearance or any other, and ensuring that these
activities are retained when the strains are delivered in combination.

There have been fewer studies focusing on the clearance of indoxyl sulfate using probiotics; however, they
are still worth considering. In cohorts of hemodialysis patients, who often have a high burden of uremic
toxins, three studies assessed probiotics using different strains of B. longum. Two of these studies showed a
clear decrease in indoxyl sulfate [48,50] after 5 weeks of oral administration, while another indicated decreased
indoxyl glucuronide without reaching traditional measures of significance . Beyond probiotics, AST-120,
[41]
an oral activated carbon supplement, reduces the serum and urine levels of indoxyl sulfate in patients with
uremia by adsorbing indole in the intestines, thereby increasing its excretion into feces . Unfortunately,
[54]
AST-120 often requires the patient to consume 30 or more capsules daily, not considering any other
medications they may be taking [54,55] . It would, therefore, be beneficial to identify probiotic strains that could
effectively reduce indole in the gut, similar to what has been done for p-cresol, the microbial precursor of p-
cresyl sulfate.

PROBIOTICS FOR TRADITIONAL RISK FACTORS OF ATHEROSCLEROSIS
Beyond reducing metabolites produced by the intestinal microbiota, probiotics have also shown great
potential in protecting against traditional atherosclerosis risk factors such as lipid metabolism, endothelial
dysfunction, and inflammation.

Cholesterol
Maintaining a well-controlled cholesterol equilibrium is paramount in slowing atherosclerosis
progression [56-59] . Regrettably, numerous inquiries into antiatherosclerotic drugs have yielded disappointing
results [60-62] . Alternatively, there have been various reports of probiotics having favorable impacts on lipid
metabolism, suggesting their potential utility in atherosclerosis patients.

Several strains of lactobacilli have demonstrated robust hypocholesterolemic effects in vivo [56-59] . Among
these, the Lab4 probiotic consortium with Lactobacillus plantarum CUL66 stood out because it caused a
notable reduction in total plasma cholesterol levels while also mitigating diet-induced weight gain . It must
[63]
be noted that these studies were conducted in mice, necessitating further validation in human cohorts
before any assertions can be made regarding their efficacy against atherosclerosis. The use of probiotics to
reduce serum cholesterol remains blurred. For instance, a clinical trial utilizing Lactobacillus acidophilus
and Bifidobacterium animalis via yogurt or capsules did not improve atherosclerosis risk factors in
overweight individuals . The lack of success in this study does not negate the potential effectiveness of
[64]
probiotics. Researchers often rely on commercially available strains lacking documented activity against the
disease. Therefore, future clinical trials should focus on utilizing strains with established cholesterol-
lowering properties, such as those identified in the murine investigations [63,65-67] .