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

Inflammation
The orchestration of the inflammatory response is a pivotal determinant of atherosclerosis progression and
[68]
stability . Within this complex milieu, cytokines, notably TNF-α, CRP, and IL-6, emerge as influential
players in atherosclerosis development. During the nascent stages of atherosclerosis, these cytokines act as
catalysts, inciting endothelial cell activation, amplifying the synthesis of adhesion molecules, and leading to
[69]
the migration of immune cells . As atherosclerosis advances to later stages, the presence of
proinflammatory cytokines manifests as plaque rupture and thrombosis. Thus, promoting an anti-
inflammatory environment raises hope for atherosclerosis treatment, which has been corroborated by
compelling clinical trials [70,71] .

The production of TNF-α within atherosclerotic plaques and elevated levels of the compound in the
bloodstream correlate with atherosclerosis progression . Recent investigations have highlighted a
[72]
consortium of probiotics such as Lactobacillus mucosae NK41, Bifidobacterium longum NK46,
Bifidobacterium breve DSM 16604 and DSM 24706 that can reduce TNF-α in vivo [73,74] . While the mechanism
behind this observation is still unclear, this nuanced influence of probiotics on the release of inflammatory
[75]
mediators appears to be intertwined with altered miRNA expression within the gastrointestinal tract . For
example, a strain of Lactobacillus plantarum has been shown to reduce TNF-α mRNA expression over the
[76]
span of three weeks, likely by regulating miRNA-450a expression . In contrast, a clinical investigation of
the same strain showed that there were no substantial shifts in TNF-α, IL-6, IL-1b, nor cortisol after a four-
week period, compared to placebo . The difference in outcomes underscores the need to tailor probiotic
[77]
interventions to the unique attributes of study participants, because the second intervention was in patients
with depression, not atherosclerosis. Elevated IL-6 has also emerged as a biomarker for atherosclerosis risk
and progression [78,79] . Some probiotics have been shown to reduce the presence of such inflammatory
cytokines. Indeed, a study involving colon cancer patients revealed that the postoperative administration of
a probiotic blend containing multiple strains of lactobacilli and bifidobacteria for four weeks resulted in a
marked reduction in proinflammatory cytokines TNF-α, IL-6, and IL-22 in peripheral blood . These
[80]
findings and others from animal studies are promising, but there is a need for randomized, double-blind
human trials to authenticate the anti-inflammatory potential of probiotics in atherosclerosis patients.

C-reactive protein (CRP) is another inflammatory marker produced in response to cytokines like IL-6, IL-1
β, and TNF-α, and is associated with vascular endothelial cell impairment, thrombosis, and ultimately
atherosclerosis progression [81,82] . Detectable within early lesions, CRP levels also increase as atherosclerosis
[83]
advances to later stages . To date, some studies investigating the impact of probiotics on CRP levels have
been successful. An 8-week course of probiotic capsules containing L. acidophilus, Lactobacillus casei, and
Bifidobacterium bifidum significantly reduced CRP . Another study involving a probiotic capsule
[84]
containing four strains, combined with vitamin D administration for 12 weeks, demonstrated decreased
[85]
CRP in women with polycystic ovarian syndrome . While direct evidence linking gut microbiota
modulation of inflammatory factors to atherosclerosis progression remains inconclusive, these studies offer
valuable insights and avenues for exploring novel preventive and therapeutic strategies for atherosclerosis.

While further research is needed to validate the efficacy of probiotics in modulating inflammatory factors
and slowing atherosclerosis advancement, these findings pave the way for innovative strategies in
preventing and treating atherosclerosis.

Endothelial function
Endothelial dysfunction is a key event in the early stages of atherosclerosis development/progression and is
caused by disrupted vascular homeostasis due to oxidative stress and inflammation [86,87] . Probiotics can
reduce oxidative stress, quell vascular inflammation, and increase nitric oxide (NO) production, each of