The Gut Microbiota and Its Implication in the Development of Atherosclerosis and Related Cardiovascular Diseases

The importance of gut microbiota in health and disease is being highlighted by numerous research groups worldwide. Atherosclerosis, the leading cause of heart disease and stroke, is responsible for about 50% of all cardiovascular deaths. Recently, gut dysbiosis has been identified as a remarkable factor to be considered in the pathogenesis of cardiovascular diseases (CVDs). In this review, we briefly discuss how external factors such as dietary and physical activity habits influence host-microbiota and atherogenesis, the potential mechanisms of the influence of gut microbiota in host blood pressure and the alterations in the prevalence of those bacterial genera affecting vascular tone and the development of hypertension. We will also be examining the microbiota as a therapeutic target in the prevention of CVDs and the beneficial mechanisms of probiotic administration related to cardiovascular risks. All these new insights might lead to novel analysis and CVD therapeutics based on the microbiota.Ye

Concentrations of serum TNF-α (A) and IL-6 (B) of Zucker-lean^+/<i>fa</i> and Zucker-Lepr<i>^fa/fa</i> rats that were fed either a placebo or LAB strains for 30 days.

<p>Values are the means ± SEM, n = 8 per group. ^†<i>P</i><0.05 (ZL + placebo vs. ZO + placebo), and *<i>P</i><0.05 (ZO + placebo vs. ZO + probiotic strains). ZL, Zucker-lean^+/<i>fa</i> rats; ZO, Zucker-Lepr<i>^fa/fa</i> rats.</p

Serum biochemical parameters of Zucker-lean^+/<i>fa</i> and Zucker-Lepr<i>^fa/fa</i> rats fed either a placebo or LAB strains.

<p>Values are the means ± SEM, n = 8 per group. ^#<i>P</i><0.05 (ZL baseline vs. ZO baseline), ^†<i>P</i><0.05 (ZL + placebo vs. ZO + placebo), *<i>P</i><0.05 (ZO baseline vs. ZO + placebo). ALT, alanine aminotransferase; AST, aspartate aminotransferase; NEFA, non-esterified fatty acids. HOMA-IR, homeostasis model assessment of insulin resistance. ZL, Zucker-lean^+/<i>fa</i> rats; ZO, Zucker-Lepr<i>^fa/fa</i> rats.</p

Liver triacylglycerol content of Zucker-lean^+/<i>fa</i> and Zucker-Lepr<i>^fa/fa</i> rats that were fed either a placebo or LAB strains for 30 days.

<p>Values are the means ± SEM, n = 8 per group. ^†<i>P</i><0.05 (ZL + placebo vs. ZO + placebo), and *<i>P</i><0.05 (ZO + placebo vs. ZO + LAB strains). ZL, Zucker-lean^+/<i>fa</i> rats; ZO, Zucker-Lepr<i>^fa/fa</i> rats.</p

Representative micrographs of 7-µm-thick liver sections stained with 0.3% Oil red O in 60% isopropanol of Zucker-lean^+/<i>fa</i> and Zucker-Lepr<i>^fa/fa</i> rats that were fed either a placebo or LAB strains for 30 days (A).

<p>Percentage of the micrograph area corresponding to the lipid staining of liver sections described in panel A was calculated (B). Values are the means ± SEM, n = 2 per group. ^†<i>P</i><0.05 (ZL + placebo vs. ZO + placebo), and *<i>P</i><0.05 (ZO + placebo vs. ZO + LAB strains). ZL, Zucker-lean^+/<i>fa</i> rats; ZO, Zucker-Lepr<i>^fa/fa</i> rats.</p

Serum leptin (A) and adiponectin (B) concentrations of Zucker-lean^+/<i>fa</i> and Zucker-Lepr<i>^fa/fa</i> rats that were fed either a placebo or LAB strains for 30 days.

<p>Values are the means ± SEM, n = 8 per group. ^#<i>P</i><0.05 (ZL baseline vs. ZO baseline), and ^†<i>P</i><0.05 (ZL + placebo vs. ZO + placebo). ZL, Zucker-lean^+/<i>fa</i> rats; ZO, Zucker-Lepr<i>^fa/fa</i> rats.</p

Haematoxylin-eosin stained, 5-µm-thick sections of ileal (top panels, A–D) and colonic (bottom panels, E–H) mucosa of Zucker-lean^+/<i>fa</i> and Zucker-Lepr<i>^fa/fa</i> rats that were fed either a placebo or LAB strains for 30 days.

<p>Two rats per group were used for this staining. Three pieces of tissue from each animal were fixed and embedded in the same paraffin block. Four to 8 sections per block were cut, stained and analyzed. Representative micrographs from various groups are shown. A and E: Zucker-lean^+/<i>fa</i> rats at baseline; B and F: Zucker-Lepr<i>^fa/fa</i> rats + placebo; C and G: Zucker-Lepr<i>^fa/fa</i> rats +<i>L. rhamnosus</i>; and D and H: Zucker-Lepr<i>^fa/fa</i> rats + LAB mixture.</p

Effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 on Hepatic Steatosis in Zucker Rats

We have previously described the safety and immunomodulatory effects of Lactobacillus paracasei CNCM I-4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 in healthy volunteers. The scope of this work was to evaluate the effects of these probiotic strains on the hepatic steatosis of obese rats. We used the Zucker rat as a genetic model of obesity. Zucker-Leprfa/fa rats received one of three probiotic strains, a mixture of L. paracasei CNCM I-4034 and B. breve CNCM I-4035, or a placebo for 30 days. An additional group of Zucker-lean+/fa rats received a placebo for 30 days. No alterations in intestinal histology, in the epithelial, lamina propria, muscular layers of the ileal or colonic mucosa, or the submucosae, were observed in any of the experimental groups. Triacylglycerol content decreased in the liver of Zucker-Leprfa/fa rats that were fed L. rhamnosus, B. breve, or the mixture of B. breve and L. paracasei. Likewise, the area corresponding to neutral lipids was significantly smaller in the liver of all four groups of Zucker-Leprfa/fa rats that received probiotics than in rats fed the placebo. Zucker-Leprfa/fa rats exhibited significantly greater serum LPS levels than Zucker-lean+/fa rats upon administration of placebo for 30 days. In contrast, all four groups of obese Zucker-Leprfa/fa rats that received LAB strains exhibited serum LPS concentrations similar to those of Zucker-lean+/fa rats. Serum TNF-α levels decreased in the Zucker-Leprfa/fa rats that received B. breve, L. rhamnosus, or the mixture, whereas L. paracasei feeding decreased IL-6 levels in the serum of Zucker-Leprfa/fa rats. In conclusion, the probiotic strains reduced hepatic steatosis in part by lowering serum LPS, and had an anti-inflammatory effect in obese Zucker rats.Part of the research currently in progress in the authors' laboratory is funded by the company Hero Spain, S. A. through the grant #3545 managed by the Fundacion General Empresa-Universidad de Granada