Abstract
ScopePrevious studies show that Lab4 probiotic consortium plus Lactobacillus plantarum CUL66 (Lab4P) reduces diet‐induced weight gain and plasma cholesterol levels in C57BL/6J mice fed a high fat diet (HFD). The effect of Lab4P on atherosclerosis is not known and is therefore investigated.Methods and ResultsAtherosclerosis‐associated parameters are analyzed in LDL receptor deficient mice fed HFD for 12 weeks alone or supplemented with Lab4P. Lab4P increases plasma HDL and triglyceride levels and decreases LDL/VLDL levels. Lab4P also reduces plaque burden and content of lipids and macrophages, indicative of dampened inflammation, and increases smooth muscle cell content, a marker of plaque stabilization. Atherosclerosis arrays show that Lab4P alters the liver expression of 19 key disease‐associated genes. Lab4P also decreases the frequency of macrophages and T‐cells in the bone marrow. In vitro assays using conditioned media from probiotic bacteria demonstrates attenuation of several atherosclerosis‐associated processes in vitro such as chemokine‐driven monocytic migration, proliferation of monocytes and macrophages, foam cell formation and associated changes in expression of key genes, and proliferation and migration of vascular smooth muscle cells.ConclusionThis study provides new insights into the anti‐atherogenic actions of Lab4P together with the underlying mechanisms and supports further assessments in human trials.
Highlights
We have previously shown the cholesterol lowering ability of Lactobacillus plantarum CUL66 in Caco-2 enterocytes via modulation of pathways associated with
For genes implicated in control of inflammation, expression of chemokine C-C motif receptor 1 (Ccr1; p = 0.003), Ccr2 (p = 0.006), interferonγ (Ifng; p < 0.001), interleukin (IL)-2 (Il2; p = 0.048), integrin β2 (Itgb2; p = 0.001), peroxisome proliferator activated receptor (Ppar) γ (Pparg; p = 0.046) and tumor necrosis factor (Tnf; p = 0.035) were significantly reduced in the Lab4P group
To rule out possibility that the decrease was due to THP-1 cell line, experiments were performed in primary human monocyte-derived macrophages (HMDM) where Dil-oxidized LDL (oxLDL) uptake was significantly inhibited by Lab4 (p = 0.001) and CUL66 (p < 0.001) conditioned medium (CM) (Figure 8B)
Summary
Atherosclerosis, a disease of the vasculature associated with inflammation and lipid accumulation, is the principal cause of cardiovascular disease.[1,2,3] Current therapies against atherosclerosis such as statins are not fully effective and many promising pharmaceutical leads from various drug discovery and other screening programs have failed because of safety concerns and/or off-target effects.[1,2] Substantial interest has been fuelled in the use of natural products in the prevention and treatment of atherosclerosis, possibly as adds-on with pharmaceutical agents.[1,2]. P. Rodrigues European Cancer Stem Cell Research Institute, Cardiff School of Biosciences Cardiff University Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK. Lactis CUL34 (NCIMB 30172) in combination with L. plantarum CUL66 (called Lab4P hereafter) reduced plasma levels of total cholesterol and suppressed diet-induced weight gain.[5] More recently, Lab4P was shown to reduce body weight and improve well-being in a randomized control trial of overweight and obese adults.[6] the effects of Lab4P on atherosclerosis are not known and were investigated using LDL receptor deficient (LDLr−/−) mice fed HFD for 12 weeks. Lab4P produced beneficial changes in the plasma cholesterol profile, plaque burden, inflammation and a marker of stability, liver expression of several atherosclerosisassociated genes and bone marrow cell populations. The use of conditioned medium (CM) from probiotic bacteria demonstrated beneficial regulation of several atherosclerosis-associated processes in vitro and provided mechanistic insights
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