High fat diet induced atherosclerosis is accompanied with low colonic bacterial diversity and altered abundances that correlates with plaque size, plasma A-FABP and cholesterol: a pilot study of high fat diet and its intervention with Lactobacillus rhamnosus GG (LGG) or telmisartan in ApoE−/− mice

Abstract

BackgroundAtherosclerosis appears to have multifactorial causes – microbial component like lipopolysaccharides (LPS) and other pathogen associated molecular patterns may be plausible factors. The gut microbiota is an ample source of such stimulants, and its dependent metabolites and altered gut metagenome has been an established link to atherosclerosis. In this exploratory pilot study, we aimed to elucidate whether microbial intervention with probiotics L. rhamnosus GG (LGG) or pharmaceuticals telmisartan (TLM) could improve atherosclerosis in a gut microbiota associated manner.MethodsAtherosclerotic phenotype was established by 12 weeks feeding of high fat (HF) diet as opposed to normal chow diet (ND) in apolipoprotein E knockout (ApoE−/−) mice. LGG or TLM supplementation to HF diet was studied.ResultsBoth LGG and TLM significantly reduced atherosclerotic plaque size and improved various biomarkers including endotoxin to different extents. Colonial microbiota analysis revealed that TLM restored HF diet induced increase in Firmicutes/Bacteroidetes ratio and decrease in alpha diversity; and led to a more distinct microbial clustering closer to ND in PCoA plot. Eubacteria, Anaeroplasma, Roseburia, Oscillospira and Dehalobacteria appeared to be protective against atherosclerosis and showed significant negative correlation with atherosclerotic plaque size and plasma adipocyte – fatty acid binding protein (A-FABP) and cholesterol.ConclusionLGG and TLM improved atherosclerosis with TLM having a more distinct alteration in the colonic gut microbiota. Altered bacteria genera and reduced alpha diversity had significant correlations to atherosclerotic plaque size, plasma A-FABP and cholesterol. Future studies on such bacterial functional influence in lipid metabolism will be warranted.

Antihypertensive Effects of Probiotics

“…For example, some probiotics display cholesterollowering properties [43,44], improve atherosclerosis [45,46], or attenuate myocardial hypertrophy and heart failure after myocardial infarction [47].…”

The Western Diet–Microbiome-Host Interaction and Its Role in Metabolic Disease

“…Recent studies demonstrate that gut bacteria have significant influence on lipid metabolism in mice, and that hypercholesterolemia and atherosclerosis are affected by functional changes in gut microbiota [101,102]. Also, the lack of suitable diets in animal studies is further complicating matter.…”

Lysosomes ‘in control’

“…In response to the first observation, we and others identified the modified lipoprotein oxidized low-density lipoprotein (oxLDL) as an essential determinant for hepatic inflammation. [69][70][71][72] Furthermore, these studies demonstrated that oxLDL-induced hepatic inflammation was accompanied by low levels of cytoplasmic lipids and large, swollen lysosomes in hepatic macrophages. In contrast, when inflammation was low, lipids tended to accumulate in the cytoplasm instead of the lysosomes 68,73 (Figure 1.4).…”

“…Being the most abundant liver cell, the hepatocyte is a crucial cell type for the regulation of general liver metabolism. 72 Currently, oxLDL-mediated hepatocyte damage has mainly been explained as a secondary effect of KC activation, whereby the KC directly communicates with the hepatocyte. 73 However, especially because hepatocytes are responsive to elevated circulating oxLDL levels by upregulating CD36 expression, 64,74 it is likely that oxLDL also mediates certain pro-inflammatory effects directly via the hepatocyte.…”

“…70,71 Besides genetics, another obvious component that influences gut microbiota is the composition of an individual's diet. High fat diet-induced changes in gut microbiota have been associated with metabolic syndrome-associated pathologies such as atherosclerosis, 72,73 NAFLD/NASH, 65 insulin resistance 74 and adipose tissue dysfunction. 65,75 However, malondialdehyde (which is a lipid peroxidation product contained inside oxLDL particles)-induced hepatic inflammation was independent of gut microbiota composition, 76 questioning the mechanistic role of gut microbiota to hepatic inflammation in this particular model.…”