Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis

Abstract

The gut microbiome is a malleable microbial community that can remodel in response to a number of factors, including diet, and contribute to the development of several chronic diseases, including atherosclerosis. We devised an in vitro screening protocol of the mouse gut microbiome to discover molecules that can selectively modify bacterial growth. This approach was used to identify cyclic d,l -α-peptides that remodeled the Western diet (WD) gut microbiome toward the low fat diet microbiome state. Daily oral administration of the peptides in WD-fed LDLr −/− mice reduced plasma total cholesterol levels and atherosclerotic plaques. Depletion of the microbiome with antibiotics abrogated these effects. Peptide treatment reprogrammed the microbiome transcriptome, suppressed the production of pro-inflammatory cytokines (including IL-6, TNF-α, and IL-1β), rebalanced levels of short-chain fatty acids and bile acids, improved gut barrier integrity, and increased intestinal T regulatory cells. Directed chemical manipulation provides an additional tool to decipher the chemical biology of the gut microbiome and may advance microbiome-targeted therapeutics.

High fructose corn syrup, excess-free-fructose, and risk of coronary heart disease among African Americans– the Jackson Heart Study

“…Notably, in prior analyses with NHANES [10], and in the Health Professionals Follow-Up Study (n = 42, 883) [6], associations with CHD persisted, independent of hypertension, and serum triglyceride, glucose [6,10], and cholesterol concentrations [10]. Results from these studies are consistent with the possibility that the CHD association is with gut-heart mechanisms that precede fructose metabolism [13,[28][29][30]. Industry sponsored messaging has promoted the viewpoint that HFCS is chemically similar to, and no more problematic to health and wellness than table sugar (sucrose) [52][53][54].…”

“…Higher fructose malabsorption prevalence may contribute to the different atherogenic profile (lower visceral adipose tissue/serum free fatty acid concentrations) and different diabetogenic profile (impaired insulin secretion) [51] seen in non-Hispanic blacks relative to non-Hispanic whites. The high percentage of participants with normal fasting triglycerides is consistent with the possibility that the CHD association is, in part, with gut-heart mechanisms that stem from unabsorbed fructose and less so with fructose metabolism by the liver [13,[28][29][30].…”

“…Existing epidmiogical studies of SSB and CHD [6,10], including our findings, suggest that other mechanisms are involved, as regular consumption of HFCS sweetened beverages remained significantly associated with increased CHD risk, independent of serum glucose, triglyceride and LDL-C concentrations. Potential mechanisms that could explain our results include disruptions to the microbiome by unabsorbed/luminal fructose [28] that promote hypertension and atherosclerosis [29,30], as previously described. Individuals with lower intestinal fructose absorption have higher luminal fructose concentration.…”

“…Between 1980 and 2010, consumption of excess-freefructose exceeded dosages associated with fructose malabsorption (~5 g-10 g) [13][14][15][16][17][18][19][20][21][22], as extrapolated from food availability data [23,24] before subjective, retroactively applied loss adjustments [25][26][27]. Fructose malabsorption may be an underlying CHD risk factor, as unabsorbed/luminal fructose alters gut bacterial load, composition and diversity [28], and recent research shows that such detrimental shifts in the microbiome promote hypertension and atherosclerosis [29,30]. African Americans may be at increased risk, as fructose malabsorption prevalence is higher among non-Hispanic blacks relative to Hispanics, despite the fact that both ethnicities exhibit high consumption of HFCS sweetened beverages [31].…”

The Microbiome in Health and Disease from the Perspective of Modern Medicine and Ayurveda

“…While the precise manner in which the microbiome participates in these many disease states is still not completely clear, there are currently a number of therapeutic approaches that are now being tested in clinical trials including diet, prebiotics, probiotics, antibiotics, and fecal microbiome transplantation (FMT) [ 45 , 46 , 47 ]. Recent studies, for example, have utilized personalized nutritional advice based on microbiome data and other factors [ 48 , 49 , 50 ]…”