An antiatherosclerotic signaling cascade involving intestinal microbiota, microRNA-10b, and ABCA1/ABCG1-mediated reverse cholesterol transport.

A sobering fact is that human DNA represents <10% of the total DNA within each of us. Every mucosal surface harbors a diverse and distinct microbial composition, with the human intestines containing by far the largest and most complex microbial ecosystem (intestinal microbiota). Serving as the filter for our largest environmental exposure—what we eat—the human intestinal microbiota is enormous—at least 3.3 million nonredundant microbial genes, making it ≈150× larger than the human gene complement. 1 Analyses of fecal metagenomes (genomic analysis of a community of microorganisms) from individuals, both with distinct long-term dietary patterns 2 and from around the world, 3 demonstrate the existence of a more limited number of stable clusters of microbial compositions, termed enterotypes, which represent relatively durable host-microbial symbiotic states. Metabolomics analyses reveal that intestinal microflora exert a significant effect on mammalian blood metabolites, 4 raising the possibility that distinct enterotypes may respond differently to environmental (dietary or drug) exposures. Consistent with this notion, significant mounting evidence indicates that numerous cardiometabolic phenotypes within the human superorganism are influenced by a complex interplay among environmental (typically dietary nutrient) exposures, intestinal microbiota composition, and host factors. One of the earlier examples demonstrating the importance of intestinal mi-croflora in a complex cardiometabolic phenotype was first reported by Turnbaugh et al, 5 who showed that differences in the efficiency of energy harvest from food of distinct microflora compositions within lean versus obese inbred strains of mice could contribute to the development of obesity. Importantly, the obese phenotype was shown to be a transmissible trait, with obese versus lean cecal microbiota transplant into germ-free mice resulting in significantly greater body fat accumulation , despite equivalent caloric intake. 5 Metabolomics studies by Nicholson et al 6 suggested that intestinal microbiota may similarly play an active role in the development of complex metabolic abnormalities, such as susceptibility to insulin resistance and fatty liver disease. Subsequent examination of germ-free versus conventional mice on high-fat diet revealed that both insulin sensitivity and cholesterol metabolism are metabolic targets influenced by the intestinal microbiota. 7 And more recently, studies with mice defective in NLRP3 and NLRP6 inflammasome sensing demonstrate that inflammasome-mediated intestinal dysbiosis (imbalance in microbial composition) enhances susceptibility to hepatic steatosis, inflammation, and obesity. 8 Remarkably, cohousing of inflammasome-deficient mice with wild-type mice conferred hepatic steatosis and obesity phenotypes to the wild-type mice, suggesting that some aspects of metabolic syndrome may be communicable. 8 A study …