Abstract
SummaryThe human microbiome encodes extensive metabolic capabilities, but our understanding of the mechanisms linking gut microbes to human metabolism remains limited. Here, we focus on the conversion of cholesterol to the poorly absorbed sterol coprostanol by the gut microbiota to develop a framework for the identification of functional enzymes and microbes. By integrating paired metagenomics and metabolomics data from existing cohorts with biochemical knowledge and experimentation, we predict and validate a group of microbial cholesterol dehydrogenases that contribute to coprostanol formation. These enzymes are encoded by ismA genes in a clade of uncultured microorganisms, which are prevalent in geographically diverse human cohorts. Individuals harboring coprostanol-forming microbes have significantly lower fecal cholesterol levels and lower serum total cholesterol with effects comparable to those attributed to variations in lipid homeostasis genes. Thus, cholesterol metabolism by these microbes may play important roles in reducing intestinal and serum cholesterol concentrations, directly impacting human health.
Highlights
Cholesterol is a key biological molecule that functions as a structural component of all animal cell membranes and is a precursor of steroid hormones, vitamin D, and bile acids (Goldstein and Brown, 2015)
We find that the presence of these intestinal sterol metabolism A genes in a microbiome is associated with the presence of coprostanol in stool and reduced stool cholesterol levels
To demonstrate the potential for these cholesterol-metabolizing bacteria to influence human health, we show that the presence of intestinal sterol metabolism A genes (ismA) genes in human metagenomes is significantly associated with a decrease in total cholesterol concentrations in serum that is on par with the effects observed from variants in human genes involved in lipid homeostasis
Summary
Cholesterol is a key biological molecule that functions as a structural component of all animal cell membranes and is a precursor of steroid hormones, vitamin D, and bile acids (Goldstein and Brown, 2015). Two main sources of cholesterol are thought to influence concentrations of this metabolite in serum: endogenous cholesterol synthesized in the liver and exogenous cholesterol derived from dietary components of animal origin (Figure 1) (Bays et al, 2008). The cholesterol synthesized in hepatocytes is transported to the gallbladder and is secreted into the small intestine along with other bile salts. Reducing cholesterol transport in the intestine is a clinically validated strategy for lowering serum cholesterol levels as demonstrated by ezetimibe, an FDA-approved small molecule inhibitor of the intestinal cholesterol transporter (Figure 1) (Bays et al, 2008)
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