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.

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