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

Nat Biotechnol. 2020 Nov;38(11):1288-1297. doi: 10.1038/s41587-020-0549-5. Epub 2020 Jun 15.


The gut microbiome is a malleable microbial community that can remodel in response to various 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 interleukin-6, tumor necrosis factor-α and interleukin-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 for deciphering the chemical biology of the gut microbiome and might advance microbiome-targeted therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Inflammatory Agents / pharmacology
  • Atherosclerosis / blood
  • Atherosclerosis / microbiology*
  • Bacteria / drug effects
  • Bacteria / growth & development
  • Biomarkers / metabolism
  • Cholesterol / blood
  • Diet, Western
  • Feeding Behavior
  • Female
  • Gastrointestinal Microbiome* / genetics
  • Gene Expression Regulation / drug effects
  • Host-Pathogen Interactions / drug effects
  • Host-Pathogen Interactions / genetics
  • Immunologic Factors / pharmacology
  • Mice, Inbred C57BL
  • Models, Biological
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology
  • Receptors, LDL / metabolism
  • Tight Junction Proteins / metabolism
  • Transcription, Genetic


  • Anti-Bacterial Agents
  • Anti-Inflammatory Agents
  • Biomarkers
  • Immunologic Factors
  • Peptides, Cyclic
  • Receptors, LDL
  • Tight Junction Proteins
  • Cholesterol