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

• Published in: Nature biotechnology Vol. 38; no. 11; pp. 1288 - 1297
• Main Authors: Chen, Poshen B., Black, Audrey S., Sobel, Adam L., Zhao, Yannan, Mukherjee, Purba, Molparia, Bhuvan, Moore, Nina E., Aleman Muench, German R., Wu, Jiejun, Chen, Weixuan, Pinto, Antonio F. M., Maryanoff, Bruce E., Saghatelian, Alan, Soroosh, Pejman, Torkamani, Ali, Leman, Luke J., Ghadiri, M. Reza
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-11-2020; Nature Publishing Group
• Subjects: 631/326/2565/2134; 639/638/92/611; Agriculture; Animals; Anti-Bacterial Agents - pharmacology; Anti-Inflammatory Agents - pharmacology; Antibiotics; Arteriosclerosis; Atherosclerosis; Atherosclerosis - blood; Atherosclerosis - microbiology; Bacteria - drug effects; Bacteria - growth & development; Bile acids; Bioinformatics; Biomarkers - metabolism; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cholesterol; Cholesterol - blood; Chronic illnesses; Composition; Cytokines; Depletion; Development and progression; Diet; Diet, Western; Digestive system; Fatty acids; Feeding Behavior; Female; Gastrointestinal Microbiome - genetics; Gastrointestinal tract; Gene expression; Gene Expression Regulation - drug effects; Growth; Host-Pathogen Interactions - drug effects; Host-Pathogen Interactions - genetics; IL-1β; Immunologic Factors - pharmacology; Immunoregulation; Inflammation; Interleukin 6; Intestinal microflora; Intestine; Life Sciences; Low fat diet; Lymphocytes T; Mice, Inbred C57BL; Microbiomes; Microbiota; Microbiota (Symbiotic organisms); Microorganisms; Models, Biological; Nutrient deficiency; Oral administration; Peptides; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Plaques; Prevention; Receptors, LDL - metabolism; Tight Junction Proteins - metabolism; Transcription, Genetic; Tumor necrosis factor-α; United States
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/s41587-020-0549-5

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.
Gut microbiome composition is remodeled using small peptides.