Cardiovascular disease (CVD) is the leading cause of human deaths worldwide. The gut microbiome plays a significant role in cardiovascular health, as imbalances in the microbiome have been associated with elevated cholesterol and CVD. The question is whether we can modulate the gut microbiota to remodel a dysfunctional microbiome to a healthy one. We report the discovery of orally efficacious, self-assembling amphiphilic cyclic peptides that remodel the composition of the gut microbiome and reduce the progression of atherosclerosis in a mouse model of human hyperlipidemia. Using an in vitro antimicrobial activity assay, we identified several small, cyclic D,L-alpha-peptides with antibacterial activity against representative strains of normal gut bacteria present in humans and mice. The cyclic peptides act via a unique mechanism involving self-assembly and interaction with multiple components of the bacterial membrane, thus resisting the spontaneous development of bacterial resistance. Interestingly, daily oral administration of such peptides for two weeks in the mice fed a high-fat diet markedly reduced plasma low-density lipoprotein cholesterol levels and raised high-density lipoprotein levels. In two independent studies involving oral administration of two different peptides to mice for ten weeks, the overall structure of the gut microbiota was different in peptide-treated animals relative to controls. Quantitative PCR analysis of 16S rRNA genes showed that peptide treatment yielded a gut bacteria composition resembling that of animals fed a standard low-fat diet. Moreover, the peptides were remarkably effective in preventing atherosclerosis in vivo; atherosclerotic lesions in the aorta and heart were reduced by up to 50% (vs. controls). Thus, the self-assembly cyclic peptides can serve as a new approach for developing orally efficacious therapeutic agents to modulate the gut microbiome to treat atherosclerosis.

Self-assembling cyclic peptides that modulate the gut microbiome to treat atherosclerosis

248th National Meeting (2014)

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