In humans and mammals, Western-type diet can induce imbalances in gut microbiota that strongly correlate with the development of several chronic diseases including atherosclerosis. I will describe that self-assembling cyclic d,l-a-peptides selected by using an in vitro en masse screening protocol can function as bacterial growth modulators to remodel a Western diet-induced imbalance in the gut microbiome and thus prevent atherosclerosis development in LDLr-/- mice. Daily oral administration of selected peptides to mice remodeled the gut microbiome and caused diverse effects in the host, including marked reductions in plasma cholesterol levels and atherosclerotic plaques. There was extensive reprogramming of the microbiome transcriptome and host gene expression levels, suppressed production of several pro-inflammatory cytokines, improved gut barrier integrity, increased populations of intestinal Helios positive regulatory T cells (Helios+ Treg) and rebalanced levels of disease-relevant metabolites, such as short-chain fatty acids (SCFAs) and bile acids. The ability to chemically manipulate the gut microbiome in a targeted fashion within a living organism provides not only an additional tool for deciphering the chemical biology of the gut microbiome, but also an avenue for advancing personalized therapeutics.

Toward novel therapeutics via directed remodeling of the gut microbiome

ACS Spring 2022

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