(567e) A Pro-Drug Strategy Enhances Butyrate Bioavailability and Therapeutic Efficacy in Atherosclerosis

Introduction: Atherosclerosis underlies cardiovascular disease, the leading cause of death globally. While current treatments focus on reducing low-density lipoprotein (LDL) cholesterol, chronic inflammation has also been found to be a key driver of atherosclerosis. The short chain fatty acid butyrate has a multitude of pharmacologic functions including in lipid metabolism and inflammation. However, its low bioavailability and pungent odor limit its therapeutic potential.

Methods: To overcome these challenges, we engineered a butyrate pro-drug by conjugating it to the amino acid serine (Ser-But). By co-opting gut amino acid transporters, orally administered Ser-But has high bioavailability. Furthermore, conjugation to serine masks the foul odor of butyrate.

Results: We added Ser-But to the drinking water of apolipoprotein E^-/- mice on a high fat diet for six weeks as a murine model of atherosclerosis. Our results show that Ser-But reduces vascular inflammation, LDL cholesterol, and atherosclerotic plaque area compared to mice on regular drinking water. We further show that Ser-But is absorbed by gut-draining lymph nodes and has a tolerogenic effect on multiple immune cell populations.

Conclusions: By chemically modifying butyrate, we successfully increased its bioavailability to enhance its translation in the treatment of cardiovascular diseases.