Small molecule inhibition of gut microbial choline trimethylamine lyase activity alters host cholesterol and bile acid metabolism
Preeti Pathak, Robert N. Helsley, Amanda L. Brown, Jennifer A. Buffa, Ibrahim Choucair, Ina Nemet, Camelia Baleanu Gogonea, Valentin Gogonea, Zeneng Wang, José Carlos Garcı́a-Garcı́a, Lei Cai, Ryan E. Temel, Naseer Sangwan, Stanley L. Hazen, J. Mark Brown
Abstract
-oxide (TMAO) has been strongly associated with cardiovascular mortality, prompting drug discovery efforts to identify points of therapeutic intervention within the microbe host TMAO pathway. Recently, mechanism-based small molecule inhibitors of the major bacterial trimethylamine (TMA) lyase enzymes have been developed, and these drugs show efficacy as anti-atherothrombotic agents. The novel findings of this study are that small molecule TMA lyase inhibition results in beneficial reorganization of host cholesterol and bile acid metabolism. This study confirms previous observations that the gut microbial TMAO pathway is intimately linked to host cholesterol and bile acid metabolism and provides further rationale for the development of small molecule choline TMA lyase inhibitors for the treatment of cardiometabolic disorders.