Thrombosis Prevention: Let's Drug the Microbiome!

Francesca Vinchi Lindsley F. Kimball Research Institute (LFKRI), New York Blood Center, New York, NY Funding/support: None. Disclosure: The authors have indicated they have no potential conflicts of interest to disclose. Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. HemaSphere (2019) 3:1(e165) Citation: Vinchi F. Thrombosis Prevention: Let’s Drug the Microbiome! HemaSphere, 2019;3:1. http://dx.doi. org/10.1097/ HS9.0000000000000165 an emerging topic in all aspects of healthcare. The gut is home to a vast number of commensal microorganisms, which influence physiology and metabolism throughout the body. Indeed, the microbiome has been implicated in a whole variety of health conditions, suggesting a critical role of our commensals in human health and disease. Disruption of the gut microbiome has been associated with a range of conditions, from infectious diseases to cardiovascular and metabolic disorders, gastrointestinal illnesses and neurologic diseases. The development of novel ad hoc interventions to both prevent and treat conditions linked to changes or disruptions in the gut microbiome is of increasing interest. Some of these drugs are meant to maintain the overall health of the microbiome, whereas others specifically target disease mechanisms by altering microbial functions and/or composition of the gut microbiome. Modulating the microbiome can be achieved in different ways, ranging from probiotics and prebiotics to fecal microbiome transplants, the use of bacteria as drugs and more traditional pharmaceutical approaches (e.g., small molecules). Treatments that try to regulate the microbial composition/activity for therapeutic purposes are potentially successful only when the disease is in a causative relationship to our symbionts. Recent evidence has implicated the gut microbiota in the susceptibility to cardiovascular disease (CVD). Metabolomics studies identified choline and its derivative trimethylamine-N-oxide (TMAO) as metabolites that predispose to CVD and thrombosis. The gut microbiota play an intermediate role in converting choline to trimethylamine (TMA). Thismetabolite thenundergoes oxidation in the liver by flavin-monooxygenase enzymes (FMOs) to TMAO, which is finally released into the circulation. In a mouse model susceptible to atherosclerosis, increased dietary choline resulted in elevated plasma levels of TMAOand accelerated plaque development. Dietary exposure to TMAO elicited significant alterations in sterol/cholesterol metabolism, accounting for increased atherosclerosis. In contrast, mice deprived of the intestinal flora, either germ-free or treated with antibiotics, showed reduced circulating TMAO levels and atherosclerosis, even in associationwith a high-choline diet. In addition, TMAO enhanced platelet responsiveness and thrombotic potential in animal models. Platelet activation and aggregation and the subsequent generation of occlusive intraarterial thrombi are essential steps in atherothrombotic disease. Platelet exposure to TMAO enhanced stimulus-dependent platelet activation through increased Ca release from intracellular stores. Enhanced platelet reactivity is associated with both the extent of end-organ injury and adverse prognosis. Animal model studies employing dietary choline or TMAO, germ-free mice and microbial transplantation confirmed a role for gut microbiota-dependent TMAO production in modulating platelet hyperresponsiveness and thrombosis potential and identified microbial taxa associated with plasma TMAO and thrombotic potential. Consistently, patients with the highest TMAO plasma levels had an increased risk of myocardial infarction or stroke, suggesting that elevated plasma TMAO concentration is predictive of thrombotic events and CVD. Collectively, these studies demonstrated that the gut microbiota is an important player in atherogenesis and thrombosis and represents an environmental risk factor for CVD. Thus, targeting gut microbiota-dependent TMAO formation is emerging as a novel potential therapeutic strategy to reduce thrombotic risk. A growing effort is currently made by scientists to “drug the microbiome” for clinical purposes, including the maintenance of cardiovascular health. In a recent Nature Medicine paper, Roberts et al have developed and tested selective choline analogs capable to counteract TMAO formation. The aim of the authors was to select drugs that optimally target a gut microbial pathway with well-known relevance for a specific disease, in this case thrombosis. By applying a comprehensive screening strategy, 2 halomethylcholine-based inhibitors were identified. These compounds have the ability to interfere with the function of a