MIAMI – Researchers are one step closer to developing “drugs for bugs” – agents that target the gut microbiome to prevent and treat cardiometabolic diseases, Stanley L. Hazen, MD, PhD, said at the 2019 Gut Microbiota for Health World Summit.
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“Each person experiences a meal differently through the filter of their gut microbiome, which helps explain individual differences in susceptibility to disease,” said Dr. Hazen of Cleveland Clinic. “In the future, our medicine cabinets will have drugs in them that not only affect us, but also target the microbial enzymes that affect levels of metabolites like TMAO.”
Trimethylamine N-oxide (TMAO) is produced by gut bacteria. High levels (in one study, approximately 6.2 micromolar) significantly increase the risk of major adverse cardiovascular events even after controlling for traditional demographic and clinical risk factors. Studies indicate that TMAO alters cholesterol and bile acid metabolism, upregulates inflammatory pathways, and promotes foam cell formation, all of which worsen atherosclerosis. In addition, TMAO increases clotting risk by enhancing platelet reactivity.
“Reducing the amount of animal products in one’s diet helps reduce TMAO levels,” said Dr. Hazen. Certain fish – mainly those found in deep, cold water, such as cod – are high in TMAO. However, a bigger culprit in the United States is red meat, which contains two major TMAO precursors – choline and carnitine. In a recent study, Dr. Hazen and his associates gave 113 healthy volunteers three isocaloric diets in random order based on red meat, white meat, or plant-based protein. After 4 weeks, eating the daily equivalent of 8 ounces of steak or two quarter-pound beef patties nearly tripled plasma TMAO levels (P less than .05) from baseline. The white meat and vegetarian diets showed no such effect.
Crucially, the effect of red meat was reversible – TMAO levels fell significantly within 4 weeks after participants stopped consuming red meat. Eating red meat low in saturated fat did not prevent TMAO levels from rising, Dr. Hazen noted at the meeting at the meeting sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility.
In a second study, Dr. Hazen and his associates identified a two-step process by which gut bacteria metabolize carnitine to TMAO. The second step was greatly enhanced in individuals who eat red meat, suggesting a possible therapeutic target. In a third study, they found that high TMAO levels in mice fell significantly with a single oral dose of a second-generation inhibitor of trimethylamine lyase, the enzyme used by gut bacteria to convert choline to TMAO. The inhibitory effect was irreversible, did not reduce the viability of commensal microorganisms, and significantly lowered platelet hyperreactivity and clot formation.
Such results are exciting, but “drugs for bugs” will exhibit varying effects depending on which gut species are present at baseline, Dr. Hazen explained. Investigators will need to understand and account for these differences before therapies for the microbiome can enter the clinic. For now, a blood test for TMAO is available and can help clinicians tailor their suggestions on what to eat.
Dr. Hazen disclosed a consulting relationship with Proctor & Gamble, royalties for patents from Proctor & Gamble, Cleveland Heart Lab, and Quest Diagnostics, and research support from AstraZeneca, Pfizer, Roche Diagnostics, and Proctor & Gamble.