Which Came First, the Bacteria or the Egg? Gut Microbiota, Diet, and CVD

Brown, Donald J.
June 2013
Integrative Medicine Alert;Jun2013, Vol. 16 Issue 6, p61
Two prospective clinical studies, which were funded by the National Institutes of Health, were completed at the Lerner Research Institute of the Cleveland Clinic. In the first study, 40 healthy adults who had not taken antibiotics or probiotics in the past month underwent a phosphatidylcholine (PC) challenge during visit 1. For each participant, baseline blood and spot urine samples were obtained after an overnight fast (≥ 12 hours). At baseline, participants were given two large hard-boiled eggs including the yolk (approximately 500 mg of choline each) to be eaten within a 10-minute period together with 250 mg of deuterium-labeled PC (d9-PC), as a tracer. Serial venous blood sampling was performed at 1, 2, 3, 4, 6, and 8 hours after baseline, along with a 24-hour urine collection. These samples were used to measure trimethylamine-N-oxide (TMAO) and d9-TMAO, and choline and betaine levels were also measured in the plasma samples. Time-dependent increases in levels of both TMAO and d9-TMAO, as well other choline metabolites, were detected after the PC challenge. Urine samples also showed the presence of both TMAO and d9-TMAO, and there was a strong correlation between plasma levels of TMAO and absolute urine TMAO level (Spearman's r = 0.58, P < 0.001). Six participants then received metronidazole (500 mg twice daily) plus ciprofloxacin (500 mg/day) for 1 week. After receipt of the antibiotics, a repeat PC challenge was performed at visit 2. A third and final PC challenge was performed 1 month or more after the withdrawal of antibiotics (and subsequent "reacquisition of gut flora"), at visit 3. The same plasma and urine measurements were repeated at each visit. Antibiotic use resulted in a near complete suppression of detectable TMAO and d9-TMAO in both plasma and urine at visit 2. In contrast, the time courses of changes in free choline and betaine were not altered by antibiotic use. Following the PC challenge at visit 3, there was a notable time-dependent increase in plasma and urine TMAO and d9-TMAO. (See Table.) Finally, a second study (clinical outcomes) enrolled 4007 adults who were undergoing elective coronary angiography. During a 3-year follow-up, the relationship between fasting plasma levels of TMAO and incidence of major adverse cardiovascular events (death, myocardial infarction [MI], or stroke) was studied. Increased levels of TMAO were associated with an increased risk of major adverse cardiovascular events (hazard ratio for highest vs lowest TMAO quartile, 2.54; 95% confidence interval, 1.96-3.28; P < 0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P < 0.001), as well as in lower-risk groups.


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