Stremmel Wolfgang, Schmidt Kathrin V, Schuhmann Vera, Kratzer Frank, Garbade Sven F, Langhans Claus-Dieter, Fricker Gert, Okun Jürgen G
Department of Gastroenterology, University Clinics of Heidelberg, Heidelberg, Germany.
Department of Pediatrics, University Clinics of Heidelberg, Heidelberg, Germany.
PLoS One. 2017 Jan 27;12(1):e0170742. doi: 10.1371/journal.pone.0170742. eCollection 2017.
Elevated serum trimethylamine-N-oxide (TMAO) was previously reported to be associated with an elevated risk for cardiovascular events. TMAO originates from the microbiota-dependent breakdown of food-derived phosphatidylcholine (PC) to trimethylamine (TMA), which is oxidized by hepatic flavin-containing monooxygenases to TMAO. Our aim was to investigate the predominant site of absorption of the bacterial PC-breakdown product TMA. A healthy human proband was exposed to 6.9 g native phosphatidylcholine, either without concomitant treatment or during application with the topical antibiotic rifaximin, or exposed only to 6.9 g of a delayed-release PC formulation. Plasma and urine concentrations of TMA and TMAO were determined by electrospray ionization tandem mass spectrometry (plasma) and gas chromatography-mass spectrometry (urine). Native PC administration without concomitant treatment resulted in peak plasma TMAO levels of 43 ± 8 μM at 12 h post-ingestion, which was reduced by concomitant rifaximin treatment to 22 ± 8 μM (p < 0.05). TMAO levels observed after delayed-release PC administration were 20 ± 3 μM (p < 0.001). Accordingly, the peak urinary concentration at 24 h post-exposure dropped from 252 ± 33 to 185 ± 31 mmol/mmol creatinine after rifaximin treatment. In contrast, delayed-release PC resulted in even more suppressed urinary TMAO levels after the initial 12-h observation period (143 ± 18 mmol/mmol creatinine) and thereafter remained within the control range (24 h: 97 ± 9 mmol/mmol creatinine, p < 0.001 24 h vs. 12 h), indicating a lack of substrate absorption in distal intestine and large bowel. Our results showed that the microbiota in the small intestine generated the PC breakdown product TMA. The resulting TMAO, as a cardiovascular risk factor, was suppressed by topical-acting antibiotics or when PC was presented in an intestinally delayed release preparation.
此前有报道称，血清三甲胺 - N - 氧化物（TMAO）升高与心血管事件风险升高有关。TMAO源自微生物群依赖的食物源性磷脂酰胆碱（PC）分解为三甲胺（TMA），TMA再被肝脏含黄素单加氧酶氧化为TMAO。我们的目的是研究细菌PC分解产物TMA的主要吸收部位。一名健康的人类受试者分别接受6.9 g天然磷脂酰胆碱，一种是未同时进行治疗，另一种是在使用局部抗生素利福昔明期间，或者仅接受6.9 g缓释PC制剂。通过电喷雾电离串联质谱法（血浆）和气相色谱 - 质谱法（尿液）测定血浆和尿液中TMA和TMAO的浓度。未同时进行治疗时给予天然PC，摄入后12小时血浆TMAO峰值水平为43±8 μM，同时使用利福昔明治疗可将其降至22±8 μM（p<0.05）。给予缓释PC后观察到的TMAO水平为20±3 μM（p<0.001）。相应地，利福昔明治疗后，暴露后24小时的尿峰值浓度从252±33降至185±31 mmol/mmol肌酐。相比之下，缓释PC在最初12小时观察期后导致尿TMAO水平进一步降低（143±18 mmol/mmol肌酐），此后保持在对照范围内（24小时：97±9 mmol/mmol肌酐），表明在远端小肠和大肠中缺乏底物吸收。我们的结果表明，小肠中的微生物群产生了PC分解产物TMA。作为心血管危险因素的TMAO，可通过局部作用的抗生素或当PC以肠道延迟释放制剂形式存在时受到抑制。
