The use of an in-vitro batch fermentation (human colon) model for investigating mechanisms of TMA production from choline, L-carnitine and related precursors by the human gut microbiota.
The use of an in-vitro batch fermentation (human colon) model for investigating mechanisms of TMA production from choline, L-carnitine and related precursors by the human gut microbiota.
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使用人类肠道微生物群的胆碱，L-肉碱和相关前体的TMA产生机制，使用了体外批处理发酵（人类结肠）模型。
DOI：
10.1007/s00394-021-02572-6
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发表时间：
2021-10
影响因子：
5
通讯作者：
Kroon PA
中科院分区：
文献类型：
--
作者：
Day-Walsh P;Shehata E;Saha S;Savva GM;Nemeckova B;Speranza J;Kellingray L;Narbad A;Kroon PA
血浆三甲胺-N-氧化物(TMAO)水平已被证明与包括心血管疾病在内的代谢性疾病的风险增加相关。接触TMAO主要是由于肠道微生物区系依赖的三甲胺(TMA)从包括胆碱、肉碱和甜菜碱在内的饮食底物中产生，然后在肝脏中转化为TMAO。减少微生物TMA的产生很可能是克服人类TMAO负担的最有效和最可持续的方法。目前研究微生物TMA生产的模型有许多缺点，包括人体研究的成本和时间，动物模型中TMA(O)代谢的差异，以及使用分离的细菌菌株时无法复制多酶/多菌株途径的风险。这项研究的目的是在人结肠的体外模型中研究饮食前体产生TMA的情况。用LC-MS对胆碱、L-肉碱、甜菜碱和γ-丁基甜菜碱的体外代谢产物进行了24-48小时的研究。胆碱通过直接胆碱裂解酶途径而不是间接胆碱-甜菜碱途径代谢，L-肉碱转化为TMA慢于胆碱，并涉及中间产物γ-BB的形成，而L-肉碱代谢成TMA的Rieske型单加氧酶/还原酶途径可忽略不计。从前驱体生成三甲基甲烷的速率为choline >； carnitine >； betaine >； γ-BB.3，3-二甲基-1-丁醇(DMB)对胆碱转化为TMA没有影响。在结肠模型中，微生物TMA产生的代谢途径与人类研究中的观察结果一致。因此，该模型适合于研究TMA的肠道微生物区系代谢，并筛选旨在减少肠道微生物区系产生TMA的潜在治疗靶点。NCT02653001(http://www.clinicaltrials.gov)，已于2016年1月12日注册。网上版载有补充材料，可在10.1007/s00394-021-02572-6查阅。
Plasma trimethylamine-N-oxide (TMAO) levels have been shown to correlate with increased risk of metabolic diseases including cardiovascular diseases. TMAO exposure predominantly occurs as a consequence of gut microbiota-dependent trimethylamine (TMA) production from dietary substrates including choline, carnitine and betaine, which is then converted to TMAO in the liver. Reducing microbial TMA production is likely to be the most effective and sustainable approach to overcoming TMAO burden in humans. Current models for studying microbial TMA production have numerous weaknesses including the cost and length of human studies, differences in TMA(O) metabolism in animal models and the risk of failing to replicate multi-enzyme/multi-strain pathways when using isolated bacterial strains. The purpose of this research was to investigate TMA production from dietary precursors in an in-vitro model of the human colon. TMA production from choline, l-carnitine, betaine and γ-butyrobetaine was studied over 24–48 h using an in-vitro human colon model with metabolite quantification performed using LC–MS. Choline was metabolised via the direct choline TMA-lyase route but not the indirect choline–betaine-TMA route, conversion of l-carnitine to TMA was slower than that of choline and involves the formation of the intermediate γ-BB, whereas the Rieske-type monooxygenase/reductase pathway for l-carnitine metabolism to TMA was negligible. The rate of TMA production from precursors was choline > carnitine > betaine > γ-BB. 3,3-Dimethyl-1-butanol (DMB) had no effect on the conversion of choline to TMA. The metabolic routes for microbial TMA production in the colon model are consistent with observations from human studies. Thus, this model is suitable for studying gut microbiota metabolism of TMA and for screening potential therapeutic targets that aim to attenuate TMA production by the gut microbiota. NCT02653001 (http://www.clinicaltrials.gov), registered 12 Jan 2016. The online version contains supplementary material available at 10.1007/s00394-021-02572-6.
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影响因子：
15.5
作者：
Rath S;Heidrich B;Pieper DH;Vital M
通讯作者：
Vital M
影响因子：
3.7
作者：
Narath SH;Mautner SI;Svehlikova E;Schultes B;Pieber TR;Sinner FM;Gander E;Libiseller G;Schimek MG;Sourij H;Magnes C
通讯作者：
Magnes C
DOI：
10.1124/dmd.116.070615
发表时间：
2016-11
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Fennema D;Phillips IR;Shephard EA
通讯作者：
Shephard EA
影响因子：
4.8
作者：
Kalnins, Gints;Kuka, Janis;Tars, Kaspars
通讯作者：
Tars, Kaspars
影响因子：
5.2
作者：
Rath, Silke;Rud, Tatjana;Vital, Marius
通讯作者：
Vital, Marius