Wu Wei-Kai, Lo Yi-Ling, Chiu Jian-Ying, Hsu Chia-Lang, Lo I-Hsuan, Panyod Suraphan, Liao Yu-Chieh, Chiu Tina H T, Yang Yu-Tang, Kuo Han-Chun, Zou Hsin-Bai, Chen Yi-Hsun, Chuang Hsiao-Li, Yen Jeffrey J Y, Wang Jin-Town, Chiu Han-Mo, Hsu Cheng-Chih, Kuo Ching-Hua, Sheen Lee-Yan, Kao Hsien-Li, Wu Ming-Shiang
Bachelor Program of Biotechnology and Food Nutrition, National Taiwan University, Taipei, Taiwan.
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Gut Microbes. 2025 Dec;17(1):2446374. doi: 10.1080/19490976.2024.2446374. Epub 2024 Dec 26.
Gut microbial metabolism of L-carnitine, which leads to the production of detrimental trimethylamine N-oxide (TMAO), offers a plausible link between red meat consumption and cardiovascular risks. Several microbial genes, including , the operon, and the recently identified gene cluster, have been implicated in the conversion of dietary L-carnitine into TMA(O). However, the key microbial genes and associated gut microbes involved in this pathway have not been fully explored. Utilizing the oral carnitine challenge test (OCCT), which specifically measures TMAO production from L-carnitine intake and identifies TMAO producer phenotypes, we compared the abundance of microbial genes between low- and high-TMAO producers across three independent cohorts. Our findings consistently revealed that the gene cluster, rather than or the operon, was significantly enriched in high-TMAO producers. We further analyzed 292 paired multi-omic datasets from OCCT and shotgun metagenomic sequencing, which demonstrated a significant positive correlation between the abundance of fecal genes and L-carnitine-induced TMAO production, with showing the strongest correlation. Interestingly, these fecal genes were found to increase with L-carnitine supplementation and decrease with a plant-based diet. Notably, we verified a previously uncultured -containing bacterium, JAGTTR01 sp018223385, as the major contributor to TMA formation in the human gut. We isolated these -containing gut microbes and confirmed their role in TMA/TMAO production using anaerobic incubation and a gnotobiotic mouse model. Using an in-house collection of -containing isolates, we developed a qPCR-based method to quantify fecal and validated its correlation with L-carnitine-mediated TMAO production as measured by OCCT. Overall, these findings suggest that -containing gut microbes are crucial for TMAO increases following L-carnitine intake and may serve as biomarkers or targets for personalized nutrition.
左旋肉碱的肠道微生物代谢会导致有害的氧化三甲胺（TMAO）生成，这为红肉消费与心血管风险之间提供了一个合理的联系。包括 、 操纵子以及最近鉴定出的 基因簇在内的几个微生物基因，都与膳食左旋肉碱转化为TMA（O）有关。然而，该途径中关键的微生物基因及相关肠道微生物尚未得到充分研究。利用口服肉碱激发试验（OCCT），该试验专门测量左旋肉碱摄入后TMAO的生成情况并识别TMAO产生者表型，我们比较了三个独立队列中低TMAO产生者和高TMAO产生者之间微生物基因的丰度。我们的研究结果一致表明，在高TMAO产生者中， 基因簇而非 或 操纵子显著富集。我们进一步分析了来自OCCT和鸟枪法宏基因组测序的292对多组学数据集，结果表明粪便中 基因的丰度与左旋肉碱诱导的TMAO生成之间存在显著正相关，其中 显示出最强的相关性。有趣的是，这些粪便 基因在补充左旋肉碱时会增加，而在采用植物性饮食时会减少。值得注意的是，我们验证了一种以前未培养的含 的细菌JAGTTR01 sp018223385是人类肠道中TMA形成的主要贡献者。我们分离出这些含 的肠道微生物，并使用厌氧培养和无菌小鼠模型证实了它们在TMA/TMAO生成中的作用。利用内部收集的含 的分离株，我们开发了一种基于qPCR的方法来定量粪便中的 ，并验证了其与OCCT测量的左旋肉碱介导的TMAO生成之间的相关性。总体而言，这些发现表明含 的肠道微生物对于左旋肉碱摄入后TMAO的增加至关重要，可能作为个性化营养的生物标志物或靶点。
