Bordoni Laura, Petracci Irene, Feliziani Giulia, de Simone Gaia, Rucci Chiara, Gabbianelli Rosita
Unit of Molecular Biology and Nutrigenomics, School of Pharmacy and Health Products, University of Camerino, 62032 Camerino, Italy.
School of Advanced Studies, University of Camerino, 62032 Camerino, Italy.
Antioxidants (Basel). 2024 Aug 30;13(9):1061. doi: 10.3390/antiox13091061.
Trimethylamine (TMA), a byproduct of gut microbiota metabolism from dietary precursors, is not only the precursor of trimethylamine-N-oxide (TMAO) but may also affect gut health. An in vitro model of intestinal epithelium of Caco-2 cells was used to evaluate the impact of TMA on inflammation, paracellular permeability, epigenetics and mitochondrial functions. The expression levels of pro-inflammatory cytokines (IL-6, IL-1β) increased significantly after 24 h exposure to TMA 1 mM. TMA exposure was associated with an upregulation of SIRT1 (TMA 1 mM, 400 μM, 10 μM) and DNMT1 (TMA 1 mM, 400 µM) genes, while DNMT3A expression decreased (TMA 1 mM). In a cell-free model, TMA (from 0.1 µM to 1 mM) induced a dose-dependent reduction in Sirtuin enzyme activity. In Caco-2 cells, TMA reduced total ATP levels and significantly downregulated ND6 expression (TMA 1 mM). TMA excess (1 mM) reduced intracellular mitochondrial DNA copy numbers and increased the methylation of the light-strand promoter in the D-loop area of mtDNA. Also, TMA (1 mM, 400 µM, 10 µM) increased the permeability of Caco-2 epithelium, as evidenced by the reduced transepithelial electrical resistance values. Based on our preliminary results, TMA excess might promote inflammation in intestinal cells and disturb epigenetic and mitochondrial homeostasis.
三甲胺（TMA）是肠道微生物群对饮食前体进行代谢产生的一种副产物，它不仅是氧化三甲胺（TMAO）的前体，还可能影响肠道健康。利用Caco-2细胞的肠道上皮体外模型来评估TMA对炎症、细胞旁通透性、表观遗传学和线粒体功能的影响。在暴露于1 mM TMA 24小时后，促炎细胞因子（IL-6、IL-1β）的表达水平显著升高。TMA暴露与SIRT1基因（TMA 1 mM、400 μM、10 μM）和DNMT1基因（TMA 1 mM、400 µM）的上调有关，而DNMT3A的表达则下降（TMA 1 mM）。在无细胞模型中，TMA（0.1 µM至1 mM）诱导了Sirtuin酶活性的剂量依赖性降低。在Caco-2细胞中，TMA降低了总ATP水平，并显著下调了ND6的表达（TMA 1 mM）。TMA过量（1 mM）减少了细胞内线粒体DNA拷贝数，并增加了线粒体DNA D环区域轻链启动子的甲基化。此外，TMA（1 mM、400 µM、10 µM）增加了Caco-2上皮细胞的通透性，跨上皮电阻值降低证明了这一点。根据我们的初步结果，TMA过量可能会促进肠道细胞炎症，并扰乱表观遗传和线粒体稳态。
