Department of Medicine, Division of Gastroenterology & Nutrition, University of Texas Health, San Antonio, TX 78229, USA.
Nutrients. 2022 Jul 9;14(14):2825. doi: 10.3390/nu14142825.
Vitamin B12 (VB12) is a micronutrient that is essential for DNA synthesis and cellular energy production. We recently demonstrated that VB12 oral supplementation coordinates ileal epithelial cells (iECs) and gut microbiota functions to resist pathogen colonization in mice, but it remains unclear whether VB12 directly modulates the cellular homeostasis of iECs derived from humans. Here, we integrated transcriptomic, metabolomic, and epigenomic analyses to identify VB12-dependent molecular and metabolic pathways in human iEC microtissue cultures. RNA sequencing (RNA-seq) revealed that VB12 notably activated genes involved in fatty acid metabolism and epithelial cell proliferation while suppressing inflammatory responses in human iECs. Untargeted metabolite profiling demonstrated that VB12 facilitated the biosynthesis of amino acids and methyl groups, particularly -adenosylmethionine (SAM), and supported the function of the mitochondrial carnitine shuttle and TCA cycle. Further, genome-wide DNA methylation analysis illuminated a critical role of VB12 in sustaining cellular methylation programs, leading to differential CpG methylation of genes associated with intestinal barrier function and cell proliferation. Together, these findings suggest an essential involvement of VB12 in directing the fatty acid and mitochondrial metabolisms and reconfiguring the epigenome of human iECs to potentially support cellular oxygen utilization and cell proliferation.
维生素 B12（VB12）是一种必需的微量营养素，对于 DNA 合成和细胞能量产生至关重要。我们最近证明，VB12 口服补充可以协调回肠上皮细胞（iECs）和肠道微生物群的功能，以抵抗病原体在小鼠中的定植，但目前尚不清楚 VB12 是否直接调节源自人类的 iECs 的细胞内稳态。在这里，我们整合了转录组、代谢组和表观基因组分析，以鉴定 VB12 依赖性的人 iEC 微组织培养物中的分子和代谢途径。RNA 测序（RNA-seq）显示，VB12 显著激活了参与脂肪酸代谢和上皮细胞增殖的基因，同时抑制了人 iECs 中的炎症反应。非靶向代谢物分析表明，VB12 促进了氨基酸和甲基组的生物合成，特别是 -腺苷甲硫氨酸（SAM），并支持线粒体肉碱穿梭和 TCA 循环的功能。此外，全基因组 DNA 甲基化分析表明 VB12 在维持细胞甲基化程序中起着关键作用，导致与肠道屏障功能和细胞增殖相关的基因的 CpG 甲基化差异。总之，这些发现表明 VB12 对指导脂肪酸和线粒体代谢以及重新配置人 iECs 的表观基因组以潜在地支持细胞氧利用和细胞增殖具有重要作用。
