Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Cell Mol Gastroenterol Hepatol. 2021;11(5):1327-1345. doi: 10.1016/j.jcmgh.2021.01.004. Epub 2021 Jan 19.
BACKGROUND & AIMS: Colonization by gut microbiota in early life confers beneficial effects on immunity throughout the host's lifespan. We sought to elucidate the mechanisms whereby neonatal supplementation with p40, a probiotic functional factor, reprograms intestinal epithelial cells for protection against adult-onset intestinal inflammation.
p40 was used to treat young adult mouse colonic (YAMC) epithelial cells with and without deletion of a methyltransferase, su(var)3-9, enhancer-of-zeste and trithorax domain-containing 1β (Setd1β), and mice in early life or in adulthood. Anti-transforming growth factor β (TGFβ)-neutralizing antibodies were administered to adult mice with and without colitis induced by 2,4,6-trinitrobenzenesulfonic acid or dextran sulfate sodium. We examined Setd1b and Tgfb gene expression, TGFβ production, monomethylation and trimethylation of histone H3 on the lysine 4 residue (H3K4me1/3), H3K4me3 enrichment in Tgfb promoter, differentiation of regulatory T cells (Tregs), and the inflammatory status.
p40 up-regulated expression of Setd1b in YAMC cells. Accordingly, p40 enhanced H3K4me1/3 in YAMC cells in a Setd1β-dependent manner. p40-regulated Setd1β mediated programming the TGFβ locus into a transcriptionally permissive chromatin state and promoting TGFβ production in YAMC. Furthermore, transient exposure to p40 during the neonatal period and in adulthood resulted in the immediate increase in Tgfb gene expression. However, only neonatal p40 supplementation induced the sustained H3K4me1/3 and Tgfb gene expression that persisted into adulthood. Interfering with TGFβ function by neutralizing antibodies diminished the long-lasting effects of neonatal p40 supplementation on differentiation of Tregs and protection against colitis in adult mice.
Exposure to p40 in early life enables an epigenetic imprint on TGFβ, leading to long-lasting production of TGFβ by intestinal epithelial cells to expand Tregs and protect the gut against inflammation.
肠道微生物群在生命早期的定植对宿主整个生命周期的免疫具有有益作用。我们试图阐明通过新生儿补充 p40（一种益生菌功能因子）来重塑肠道上皮细胞以预防成人发病的肠道炎症的机制。
用 p40 处理年轻成年鼠结肠（YAMC）上皮细胞，同时敲除甲基转移酶 su(var)3-9、增强子-of-zeste 和 trithorax 结构域包含 1β（Setd1β），并在生命早期或成年期对小鼠进行处理。用抗转化生长因子β（TGFβ）中和抗体处理由 2,4,6-三硝基苯磺酸或葡聚糖硫酸钠诱导结肠炎的成年小鼠。我们检查了 Setd1b 和 Tgfb 基因表达、TGFβ 产生、赖氨酸 4 位的组蛋白 H3 的单甲基化和三甲基化（H3K4me1/3）、Tgfb 启动子中的 H3K4me3 富集、调节性 T 细胞（Tregs）分化和炎症状态。
p40 上调了 YAMC 细胞中 Setd1b 的表达。因此，p40 以 Setd1β 依赖的方式增强了 YAMC 细胞中的 H3K4me1/3。p40 调节的 Setd1β 将 TGFβ 基因座编程为转录允许的染色质状态，并促进 YAMC 中的 TGFβ 产生。此外，在生命早期和成年期短暂暴露于 p40 会立即增加 Tgfb 基因表达。然而，只有新生儿 p40 补充会诱导持续的 H3K4me1/3 和 Tgfb 基因表达，这种表达持续到成年期。用中和抗体干扰 TGFβ 功能会减弱新生儿 p40 补充对成年小鼠 Tregs 分化和预防结肠炎的长期影响。
生命早期接触 p40 可在上皮细胞中的 TGFβ 上产生表观遗传印记，导致 TGFβ 的长期产生，从而扩大 Tregs 并保护肠道免受炎症。
