Shahbazi Roghayeh, Yasavoli-Sharahi Hamed, Alsadi Nawal, Sharifzad Farzaneh, Fang Sandra, Cuenin Cyrille, Cahais Vincent, Chung Felicia Fei-Lei, Herceg Zdenko, Matar Chantal
Cellular and Molecular Medicine Department, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Int J Mol Sci. 2023 Sep 27;24(19):14610. doi: 10.3390/ijms241914610.
Puberty is a critical developmental period of life characterized by marked physiological changes, including changes in the immune system and gut microbiota development. Exposure to inflammation induced by immune stressors during puberty has been found to stimulate central inflammation and lead to immune disturbance at distant sites from the gut; however, its enduring effects on gut immunity are not well explored. Therefore, in this study, we used a pubertal lipopolysaccharides (LPS)-induced inflammation mouse model to mimic pubertal exposure to inflammation and dysbiosis. We hypothesized that pubertal LPS-induced inflammation may cause long-term dysfunction in gut immunity by enduring dysregulation of inflammatory signaling and epigenetic changes, while prebiotic/probiotic intake may mitigate the gut immune system deregulation later in life. To this end, four-week-old female Balb/c mice were fed prebiotics/probiotics and exposed to LPS in the pubertal window. To better decipher the acute and enduring immunoprotective effects of biotic intake, we addressed the effect of treatment on interleukin (IL)-17 signaling related-cytokines and pathways. In addition, the effect of treatment on gut microbiota and epigenetic alterations, including changes in microRNA (miRNA) expression and DNA methylation, were studied. Our results revealed a significant dysregulation in selected cytokines, proteins, and miRNAs involved in key signaling pathways related to IL-17 production and function, including IL-17A and F, IL-6, IL-1β, transforming growth factor-β (TGF-β), signal transducer and activator of transcription-3 (STAT3), p-STAT3, forkhead box O1 (FOXO1), and miR-145 in the small intestine of adult mice challenged with LPS during puberty. In contrast, dietary interventions mitigated the lasting adverse effects of LPS on gut immune function, partly through epigenetic mechanisms. A DNA methylation analysis demonstrated that enduring changes in gut immunity in adult mice might be linked to differentially methylated genes, including , , , , , , and , involved in Th17 cell differentiation and IL-17 production and signaling. In addition, prebiotic administration prevented LPS-induced changes in the gut microbiota in pubertal mice. Together, these results indicate that following a healthy diet rich in prebiotics and probiotics is an optimal strategy for programming immune system function in the critical developmental windows of life and controlling inflammation later in life.
青春期是生命中一个关键的发育时期，其特点是显著的生理变化，包括免疫系统和肠道微生物群发育的变化。研究发现，青春期暴露于免疫应激源诱导的炎症会刺激中枢炎症，并导致肠道远处部位的免疫紊乱；然而，其对肠道免疫的持久影响尚未得到充分研究。因此，在本研究中，我们使用青春期脂多糖（LPS）诱导的炎症小鼠模型来模拟青春期暴露于炎症和生态失调的情况。我们假设青春期LPS诱导的炎症可能通过炎症信号的持续失调和表观遗传变化导致肠道免疫长期功能障碍，而摄入益生元/益生菌可能减轻生命后期肠道免疫系统的失调。为此，对四周龄雌性Balb/c小鼠在青春期窗口期喂食益生元/益生菌并使其暴露于LPS。为了更好地解读生物摄入的急性和持久免疫保护作用，我们研究了治疗对白细胞介素（IL）-17信号相关细胞因子和信号通路的影响。此外，还研究了治疗对肠道微生物群和表观遗传改变的影响，包括微小RNA（miRNA）表达和DNA甲基化的变化。我们的结果显示，在青春期受到LPS攻击的成年小鼠的小肠中，参与与IL-17产生和功能相关的关键信号通路的特定细胞因子、蛋白质和miRNA存在显著失调，包括IL-17A和F、IL-6、IL-1β、转化生长因子-β（TGF-β）、信号转导子和转录激活子-3（STAT3）、磷酸化STAT3、叉头框O1（FOXO1）和miR-145。相比之下，饮食干预部分通过表观遗传机制减轻了LPS对肠道免疫功能的持久不良影响。DNA甲基化分析表明，成年小鼠肠道免疫的持久变化可能与差异甲基化基因有关，这些基因包括参与Th17细胞分化、IL-17产生和信号传导的 、 、 、 、 、 和 。此外，益生元给药可预防青春期小鼠LPS诱导的肠道微生物群变化。总之，这些结果表明，在生命的关键发育窗口期遵循富含益生元和益生菌的健康饮食是规划免疫系统功能和控制生命后期炎症的最佳策略。
