Sharpton Thomas, Lyalina Svetlana, Luong Julie, Pham Joey, Deal Emily M, Armour Courtney, Gaulke Christopher, Sanjabi Shomyseh, Pollard Katherine S
Department of Microbiology, Oregon State University, Corvallis, Oregon.
Department of Statistics, Oregon State University, Corvallis, Oregon.
mSystems. 2017 Sep 5;2(5). doi: 10.1128/mSystems.00036-17. eCollection 2017 Sep-Oct.
The gut microbiome is linked to inflammatory bowel disease (IBD) severity and altered in late-stage disease. However, it is unclear how gut microbial communities change over the course of IBD development, especially in regard to function. To investigate microbiome-mediated disease mechanisms and discover early biomarkers of IBD, we conducted a longitudinal metagenomic investigation in an established mouse model of IBD, where damped transforming growth factor β (TGF-β) signaling in T cells leads to peripheral immune activation, weight loss, and severe colitis. IBD development is associated with abnormal gut microbiome temporal dynamics, including damped acquisition of functional diversity and significant differences in abundance trajectories for KEGG modules such as glycosaminoglycan degradation, cellular chemotaxis, and type III and IV secretion systems. Most differences between sick and control mice emerge when mice begin to lose weight and heightened T cell activation is detected in peripheral blood. However, levels of lipooligosaccharide transporter abundance diverge prior to immune activation, indicating that it could be a predisease indicator or microbiome-mediated disease mechanism. Taxonomic structure of the gut microbiome also significantly changes in association with IBD development, and the abundances of particular taxa, including several species of , correlate with immune activation. These discoveries were enabled by our use of generalized linear mixed-effects models to test for differences in longitudinal profiles between healthy and diseased mice while accounting for the distributions of taxon and gene counts in metagenomic data. These findings demonstrate that longitudinal metagenomics is useful for discovering the potential mechanisms through which the gut microbiome becomes altered in IBD. IBD patients harbor distinct microbial communities with functional capabilities different from those seen with healthy people. But is this cause or effect? Answering this question requires data on changes in gut microbial communities leading to disease onset. By performing weekly metagenomic sequencing and mixed-effects modeling on an established mouse model of IBD, we identified several functional pathways encoded by the gut microbiome that covary with host immune status. These pathways are novel early biomarkers that may either enable microbes to live inside an inflamed gut or contribute to immune activation in IBD mice. Future work will validate the potential roles of these microbial pathways in host-microbe interactions and human disease. This study was novel in its longitudinal design and focus on microbial pathways, which provided new mechanistic insights into the role of gut microbes in IBD development.
肠道微生物群与炎症性肠病（IBD）的严重程度相关，且在疾病晚期会发生改变。然而，目前尚不清楚肠道微生物群落如何在IBD发展过程中发生变化，尤其是在功能方面。为了研究微生物群介导的疾病机制并发现IBD的早期生物标志物，我们在一个已建立的IBD小鼠模型中进行了纵向宏基因组学研究，在该模型中，T细胞中减弱的转化生长因子β（TGF-β）信号传导会导致外周免疫激活、体重减轻和严重的结肠炎。IBD的发展与肠道微生物群的异常时间动态相关，包括功能多样性的获取减弱以及KEGG模块（如糖胺聚糖降解、细胞趋化作用以及III型和IV型分泌系统）丰度轨迹的显著差异。患病小鼠和对照小鼠之间的大多数差异在小鼠开始体重减轻且外周血中检测到T细胞激活增强时出现。然而，脂寡糖转运蛋白丰度水平在免疫激活之前就出现了差异，这表明它可能是疾病前期指标或微生物群介导的疾病机制。肠道微生物群的分类结构也随着IBD的发展而发生显著变化，特定分类群的丰度，包括几种 ，与免疫激活相关。我们使用广义线性混合效应模型来测试健康小鼠和患病小鼠纵向特征的差异，同时考虑宏基因组数据中分类群和基因计数的分布，从而实现了这些发现。这些发现表明，纵向宏基因组学对于发现肠道微生物群在IBD中发生改变的潜在机制很有用。IBD患者拥有与健康人不同的具有独特功能能力的微生物群落。但这是原因还是结果呢？回答这个问题需要有关导致疾病发作的肠道微生物群落变化的数据。通过对已建立的IBD小鼠模型进行每周一次的宏基因组测序和混合效应建模，我们确定了肠道微生物群编码的几种与宿主免疫状态共变的功能途径。这些途径是新的早期生物标志物，它们可能使微生物能够在发炎的肠道内生存，或者促成IBD小鼠的免疫激活。未来的工作将验证这些微生物途径在宿主-微生物相互作用和人类疾病中的潜在作用。这项研究在其纵向设计和对微生物途径的关注方面具有创新性，为肠道微生物在IBD发展中的作用提供了新的机制性见解。
