Gut microbiome structure and metabolic activity in inflammatory bowel disease
Gut microbiome structure and metabolic activity in inflammatory bowel disease
复制标题
DOI：
10.1038/s41564-018-0306-4
复制
发表时间：
2019-02-01
影响因子：
28.3
通讯作者：
Xavier, Ramnik J.
中科院分区：
文献类型：
--
作者：
Franzosa, Eric A.;Sirota-Madi, Alexandra;Xavier, Ramnik J.
炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC），是胃肠道的多因素慢性疾病。虽然IBD与肠道微生物群的急剧变化有关，但肠道代谢组的变化-宿主和微生物群之间的分子界面-尚不清楚。为了解决这一差距，我们对来自CD、UC和非IBD对照患者的发现（n =155）和验证（n = 65）队列的横断面粪便样本进行了非靶向代谢组学和鸟枪宏基因组学分析。代谢组学和宏基因组学特征与粪便钙卫蛋白水平（肠道炎症的一种衡量标准）广泛相关。在> 8，000个测量的代谢物特征中，我们鉴定了IBD中差异丰富的化学物质和化学类别，包括鞘脂和胆汁酸的富集，以及三酰甘油和四吡咯的消耗。虽然> 50%的差异丰富的代谢物特征未被表征，但许多特征可以通过代谢组学“关联内疚”（与已知代谢物的共变异）来分配推定的作用。来自宏基因组谱的不同丰度的物种和功能反映了IBD肠道对氧化应激的适应，并且与先前的发现单独一致。然而，综合这些数据，我们确定了差异丰富的物种和充分表征的差异丰富的代谢物之间的122个强大的关联，表明可能的机制关系，在IBD中受到干扰。最后，我们发现基于代谢组和宏基因组的IBD状态分类器高度准确，并且与绝大多数个体趋势一样，很好地推广到独立验证队列。因此，我们的研究结果提供了对IBD中微生物组-代谢组界面扰动的更好理解，包括鉴定许多潜在的诊断和治疗靶点。
The inflammatory bowel diseases (IBDs), which include Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial chronic conditions of the gastrointestinal tract. While IBD has been associated with dramatic changes in the gut microbiota, changes in the gut metabolome-the molecular interface between host and microbiota-are less well understood. To address this gap, we performed untargeted metabolomic and shotgun metagenomic profiling of cross-sectional stool samples from discovery (n =155) and validation (n = 65) cohorts of CD, UC and non-IBD control patients. Metabolomic and metagenomic profiles were broadly correlated with faecal calprotectin levels (a measure of gut inflammation). Across >8,000 measured metabolite features, we identified chemicals and chemical classes that were differentially abundant in IBD, including enrichments for sphingolipids and bile acids, and depletions for triacylglycerols and tetrapyrroles. While > 50% of differentially abundant metabolite features were uncharacterized, many could be assigned putative roles through metabolomic 'guilt by association' (covariation with known metabolites). Differentially abundant species and functions from the metagenomic profiles reflected adaptation to oxidative stress in the IBD gut, and were individually consistent with previous findings. Integrating these data, however, we identified 122 robust associations between differentially abundant species and well-characterized differentially abundant metabolites, indicating possible mechanistic relationships that are perturbed in IBD. Finally, we found that metabolome- and metagenome-based classifiers of IBD status were highly accurate and, like the vast majority of individual trends, generalized well to the independent validation cohort. Our findings thus provide an improved understanding of perturbations of the microbiome-metabolome interface in IBD, including identification of many potential diagnostic and therapeutic targets.