The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Translational Microbiome Data Integration, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany; ZIEL - Institute for Food & Health, Technical University of Munich, 85354 Freising, Germany.
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cell Host Microbe. 2024 Feb 14;32(2):209-226.e7. doi: 10.1016/j.chom.2023.12.013. Epub 2024 Jan 11.
Understanding the role of the microbiome in inflammatory diseases requires the identification of microbial effector molecules. We established an approach to link disease-associated microbes to microbial metabolites by integrating paired metagenomics, stool and plasma metabolomics, and culturomics. We identified host-microbial interactions correlated with disease activity, inflammation, and the clinical course of ulcerative colitis (UC) in the Predicting Response to Standardized Colitis Therapy (PROTECT) pediatric inception cohort. In severe disease, metabolite changes included increased dipeptides and tauro-conjugated bile acids (BAs) and decreased amino-acid-conjugated BAs in stool, whereas in plasma polyamines (N-acetylputrescine and N1-acetylspermidine) increased. Using patient samples and Veillonella parvula as a model, we uncovered nitrate- and lactate-dependent metabolic pathways, experimentally linking V. parvula expansion to immunomodulatory tryptophan metabolite production. Additionally, V. parvula metabolizes immunosuppressive thiopurine drugs through xdhA xanthine dehydrogenase, potentially impairing the therapeutic response. Our findings demonstrate that the microbiome contributes to disease-associated metabolite changes, underscoring the importance of these interactions in disease pathology and treatment.
要了解微生物组在炎症性疾病中的作用，需要确定微生物效应分子。我们通过整合配对的宏基因组学、粪便和血浆代谢组学以及培养组学，建立了一种将与疾病相关的微生物与微生物代谢物联系起来的方法。我们在预测对标准化结肠炎治疗的反应（PROTECT）儿科起始队列中确定了与疾病活动、炎症和溃疡性结肠炎（UC）临床过程相关的宿主-微生物相互作用。在严重疾病中，代谢物变化包括粪便中二肽和牛磺酸结合胆汁酸（BAs）增加，而氨基酸结合的 BAs 减少，而在血浆中多胺（N-乙酰腐胺和 N1-乙酰精胺）增加。使用患者样本和小韦荣球菌作为模型，我们发现了硝酸盐和乳酸依赖性代谢途径，从实验上证明了小韦荣球菌的扩张与免疫调节色氨酸代谢物的产生有关。此外，小韦荣球菌通过 xdhA 黄嘌呤脱氢酶代谢免疫抑制性硫唑嘌呤药物，可能会损害治疗反应。我们的研究结果表明，微生物组有助于与疾病相关的代谢物变化，这突显了这些相互作用在疾病发病机制和治疗中的重要性。
