Rapid intestinal and systemic metabolic reprogramming in an immunosuppressed environment.

Bing Ma, Samuel J Gavzy, Michael France, Yang Song, Hnin Wai Lwin, Allison Kensiski, Vikas Saxena, Wenji Piao, Ram Lakhan, Jegan Iyyathurai, Lushen Li, Christina Paluskievicz, Long Wu, Marina WillsonShirkey, Emmanuel F Mongodin, Valeria R Mas, Jonathan Bromberg
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Abstract

Intrinsic metabolism shapes the immune environment associated with immune suppression and tolerance in settings such as organ transplantation and cancer. However, little is known about the metabolic activities in an immunosuppressive environment. In this study, we employed metagenomic, metabolomic, and immunological approaches to profile the early effects of the immunosuppressant drug tacrolimus, antibiotics, or both in gut lumen and circulation using a murine model. Tacrolimus induced rapid and profound alterations in metabolic activities within two days of treatment, prior to alterations in gut microbiota composition and structure. The metabolic profile and gut microbiome after seven days of treatment was distinct from that after two days of treatment, indicating continuous drug effects on both gut microbial ecosystem and host metabolism. The most affected taxonomic groups are Clostriales and Verrucomicrobiae (i.e., Akkermansia muciniphila), and the most affected metabolic pathways included a group of interconnected amino acids, bile acid conjugation, glucose homeostasis, and energy production. Highly correlated metabolic changes were observed between lumen and serum metabolism, supporting their significant interactions. Despite a small sample size, this study explored the largely uncharacterized microbial and metabolic events in an immunosuppressed environment and demonstrated that early changes in metabolic activities can have significant implications that may serve as antecedent biomarkers of immune activation or quiescence. To understand the intricate relationships among gut microbiome, metabolic activities, and immune cells in an immune suppressed environment is a prerequisite for developing strategies to monitor and optimize alloimmune responses that determine transplant outcomes.

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免疫抑制环境中的快速肠道和全身代谢重编程。
内在代谢塑造了与器官移植和癌症等环境中的免疫抑制和耐受相关的免疫环境。然而,对免疫抑制环境中的代谢活性知之甚少。在这项研究中,我们采用宏基因组、代谢组学和免疫学方法,使用小鼠模型来分析免疫抑制剂药物他克莫司、抗生素或两者在肠腔和循环中的早期影响。在肠道微生物群组成和结构改变之前,他克莫司在治疗的两天内诱导了代谢活动的快速而深刻的改变。治疗七天后的代谢谱和肠道微生物组与治疗两天后的不同,表明药物对肠道微生物生态系统和宿主代谢都有持续影响。受影响最大的分类群是梭菌属和Verrucomicrobiae(即Akkermansia muciniphila),受影响最严重的代谢途径包括一组相互连接的氨基酸、胆汁酸结合、葡萄糖稳态和能量产生。管腔和血清代谢之间观察到高度相关的代谢变化,支持它们之间的显著相互作用。尽管样本量很小,但这项研究探索了免疫抑制环境中基本上未表征的微生物和代谢事件,并证明代谢活动的早期变化可能具有重要意义,可能作为免疫激活或静止的先行生物标志物。了解免疫抑制环境中肠道微生物组、代谢活动和免疫细胞之间的复杂关系,是制定监测和优化决定移植结果的同种免疫反应策略的先决条件。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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