Engineering the gut rnicrobiota to treat hyperammonemia
Engineering the gut rnicrobiota to treat hyperammonemia
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DOI：
10.1172/jci79214
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发表时间：
2015-07-01
影响因子：
15.9
通讯作者：
Wu, Gary D.
中科院分区：
文献类型：
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作者：
Shen, Ting-Chin David;Albenberg, Lindsey;Wu, Gary D.
越来越多的证据表明，肠道微生物群可以被改变以改善或预防疾病状态，并且工程化肠道微生物群以治疗性地调节宿主代谢是微生物组研究的新兴目标。在肠道中，细菌尿素酶将宿主来源的尿素转化为氨和二氧化碳，导致肝病患者的高氨血症相关神经毒性和脑病。在这里，我们设计了小鼠肠道微生物群以降低脲酶活性。使动物耗尽其预先存在的肠道微生物群，然后用改变的Schaedler植物群（阿索，具有最小尿素酶基因含量的8种细菌的限定聚生体）接种。该方案导致建立了一个持久的新社区，促进了粪便脲酶活性和氨生产的长期减少。此外，在小鼠肝损伤模型中，ASF移植与发病率和死亡率降低相关。这些结果提供了概念证明，即用确定的肠道微生物群接种准备好的宿主可以导致具有治疗效用的持久代谢变化。
Increasing evidence indicates that the gut microbiota can be altered to ameliorate or prevent disease states, and engineering the gut microbiota to therapeutically modulate host metabolism is an emerging goal of microbiome research. In the intestine, bacterial urease converts host-derived urea to ammonia and carbon dioxide, contributing to hyperammonemia-associated neurotoxicity and encephalopathy in patients with liver disease. Here, we engineered murine gut microbiota to reduce urease activity. Animals were depleted of their preexisting gut microbiota and then inoculated with altered Schaedler flora (ASO, a defined consortium of 8 bacteria with minimal urease gene content. This protocol resulted in establishment of a persistent new community that promoted a long-term reduction in fecal urease activity and ammonia production. Moreover, in a murine model of hepatic injury, ASF transplantation was associated with decreased morbidity and mortality. These results provide proof of concept that inoculation of a prepared host with a defined gut microbiota can lead to durable metabolic changes with therapeutic utility.