美国哈佛医学院Francisco J. Quintana课题组开发出用于治疗炎症性肠病的自调节工程酵母益生菌。这一研究成果于2021年6月28日在线发表在国际学术期刊《自然—医学》上。

研究人员表示，炎症性肠病（IBD）是一种复杂的胃肠道慢性炎症性疾病。共生微生物群和宿主细胞产生的胞外三磷酸腺苷（eATP）激活嘌呤能信号促进了肠道炎症和病理。

基于eATP在肠道炎症中的作用，研究人员开发了基于酵母的工程益生菌，该益生菌表达人类P2Y2嘌呤能受体，eATP敏感性增加了1,000 倍。研究人员将这种工程化P2Y2受体的激活与ATP降解酶腺苷三磷酸双磷酸酶的分泌联系起来，从而创造出一种工程酵母益生菌，能够感知促炎性分子并成比例地中和。

这些可自我调节的酵母益生菌在IBD小鼠模型中抑制了肠道炎症，并减少了肠道纤维化和生态失调，其功效类似于或高于标准护理疗法。通过结合定向进化和合成基因回路，研究人员开发了一个独特的自我调节平台，可用于治疗IBD和其他潜在炎症驱动的病理。

附：英文原文

Title: Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease

Author: Benjamin M. Scott, Cristina Gutirrez-Vzquez, Liliana M. Sanmarco, Jessica A. da Silva Pereira, Zhaorong Li, Agustn Plasencia, Patrick Hewson, Laura M. Cox, Madelynn OBrien, Steven K. Chen, Pedro M. Moraes-Vieira, Belinda S. W. Chang, Sergio G. Peisajovich, Francisco J. Quintana

Issue&Volume: 2021-06-28

Abstract: Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder of the gastrointestinal tract. Extracellular adenosine triphosphate (eATP) produced by the commensal microbiota and host cells activates purinergic signaling, promoting intestinal inflammation and pathology. Based on the role of eATP in intestinal inflammation, we developed yeast-based engineered probiotics that express a human P2Y2 purinergic receptor with up to a 1,000-fold increase in eATP sensitivity. We linked the activation of this engineered P2Y2 receptor to the secretion of the ATP-degrading enzyme apyrase, thus creating engineered yeast probiotics capable of sensing a pro-inflammatory molecule and generating a proportional self-regulated response aimed at its neutralization. These self-tunable yeast probiotics suppressed intestinal inflammation in mouse models of IBD, reducing intestinal fibrosis and dysbiosis with an efficacy similar to or higher than that of standard-of-care therapies usually associated with notable adverse events. By combining directed evolution and synthetic gene circuits, we developed a unique self-modulatory platform for the treatment of IBD and potentially other inflammation-driven pathologies. A synthetic yeast-based therapeutic that secretes an ATP-degrading enzyme in response to pro-inflammatory extracellular ATP in the gut reduces intestinal inflammation, fibrosis and dysbiosis in mouse models of colitis and enteritis.

DOI: 10.1038/s41591-021-01390-x

Source: https://www.nature.com/articles/s41591-021-01390-x