Abstract:

Numerous bacteria and other microorganisms are living with the human body, which are parasitic in our skin, gastrointestinal tract, mouth, and other organs. While securing stable living environments, these microorganisms also help the human body to resist the invasion of pathogens, generate probiotic components (such as vitamins) and benefit the function of the immune system. Due to effective interactions between microorganisms and human being, the use of microbial agents to improve health status and treat diseases has become a research hotspot in recent years. For example, natural probiotics are used to regulate the intestinal microcommunity, and the bacterial community of healthy people is used to inoculate patients for the complementation of defective functions. Currently, the only FDA-approved and commercially available microbiotic-based treatment is fecal microbial transplantation for Clostridium difficile infections. Although fecal microbial transplantation has achieved some therapeutic effects, unclear mechanism underlying such a treatment and the uncontrollable operation process limit its applications. Therefore, there is an urgent need for better understanding of such a treatment to facilitate its application, and the development of synthetic biology has provided tools and methodology. Synthetic biology employs the ideas of modern molecular biotechnology and engineering principles to design, construct and optimize biological systems, and endow them with specific functions so that they can process information and synthesize target products including drugs. By developing gene circuits with specific functions in microorganisms, their metabolic pathways are intervened, even reconstructed, to sense physical and chemical signals and synthesize therapeutic products for use in smart and controllable treatment of diseases. Live biotherapeutic products (LBPs) have been proposed to prevent, diagnose and treat diseases by design and rebuilding of living organisms. In recent years, customized gene circuits have been continuously developed and introduced into microbial chassis cells to create engineered microorganisms with specific functions, providing a new scheme for disease treatment with recombinant LBPs. In this article, we summarize the latest progress of microbial synthetic biology in disease diagnosis and treatment, including inflammation, metabolic diseases, immune defects, pathogen infections, and cancers. Furthermore, challenges and further development are prospected. It has become a promising idea and method for clinical disease treatment with living microbial therapy by using living non-pathogenic engineered bacteria or probiotics equipped with smart gene circuits to sense and response to disease microenvironment for the controllable deliver of therapeutic agents.

Key words: microorganism, synthetic biology, live biotherapeutic product, microbial cell factory, disease diagnosis and treatment

摘要：

在人体的身体内部居住着数以万亿计的细菌和其他微生物，寄生在我们的皮肤、胃肠道和口腔等部位，微生物群失调已成为炎症性肠病、过敏、肥胖、心血管以及神经退行性疾病和癌症等多种疾病发生发展的重要原因。与此同时，利用微生物制剂改善健康状况、治疗疾病也在研究和临床中得到验证。近年来，活体生物药不断被开发用于预防、诊断与治疗疾病。采用合成生物学手段在微生物中设计、构建精准可控的基因电路，获得非致病性、具有疾病微环境感知和响应能力并按需释放治疗药物的活体工程菌，实施活体微生物疗法，已成为临床疾病治疗的新思路和新方法。本文对微生物合成生物学在疾病诊疗中的应用进展，如预防与诊疗病原菌感染、治疗代谢疾病、靶向杀伤肿瘤、缓解炎症等进行了系统性总结，并针对微生物传感器设计和推广到临床应用中面临的问题和未来的发展进行了分析与展望。利用合成生物学在微生物中设计的生物传感器能智能感知疾病微环境并可控地提供药物，在疾病的监测和治疗中有巨大的应用前景。

关键词: 微生物, 合成生物学, 活体生物药, 微生物细胞工厂, 疾病诊疗