Abstract:

The pool of microbes inhabiting our gut is known as ‘gut microbiota’. The gut microbiota, the largest symbiotic ecosystem with the host, has been shown to play important roles in maintaining intestinal homeostasis, and its structure and function have changed significantly since the industrialization era, especially with the change of lifestyle and the improvement of health care. This microbial community regulates some important metabolic and physiological functions of the host, and drives the maturation of the immune system in early life. Dysbiosis of the gut microbiome is caused by an imbalance between the commensal and pathogenic microbiomes, and alterations of the intestinal microbiota can be directly correlated with several diseases. This remodeled ‘industrialized’ gut microbiota has a profound impact on human health, accelerating the development of major chronic diseases such as digestive, metabolic and psychiatric disorders. Therefore, correcting intestinal microecological imbalance has become one of the core strategies to address the challenges in the development of major chronic non-communicable diseases. However, only a few conventional gut microbiome therapeutics developed to target the regulation of intestinal flora structure and function, such as probiotic therapy and fecal transplantation therapy have been used for the prevention and treatment of major chronic diseases with multiple intractable clinical conditions. Moreover, safety issues such as poor controllability and unclear genetic background of the flora have emerged. The iterative development of synthetic biology and microbial culture omics technology tools have promoted the development of novel microecological drugs, which have become the key to the precise identification and effective administration of major chronic diseases. This review takes the perspective of intervention and treatment of major chronic diseases such as digestive diseases, metabolic diseases and psychiatric diseases. The research progress of synthetic biology concepts and related technologies in designing and constructing engineered probiotics is systematically discussed. The application of microbiome therapeutics focusing on engineered probiotics in 3 categories of major chronic diseases is further reviewed. Moreover, we summarize the opportunities and challenges of using engineered probiotics to build synthetic flora, aiming to providing new methods and strategies for the diagnosis and prevention of major chronic diseases, thus promoting technological innovation and development of gut microbiome therapeutics.

Key words: major chronic diseases, microecological therapy, prebiotics, probiotics, fecal microbiota transplant, engineered probiotic, synthetic microbial community

摘要：

肠道菌群是人体的重要“器官”。工业化世界的发展加速了对肠道菌群研究从“传统结构”向“工业结构”的转变，而纠正肠道微生态失衡已成为解决重大慢性非传染性疾病传播难题的核心策略之一。然而，目前开发的靶向调节肠道菌群结构与功能的传统微生态疗法，如益生元疗法、益生菌疗法和粪菌移植疗法，只有少数被用于临床多发难治性重大慢病的防治，且出现了可控性差、菌群遗传背景不清晰等安全问题。合成生物学技术手段的迭代发展推动了新型微生态药物的研发，成为对重大慢病进行精准识别和精准施策的关键。本文首先以消化系统疾病、代谢性疾病和精神疾病等重大慢性疾病的干预和治疗为切入点，回顾了基于合成生物学方法设计构建工程益生菌的研究进展，并对以工程益生菌为核心的微生态疗法在上述重大慢病中的应用进行了综述。同时，考虑到单一工程益生菌的负荷和抗干扰能力等问题，本文还提出了利用工程益生菌构建人工合成肠道菌群开发新一代微生态疗法的设想，分析了这一过程所面临的机遇与挑战，旨在为工程益生菌和人工合成肠道群落基础研究和临床应用的双向转化提供借鉴，从而推动新型微生态药物的研发。

关键词: 重大慢性疾病, 微生态疗法, 益生元, 益生菌, 粪菌移植, 工程益生菌, 人工合成菌群