合成生物学在肠道微生态疗法研发中的应用

doi:10.12211/2096-8280.2021-097

合成生物学 ›› 2022, Vol. 3 ›› Issue (1): 35-52.DOI: 10.12211/2096-8280.2021-097

合成生物学在肠道微生态疗法研发中的应用

高梦学¹, 王丽娜¹, 黄鹤¹^,²

^1.天津大学化工学院，教育部合成生物学前沿科学中心，系统生物工程教育部重点实验室，天津 300072
^2.天津大学浙江绍兴研究院，浙江绍兴 312000

收稿日期:2021-10-21 修回日期:2021-12-08 出版日期:2022-02-28 发布日期:2022-03-14
通讯作者: 黄鹤
作者简介:高梦学（1996—），女，博士研究生。研究方向为产维生素类营养物质活菌制剂的制备及应用。E-mail：2018207213@tju.edu.cn
黄鹤（1971—），女，教授，博士生导师。研究方向为合成生物肠道菌（群）构建及应用、纳米抗体等功能生物大分子的理性设计及高效制备、耐药致病微生物代谢机理与应对策略等。E-mail：huang@tju.edu.cn
基金资助:
国家重点研发计划“合成生物学”重点专项(2019YFA09005600)

Advances in synthetic biology assisted intestinal microecological therapy

Mengxue GAO¹, Lina WANG¹, He HUANG¹^,²

^1.Frontiers Science Center for Synthetic Biology，Key Laboratory of Systems Bioengineering （Ministry of Education），School of Chemical Engineering and Technology，Tianjin University，Tianjin 300072，China
^2.Shaoxing Research Institute Tianjin University，Shaoxing 312000，Zhejiang，China

Received:2021-10-21 Revised:2021-12-08 Online:2022-02-28 Published:2022-03-14
Contact: He HUANG

摘要/Abstract

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

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

中图分类号:

Q 81

高梦学, 王丽娜, 黄鹤. 合成生物学在肠道微生态疗法研发中的应用[J]. 合成生物学, 2022, 3(1): 35-52.

Mengxue GAO, Lina WANG, He HUANG. Advances in synthetic biology assisted intestinal microecological therapy[J]. Synthetic Biology Journal, 2022, 3(1): 35-52.

图/表 5

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底盘细胞	治疗策略	遗传操作	疾病类型	参考文献
大肠杆菌 Nissle 1917	利用ThsSR、TtrSR双组分调控系统分别构建细菌传感器，以响应硫代硫酸盐等炎性标志物	pKD226/pKD227/pKD233.7-3/pKD239-1g-2/pKD238-1a/pKD184/pKD182/pKD237-3a-2/pKD236-4b等	IBD （诊断）	[47]
大肠杆菌 Nissle 1917	利用NarXL、TtrSR双组分调控系统构建细菌传感器，用于同时检测硫代硫酸盐和硝酸盐等炎性标志物	pSEVA141-J23114-NPG/pSEVA131-J23106-NPG/pSEVA131-AND/pSEVA131-J23113-TPG/pSEVA131-J23113-N(N509D)PG等	IBD （诊断）	[48]
大肠杆菌 Nissle 1917	利用TtrSR双组分调控系统构建细菌传感器，与具有信号读取、信息传输功能的微电子设备整合，发明了一种可植入胃肠道并直接检测硫代硫酸盐等炎性标志物的微型设备	pZE2-hrtR-RBS3-chuA/pKD236-4b/pKD237-3a-3-Lux/pZE1-LuxR-Plux-luxCDABE等	IBD （诊断）	[49]
乳酸乳球菌MG1363	由食品级益生菌原位合成治疗剂mIL-10	pT1MIL10	IBD （治疗）	[50]
乳酸乳球菌MG1363	在结肠黏膜处局部递送抗mTNF纳米抗体	pMT1/pMT1–MT1	IBD （治疗）	[51]
酵母菌BS004	基于CRISPR-Cas9编辑技术将传感（P2Y2）和响应（RROP1）元件共同引入酵母菌株基因组中，根据肠道内促炎代谢物三磷酸腺苷（eATP）水平启动三磷酸腺苷双磷酸酶的表达和分泌并产生抑制炎症的腺苷	mfa2::HIS3-pTDH3 RROP1/mfa2::HIS3-pFUS1 RROP1等	IBD （诊疗）	[52]
大肠杆菌 Nissle 1917	在患有结肠炎的小鼠肠腔中可持续生酮体3-羟基丁酸（3-HB）	敲除AdhE和ldhA基因，在malEK、rhtCB或yicS/nepI位点上整合3HB生物合成途径涉及的酶基因（乙酰辅酶A乙酰基转移酶、3HB-CoA脱氢酶和硫酯酶）	IBD （治疗）	[55]
大肠杆菌 Nissle 1917	受近红外光和pH同时调控的光诊疗纳米系统	pDawn-mil-10	IBD （诊疗）	[56]
大肠杆菌 Nissle 1917	肠内原位分泌三叶因子在较短时间内修复肠黏膜	在csgBACDEFG位点上引入CmR基因，分别导入pBbB8k-CsgA-TFF1、pBbB8k-CsgA-TFF2、pBbB8k-CsgA-TFF3、pBbB8kN22-TFF3质粒	IBD （治疗）	[57]
大肠杆菌 Nissle 1917	肠内原位分泌表皮生长因子在较短时间内修复肠黏膜	在OmpC基因处插入基因串EGF-LARD3-prtDEF	IBD （治疗）	[59]
大肠杆菌 Nissle 1917	与CRC细胞特异性结合，将十字花科蔬菜的天然成分转化为具有抗癌活性的萝卜硫烷	peAlrt-J23105-YebF-I1-J23108-INP-HlpA	CRC （预防）	[62]
戊糖片球菌SL4	分泌抗癌蛋白P8，抑制癌细胞的增殖	pCBT24-2-PK-p8-PK-p8	CRC （治疗）	[63]
大肠杆菌 Nissle 1917	利用葡萄糖生产5-氨基乙酰丙酸（5-ALA），结合光动力疗法治疗CRC	pCL1920-gltX、pCL1920-hemA、pCL1920-hemL	CRC （治疗）	[64]

底盘细胞	治疗策略	遗传操作	疾病类型	参考文献
大肠杆菌 Nissle 1917	利用ThsSR、TtrSR双组分调控系统分别构建细菌传感器，以响应硫代硫酸盐等炎性标志物	pKD226/pKD227/pKD233.7-3/pKD239-1g-2/pKD238-1a/pKD184/pKD182/pKD237-3a-2/pKD236-4b等	IBD （诊断）	[47]
大肠杆菌 Nissle 1917	利用NarXL、TtrSR双组分调控系统构建细菌传感器，用于同时检测硫代硫酸盐和硝酸盐等炎性标志物	pSEVA141-J23114-NPG/pSEVA131-J23106-NPG/pSEVA131-AND/pSEVA131-J23113-TPG/pSEVA131-J23113-N(N509D)PG等	IBD （诊断）	[48]
大肠杆菌 Nissle 1917	利用TtrSR双组分调控系统构建细菌传感器，与具有信号读取、信息传输功能的微电子设备整合，发明了一种可植入胃肠道并直接检测硫代硫酸盐等炎性标志物的微型设备	pZE2-hrtR-RBS3-chuA/pKD236-4b/pKD237-3a-3-Lux/pZE1-LuxR-Plux-luxCDABE等	IBD （诊断）	[49]
乳酸乳球菌MG1363	由食品级益生菌原位合成治疗剂mIL-10	pT1MIL10	IBD （治疗）	[50]
乳酸乳球菌MG1363	在结肠黏膜处局部递送抗mTNF纳米抗体	pMT1/pMT1–MT1	IBD （治疗）	[51]
酵母菌BS004	基于CRISPR-Cas9编辑技术将传感（P2Y2）和响应（RROP1）元件共同引入酵母菌株基因组中，根据肠道内促炎代谢物三磷酸腺苷（eATP）水平启动三磷酸腺苷双磷酸酶的表达和分泌并产生抑制炎症的腺苷	mfa2::HIS3-pTDH3 RROP1/mfa2::HIS3-pFUS1 RROP1等	IBD （诊疗）	[52]
大肠杆菌 Nissle 1917	在患有结肠炎的小鼠肠腔中可持续生酮体3-羟基丁酸（3-HB）	敲除AdhE和ldhA基因，在malEK、rhtCB或yicS/nepI位点上整合3HB生物合成途径涉及的酶基因（乙酰辅酶A乙酰基转移酶、3HB-CoA脱氢酶和硫酯酶）	IBD （治疗）	[55]
大肠杆菌 Nissle 1917	受近红外光和pH同时调控的光诊疗纳米系统	pDawn-mil-10	IBD （诊疗）	[56]
大肠杆菌 Nissle 1917	肠内原位分泌三叶因子在较短时间内修复肠黏膜	在csgBACDEFG位点上引入CmR基因，分别导入pBbB8k-CsgA-TFF1、pBbB8k-CsgA-TFF2、pBbB8k-CsgA-TFF3、pBbB8kN22-TFF3质粒	IBD （治疗）	[57]
大肠杆菌 Nissle 1917	肠内原位分泌表皮生长因子在较短时间内修复肠黏膜	在OmpC基因处插入基因串EGF-LARD3-prtDEF	IBD （治疗）	[59]
大肠杆菌 Nissle 1917	与CRC细胞特异性结合，将十字花科蔬菜的天然成分转化为具有抗癌活性的萝卜硫烷	peAlrt-J23105-YebF-I1-J23108-INP-HlpA	CRC （预防）	[62]
戊糖片球菌SL4	分泌抗癌蛋白P8，抑制癌细胞的增殖	pCBT24-2-PK-p8-PK-p8	CRC （治疗）	[63]
大肠杆菌 Nissle 1917	利用葡萄糖生产5-氨基乙酰丙酸（5-ALA），结合光动力疗法治疗CRC	pCL1920-gltX、pCL1920-hemA、pCL1920-hemL	CRC （治疗）	[64]

底盘细胞	治疗策略	遗传操作	疾病类型	参考文献
乳酸乳球菌 MG1363	构建分泌GLP-1的基因工程菌改善肥胖，通过促进肥胖小鼠的脂肪酸氧化、增加肠道微生物多样性改善肥胖状况	pMG36e-GLP-1	肥胖	[75]
大肠杆菌 Nissle 1917	对GLP-1的序列进行改进，形成新的GLP-1GM序列，并利用益生菌进行表达分泌	pGEX-GLP-1 GM	肥胖	[76]
长双歧杆菌NCC2705	建立了一种新型的双歧杆菌口服给药系统，用于降低超重小鼠的食物摄入量、体重和血脂水平	pBBADs-OXM	肥胖	[77]
乳酸乳球菌 NZ9000	通过基因工程改造乳酸乳球菌，以生产羧化或低羧化的骨钙素，以用于糖尿病和肥胖症的治疗研究	pNZ8148#2：SEC-OC	糖尿病和肥胖	[78]
乳酸乳球菌 NZ3900	使用乳酸乳球菌表达成纤维细胞生长因子21，改善肥胖小鼠的疾病状态	PNZ8149-Human FGF21	肥胖	[79]
大肠杆菌 Nissle 1917	口服表达NAPE的工程化大肠杆菌Nissle 1917可降低高脂肪饮食诱导的小鼠的肥胖水平	pNAPE	肥胖	[81]
枯草芽孢杆菌 SCK6	通过构建高产丁酸的工程菌，调节与肥胖相关的菌群及代谢物水平，发展减轻肥胖的治疗策略	敲除skfA、sdpC、acdA和ackA等基因，敲入丁酰CoA：乙酸CoA转移酶编码基因	肥胖	[82]
乳酸乳球菌MG1363 乳酸乳球菌sAGX0037	开发一种基于乳酸乳球菌的致耐受性细菌递送技术，用于控制肠道中自身抗原GAD65370-575和抗炎细胞因子白细胞介素10的分泌	pGAD65370-575	1型糖尿病	[87]
乳酸乳球菌MG1363 乳酸乳球菌sAGX0037	通过分泌完整的胰岛素原自身抗原和免疫调节细胞因子IL-10，开发一种使用黏膜递送恢复耐受性的治疗策略	pThyAhPINS	1型糖尿病	[88]
乳酸乳球菌pCYT：SNase 乳酸乳球菌 NZ9000	递送葡萄球菌核酸酶有效预防1型糖尿病，改善炎症症状，并有助于调节免疫平衡	pCYT：SNase	1型糖尿病（预防）	[89]
乳酸乳球菌 NZ9000	组成型或通过乳链菌肽诱导表达HSP65-6P277，可预防高血糖、改善葡萄糖耐量和减少胰岛炎	pCYT：HSP65-6P277 pHJ：HSP65-6P277	1型糖尿病（预防）	[90]
乳酸乳球菌	开发胰高血糖素样肽-1的活体口服给药系统，用于治疗2型糖尿病	pUBGLP-1	2型糖尿病	[91]
加氏乳杆菌 ATCC 33323	分泌胰高血糖素样肽-1将肠细胞重编程为葡萄糖反应性胰岛素分泌细胞来改善糖尿病大鼠的高血糖水平	pFD-GLPL/pBluescript-GLPL/pORI28-LGLPL	2型糖尿病	[92]
乳酸乳球菌 NZ9000	乳酸乳球菌分泌胰高血糖素样蛋白-1受体激动剂，增强葡萄糖依赖性胰岛素分泌、激活PI3-K/AKT信号通路	pNZ8048-rExd4	2型糖尿病	[93]
乳酸乳球菌 NZ9000	分泌L-阿拉伯糖异构酶的乳酸乳球菌菌株具有在体内产生D-塔格糖的能力，并赋予小鼠抗高血糖作用	pSEC:LEISS:araA	糖尿病	[94]

底盘细胞	治疗策略	遗传操作	疾病类型	参考文献
乳酸乳球菌 MG1363	构建分泌GLP-1的基因工程菌改善肥胖，通过促进肥胖小鼠的脂肪酸氧化、增加肠道微生物多样性改善肥胖状况	pMG36e-GLP-1	肥胖	[75]
大肠杆菌 Nissle 1917	对GLP-1的序列进行改进，形成新的GLP-1GM序列，并利用益生菌进行表达分泌	pGEX-GLP-1 GM	肥胖	[76]
长双歧杆菌NCC2705	建立了一种新型的双歧杆菌口服给药系统，用于降低超重小鼠的食物摄入量、体重和血脂水平	pBBADs-OXM	肥胖	[77]
乳酸乳球菌 NZ9000	通过基因工程改造乳酸乳球菌，以生产羧化或低羧化的骨钙素，以用于糖尿病和肥胖症的治疗研究	pNZ8148#2：SEC-OC	糖尿病和肥胖	[78]
乳酸乳球菌 NZ3900	使用乳酸乳球菌表达成纤维细胞生长因子21，改善肥胖小鼠的疾病状态	PNZ8149-Human FGF21	肥胖	[79]
大肠杆菌 Nissle 1917	口服表达NAPE的工程化大肠杆菌Nissle 1917可降低高脂肪饮食诱导的小鼠的肥胖水平	pNAPE	肥胖	[81]
枯草芽孢杆菌 SCK6	通过构建高产丁酸的工程菌，调节与肥胖相关的菌群及代谢物水平，发展减轻肥胖的治疗策略	敲除skfA、sdpC、acdA和ackA等基因，敲入丁酰CoA：乙酸CoA转移酶编码基因	肥胖	[82]
乳酸乳球菌MG1363 乳酸乳球菌sAGX0037	开发一种基于乳酸乳球菌的致耐受性细菌递送技术，用于控制肠道中自身抗原GAD65370-575和抗炎细胞因子白细胞介素10的分泌	pGAD65370-575	1型糖尿病	[87]
乳酸乳球菌MG1363 乳酸乳球菌sAGX0037	通过分泌完整的胰岛素原自身抗原和免疫调节细胞因子IL-10，开发一种使用黏膜递送恢复耐受性的治疗策略	pThyAhPINS	1型糖尿病	[88]
乳酸乳球菌pCYT：SNase 乳酸乳球菌 NZ9000	递送葡萄球菌核酸酶有效预防1型糖尿病，改善炎症症状，并有助于调节免疫平衡	pCYT：SNase	1型糖尿病（预防）	[89]
乳酸乳球菌 NZ9000	组成型或通过乳链菌肽诱导表达HSP65-6P277，可预防高血糖、改善葡萄糖耐量和减少胰岛炎	pCYT：HSP65-6P277 pHJ：HSP65-6P277	1型糖尿病（预防）	[90]
乳酸乳球菌	开发胰高血糖素样肽-1的活体口服给药系统，用于治疗2型糖尿病	pUBGLP-1	2型糖尿病	[91]
加氏乳杆菌 ATCC 33323	分泌胰高血糖素样肽-1将肠细胞重编程为葡萄糖反应性胰岛素分泌细胞来改善糖尿病大鼠的高血糖水平	pFD-GLPL/pBluescript-GLPL/pORI28-LGLPL	2型糖尿病	[92]
乳酸乳球菌 NZ9000	乳酸乳球菌分泌胰高血糖素样蛋白-1受体激动剂，增强葡萄糖依赖性胰岛素分泌、激活PI3-K/AKT信号通路	pNZ8048-rExd4	2型糖尿病	[93]
乳酸乳球菌 NZ9000	分泌L-阿拉伯糖异构酶的乳酸乳球菌菌株具有在体内产生D-塔格糖的能力，并赋予小鼠抗高血糖作用	pSEC:LEISS:araA	糖尿病	[94]

底盘细胞	治疗策略	遗传操作	疾病类型	参考文献
短乳杆菌CGMCC1306	构建高产γ-氨基丁酸的细胞工厂，有利于开发工程化活菌制剂用于精神疾病的治疗	pMG36e-gadA/pMG36e-gadB/pMG36e-gadC/pMG36e-gadCA/pMG36e-gadCB	抑郁症	[105]
乳酸乳球菌乳脂亚种MG1363	递送胰高血糖素样蛋白-1恢复LPS引起的小鼠空间学习和记忆障碍，治疗阿尔兹海默症	pMG36e-GLP- 1	阿尔兹海默症	[109]
枯草芽孢杆菌60015/YF256	操纵肌醇代谢构建工程菌，以允许从肌醇到鲨肌醇的生物转化，作为细胞工厂提供鲨肌醇，是治疗阿尔兹海默症的潜在的活菌生物制剂	iolE41 iolI::spc/iolR::cat/iolW::pMutin2(erm::tet)/iolX::pMutin4(erm)	阿尔兹海默症	[111]
乳酸乳球菌乳脂亚种MG1363	递送p62蛋白减少氧化和炎症标志物、调节肠道菌群结构，对阿尔兹海默症产生积极影响	pExu：p62	阿尔兹海默症	[112]

合成生物学在肠道微生态疗法研发中的应用

Advances in synthetic biology assisted intestinal microecological therapy

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