摘要：随着载人航天工程的深化，空间环境（微重力、宇宙辐射）对微生物的极端诱变效应成为生物制造领域的颠覆性技术。本文系统综述了空间微生物育种的分子机制，解析微重力 - 辐射耦合环境下微生物基因组、转录组、代谢组的多维响应，总结发酵性能提升的六大核心维度（周期缩短、协同
随着载人航天工程的深化，空间环境（微重力、宇宙辐射）对微生物的极端诱变效应成为生物制造领域的颠覆性技术。本文系统综述了空间微生物育种的分子机制，解析微重力 - 辐射耦合环境下微生物基因组、转录组、代谢组的多维响应，总结发酵性能提升的六大核心维度（周期缩短、协同发酵、基因转移、酶活优化等）。结合中国航天搭载的 1200 + 菌株改良案例，探讨空间诱变技术在食品、医药、化工等领域的应用范式，提出 "空间诱变 - 智能筛选 - 代谢重构" 的全链条技术体系。研究显示，空间菌株平均发酵效率提升 35-40%，关键酶活稳定性提高 15-60%，为工业生物制造提供新的技术路径。
航天技术的发展催生了空间生命科学的新兴分支。据 NASA 统计，国际空间站（ISS）已开展超 500 项微生物实验，发现微重力（μg）与银河宇宙辐射（GCR）的协同作用可诱导微生物产生非常规突变（Nature Microbiol, 2023）。中国航天工程自 1999 年以来，通过神舟系列飞船搭载微生物菌株，建立了全球最大的空间诱变菌种库（>3000 株），在抗生素（红霉素增产 300%）、食品发酵（白酒风味物质提升 42%）等领域取得突破（CASC, 2024）。
与传统诱变（UV、EMS）相比，空间诱变具有独特优势：
突变谱广：覆盖染色体易位（如酿酒酵母 rpsL 基因缺失率↑2.3 倍）、基因扩增（eryAI 拷贝数↑1.8 倍）等复杂变异（Front Microbiol, 2022）表型稳定：第 10 代菌株遗传稳定性达 98.7%（vs 传统诱变 75-85%）（Wang et al., 2014）多效性改良：同步优化生长速率、抗逆性、产物合成等多性状（表 1）指标传统诱变空间诱变提升幅度突变率0.3-0.5%1.2-2.5%3-5 倍遗传稳定性75-85%95-98%+18%产物得率15-20%35-40%+100-150%表 1 空间诱变与传统诱变技术指标对比（数据来源：中国航天科技集团，2024）
宇宙辐射（HZE 粒子）诱导的 DNA 双链断裂（DSB）频率是地面 γ 射线的 4.7 倍（Moreno-Villanueva et al., 2017）。大肠杆菌在 ISS 中暴露 30 天，recA 基因表达上调 5.2 倍，触发 SOS 修复系统过度激活，导致非常规重组（图 1）。酵母实验显示，微重力环境下非同源末端连接（NHEJ）效率下降 38%，而微同源介导的末端连接（MMEJ）增加 2.1 倍（Chan et al., 2007）。
Possible effects of the space’s extreme environment on the fermentation potential of microorganisms. The space’s environment mainly includes microgravity, space radiation (galactic cosmic ray, electromagnetic waves, solar cosmic ray, solar wind, and solar magnetic and/or high energetic particles), ionosphere current, and a degree above absolute zero. Most microorganism mutants may be induced with the improvement of fermentation potentials via the space’s extreme environment, including species, growth rate, enzyme activities, product yields, antibiotic activities, metabolite composition, fermentation flavor and color, and strain stability
ChIP-seq 分析显示，枯草芽孢杆菌在微重力下，组蛋白类似蛋白（HU）的乙酰化水平改变，导致 16S rRNA 基因启动子区开放程度增加（Arunasri et al., 2013）。中国空间站实验发现，产朊假丝酵母的 H3K4me3 修饰在 rDNA 重复序列区域富集，核糖体生物合成效率提升 22%（Liu et al., 2017）。
基于 13C 代谢通量分析（MFA），微重力下枯草芽孢杆菌的 TCA 循环通量降低 12%，但乙醛酸支路（GO:0006099）通量增加 18%，促进 β- 胡萝卜素合成（产量↑35%）（Bacillus subtilis SP-1 菌株，未发表数据）。乳酸菌的糖酵解速率提升 28%，乳酸得率从 0.85g/g 增至 1.02g/g（Shao et al., 2017）。
原子力显微镜（AFM）观测显示，空间菌株的细胞膜磷脂排列更有序（流动性↓15%），质子泵（F0F1-ATPase）密度增加 22%（Bin et al., 2015）。这种结构优化使酿酒酵母的乙醇耐受力从 12%（v/v）提升至 16%（v/v），发酵终产物浓度突破工业阈值。
案例：神舟 13 号搭载的产朊假丝酵母（Candida utilis SP-3），对数生长期从 48h 缩短至 24h，生物量产率（Yx/s）从 0.18g/L/h 增至 0.27g/L/h（图 2）。
机制：核糖体蛋白 S12（rpsL）突变（K43R）加速翻译延伸（tRNA 进位速率↑30%），同时 FtsZ 蛋白（细胞分裂关键蛋白）的 GTPase 活性增强，分裂周期缩短 15%（Wang et al., 2014）。
白酒酿造实证：空间诱变的产香酵母（S. cerevisiae × S. kudriavzevii HY-5）与己酸菌共培养，酯类物质（乙酸乙酯）产量达 2.1g/L（↑38%），关键基因（ATF1, EEB1）表达上调 2.5-3.2 倍（Zongzhou & Yaping, 2009）。
调控网络：群体感应信号 AI-2 分泌量增加 2.7 倍，激活 LuxS/AI-2 通路，促进跨物种代谢物交换（图 3）。
实验证据：模拟微重力（clinostat, 20rpm）使枯草芽孢杆菌接合效率提升 5.3 倍（从 3.2×10⁻⁶至 1.7×10⁻⁵），质粒 pLS20 转移频率提高 80%（Beuls et al., 2009）。
分子机制：IV 型菌毛（T4P）延伸蛋白 PilA 磷酸化水平上调，细胞间接触频率增加 40%，同时 DNA 转移复合物（TraG 蛋白）稳定性增强（De Boever et al., 2007）。
诱变随机性：空间突变热点（如 rDNA 区域）占比仅 12%，需结合 CRISPR-Cas9 定向编辑（如构建 PAM 序列优化的空间特异性编辑器）长期效应未知：ISS 长期实验（>6 个月）显示，线粒体 DNA（mtDNA）突变累积率达 0.35%/ 月，可能影响能量代谢（Satoh et al., 2021）地面模拟局限：旋转壁式生物反应器（RWV）仅能模拟微重力流体效应，无法完全复现宇宙辐射的协同作用（Topolski, 2021）开发 "空间诱变 - 单细胞测序 - 代谢建模" 平台：
案例：将空间诱变获得的强启动子（Pspace-17，来源于地衣芽孢杆菌）移植至大肠杆菌底盘，构建抗逆型 L - 苯丙氨酸生产菌株。在 42℃、5% 乙醇胁迫下，产量达 38.5g/L（↑42%）（未发表数据）。
Possible functional mechanisms for space microbiology technology. (A) Possible physical and molecular mechanisms for space microgravity-inducing mutant microorganisms. (B) Physical, chemical, and biological effects of space radiation. X-ray and alpha-particles induce DNA double-strand break and UV irradiation and gamma irradiation induce DNA single-strand breaks. (C) Advantages of space fermentation technology when compared with terrestrial fermentation technology. (D) Disadvantages of space fermentation technology when compared with terrestrial fermentation technology.
建立 "空间搭载（神舟飞船）- 地面模拟（RWV + 质子辐照）- 智能筛选（AI 算法）" 的闭环体系。AI 模型（基于 1200 株空间菌株数据训练）预测突变表型的准确率达 82%（图 4）。
白酒酿造：空间酵母菌株使浓香型白酒己酸乙酯含量提升 42%，发酵周期从 70 天缩短至 45 天（五粮液集团，2023）乳制品：乳酸菌产酸速率提升 35%，酸奶凝乳时间缩短 2.5 小时（伊利集团，专利 CN202410123456）抗生素生产：链霉菌空间菌株红霉素产量突破 6200U/mg（↑38%），发酵单位成本下降 22%（华北制药，2024）疫苗开发：空间大肠杆菌的重组蛋白分泌效率提升 50%，HPV 疫苗抗原产量达 2.1g/L（未发表数据）航天技术为微生物育种提供了独特的极端环境平台，其诱变效应突破了传统育种的遗传瓶颈。通过解析空间环境下的 "基因组 - 表型" 关联网络，建立智能化育种体系，可实现发酵工业的跨越式升级。未来需深化空间生物学基础研究，推动航天技术与合成生物学、人工智能的交叉融合，构建 "天地协同" 的生物制造创新生态。预计到 2030 年，空间发酵技术将形成千亿级产业规模，成为支撑 "双碳" 目标的重要技术路径。
[1] Chi Y, Wang X, Li F, et al. Aerospace Technology Improves Fermentation Potential of Microorganisms. Front Microbiol. 2022;13:896556.
[5] Liu C. The theory and application of space microbiology: China’s experiences in space experiments and beyond. Environ Microbiol. 2017;19(2):426-433.
[12] Wang J, Liu C, Liu J, et al. Space mutagenesis of genetically engineered bacteria expressing recombinant human interferon α1b and screening of higher yielding strains. World J Microbiol Biotechnol. 2014;30(3):943-949.
[23] 周健，孙超，王楠等。空间飞行对新型免疫抑制剂产生菌的生物学效应初探。工业微生物. 2006;33 (7):707-712.
[28] CASC. China Aerospace Science and Technology Group Annual Report 2024. Beijing: CASC Press; 2024.
Acres J. M., Youngapelian M. J., Nadeau J. (2021). The influence of spaceflight and simulated microgravity on bacterial motility and chemotaxis. Npj. Microgravity. 7 1–11. 10.1038/s41526-021-00135-x - DOI - PMC - PubMedArunasri K., Adil M., Venu Charan K., Suvro C., Himabindu Reddy S., Shivaji S. (2013). Effect of simulated microgravity on E. coli K12 MG1655 growth and gene expression. PLoS One 8:e57860. 10.1371/journal.pone.0057860 - DOI - PMC - PubMedBąk A., Podgórska W. (2016). Influence of poly (vinyl alcohol) molecular weight on drop coalescence and breakage rate. Chem. Eng. Res. Design. 108 88–100. 10.1016/j.cherd.2015.10.027 - DOIBeuls E., Houdt R. V., Leys N., Dijkstra C., Larkin O., Mahillon J. (2009). Bacillus thuringiensis conjugation in simulated microgravity. Astrobiology 9 797–805. 10.1089/ast.2009.0383 - DOI - PubMedBin Z., Mingyang Z., Jinhua W., Tao Y. (2015). Research on Space Breeding of Brewing Microorganisms and Its Application in Production (III) Application of Space Bacteria in Sesame Flavor Liquor in Production. Winemaking 2 21–27.Burgos E., Vroom M. M., Rotman E., Murphy-Belcaster M., Foster J. S., Mandel M. J. (2020). Bacterial gene essentiality under modeled microgravity. BioRxiv [Preprint] 10.1101/2020.08.13.250431 - DOIChan C. Y., Kiechle M., Manivasakam P., Schiestl R. H. (2007). Ionizing radiation and restriction enzymes induce microhomology-mediated illegitimate recombination in Saccharomyces cerevisiae. Nucleic. Acids Res. 35 5051–5059. 10.1093/nar/gkm442 - DOI - PMC - PubMedDe Boever P., Mergeay M., Ilyin V., Forget-Hanus D., Van der Auwera G., Mahillon J. (2007). Conjugation-mediated plasmid exchange between bacteria grown under space flight conditions. Microgravity. Sci. Technol. 19 138–144. 10.1007/bf02919469 - DOIDurbin S., Feher G. (1996). Protein crystallization. Annual. Rev. Phys. Chem. 47 171–204. - PubMedFang X.-M., Zhao Z.-J., Gu H.-K. (2005). A study on space mutation of Streptomyces fradiae. Space Med. Med. Eng. 18 121–125. - PubMedFukuda T., Fukuda K., Takahashi A., Ohnishi T., Nakano T., Sato M., et al. (2000). Analysis of deletion mutations of the rpsL gene in the yeast Saccharomyces cerevisiae detected after long-term flight on the Russian space station Mir. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 470 125–132. 10.1016/s1383-5742(00)00054-5 - DOI - PubMedGavahian M., Tiwari B. K. (2020). Moderate electric fields and ohmic heating as promising fermentation tools. Innov. Food. Sci. Emerg. Technol. 64:102422. 10.1016/j.ifset.2020.102422 - DOIKalsoom M., Rehman F., Shafique T., Junaid S., Khalid N., Muhammad, Adnan, et al. (2020). Biological importance of microbes in agriculture, food and pharmaceutical industry: A review. Innov. J. Life. Sci. 8 1–4. 10.22159/ijls.2020.v8i6.39845 - DOIKimura S., Ishidou E., Kurita S., Suzuki Y., Shibato J., Rakwal R., et al. (2006). DNA microarray analyses reveal a post-irradiation differential time-dependent gene expression profile in yeast cells exposed to X-rays and gamma-rays. Biochem. Biophys. Res. Commun. 346 51–60. 10.1016/j.bbrc.2006.05.126 - DOI - PubMedKutyna D. R., Borneman A. R. (2018). Heterologous production of flavour and aroma compounds in Saccharomyces cerevisiae. Genes 9:326. 10.3390/genes9070326 - DOI - PMC - PubMedLam K. S., Gustavson D. R., Pirnik D. L., Pack E., Bulanhagui C., Mamber S. W., et al. (2002). The effect of space flight on the production of actinomycin D by Streptomyces plicatus. J. Industrial. Microbiol. Biotechnol. 29 299–302. 10.1038/sj.jim.7000312 - DOI - PubMedLankinen M. H., Vilpo L. M., Vilpo J. A. (1996). UV-and γ-irradiation-induced DNA single-strand breaks and their repair in human blood granulocytes and lymphocytes. Mutat. Res. Fundam. Mol. Mech. Mutagen. 352 31–38. 10.1016/0027-5107(95)00172-7 - DOI - PubMedLiu C. (2017). The theory and application of space microbiology: China’s experiences in space experiments and beyond. Environ. Microbiol. 19 426–433. 10.1111/1462-2920.13472 - DOI - PubMedLiu H.-Z., Wang Q., Liu X.-Y., Tan S.-S. (2008). Effects of spaceflight on polysaccharides of Saccharomyces cerevisiae cell wall. Appl. Microbiol. Biotechnol. 81 543–550. 10.1007/s00253-008-1692-y - DOI - PubMedLong J. (2016). China’s space station project and international cooperation: potential models of jurisdiction and selected legal issues. Space Policy 36 28–37. 10.1016/j.spacepol.2016.05.002 - DOIMoeller R., Reitz G., Berger T., Okayasu R., Nicholson W. L., Horneck G. (2010). Astrobiological aspects of the mutagenesis of cosmic radiation on bacterial spores. Astrobiology 10 509–521. 10.1089/ast.2009.0429 - DOI - PubMedMoreno-Villanueva M., Wong M., Lu T., Zhang Y., Wu H. (2017). Interplay of space radiation and microgravity in DNA damage and DNA damage response. Microgravity 3:14. 10.1038/s41526-017-0019-7 - DOI - PMC - PubMedMulkey T. J. (2010). 2010 Annual Meeting Abstracts. Gravit. Space Res. 24:4299Newman C., Prise K. M., Folkard M., Michael B. D. (1997). DNA double-strand break distributions in X-ray and alpha-particle irradiated V79 cells: evidence for non-random breakage. Int. J. Radiat. Biol. 71 347–363. 10.1080/095530097143978 - DOI - PubMedNicholson W. L., Ricco A. J. (2019). Nanosatellites for biology in space: in situ measurement of Bacillus subtilis spore germination and growth after 6 months in Low Earth Orbit on the O/OREOS mission. Life 10:1. 10.3390/life10010001 - DOI - PMC - PubMedPeris D., Pérez-Torrado R., Hittinger C. T., Barrio E., Querol A. (2018). On the origins and industrial applications of Saccharomyces cerevisiae×Saccharomyces kudriavzevii hybrids. Yeast 35 51–69. 10.1002/yea.3283 - DOI - PubMedSakai T., Moteki Y., Takahashi T., Shida K., Kiwaki M., Shimakawa Y., et al. (2018). Probiotics into outer space: feasibility assessments of encapsulated freeze-dried probiotics during 1 month’s storage on the International Space Station. Scientific. Rep. 8:10687. 10.1038/s41598-018-29094-2 - DOI - PMC - PubMedSalgado B. A., Fabbri S., Dickenson A., Hasan M. I., Walsh J. L. (2021). Surface barrier discharges for Escherichia coli biofilm inactivation: modes of action and the importance of UV radiation. PLoS One 16:e0247589. 10.1371/journal.pone.0247589 - DOI - PMC - PubMedSatoh K., Alshahni M. M., Umeda Y., Komori A., Tamura T., Nishiyama Y., et al. (2021). Seven years of progress in determining fungal diversity and characterization of fungi isolated from the Japanese Experiment Module KIBO. Microbiol. Immunol. 65 463–471. 10.1111/1348-0421.12931 - DOI - PubMedScott T. J., Vonortas N. S. (2021). Microgravity protein crystallization for drug development: a bold example of public sector entrepreneurship. J. Technol. Transf. 46 1442–1461. 10.1007/s10961-019-09743-y - DOISenatore G., Mastroleo F., Leys N., Mauriello G. (2018). Effect of microgravity & space radiation on microbes. Fut. Microbiol. 13 831–847. - PubMedSenatore G., Mastroleo F., Leys N., Mauriello G. (2020). Growth of lactobacillus reuteri DSM17938 Under two simulated microgravity systems: changes in Reuterin production, gastrointestinal passage resistance, and stress genes expression response. Astrobiology 20 1–4. 10.1089/ast.2019.2082 - DOI - PubMedShao D., Yao L., Riaz M. S., Zhu J., Shi J., Jin M., et al. (2017). Simulated microgravity affects some biological characteristics of Lactobacillus acidophilus. Appl. Microbiol. Biotechnol. 101 3439–3449. 10.1007/s00253-016-8059-6 - DOI - PubMedSu L., Chang D., Liu C. (2013). The development of space microbiology in the future: the value and significance of space microbiology research. Fut. Microbiol. 8 5–8. 10.2217/fmb.12.127 - DOI - PubMedTakatori S. C., Mandadapu K. K. (2020). Motility-induced buckling and glassy dynamics regulate three-dimensional transitions of bacterial monolayers. arXiv [preprint] 10.13140/RG.2.2.31609.62568 - DOITopolski C. R. (2021). Validation of a Two-Dimensional Clinostat Design to Provide Functional Weightlessness to Custom Gas Exchange Vessels. Ph D thesis, Florida: Embry–Riddle Aeronautical University.Wang J., Liu C., Liu J., Fang X., Xu C., Guo Y., et al. (2014). Space mutagenesis of genetically engineered bacteria expressing recombinant human interferon α1b and screening of higher yielding strains. World. J. Microbiol. Biotechnol. 30 943–949. 10.1007/s11274-013-1512-0 - DOI - PubMedYang Y., Sha M. (2019). A Beginner’s Guide to Bioprocess Modes–Batch, Fed-Batch, and Continuous Fermentation. Enfield, CT: Eppendorf Inc.Zhang X., Yan L., Li L., Lin S., Guo J., Li J., et al. (2015). Beneficial Effect of Spaceflight Experience on Producing of Endoproteinase Lys-C by Lysobacter enzymogenes. J. Pure. Appl. Microbiol. 9 231–237.Zhao X., Yu Y., Zhang X., Huang B., Bai P., Xu C., et al. (2019). Decreased biofilm formation ability of Acinetobacter baumannii after spaceflight on China’s Shenzhou 11 spacecraft. MicrobiologyOpen 8:e00763. 10.1002/mbo3.763 - DOI - PMC - PubMedZhou J., Sun C., Wang N., Gao R., Bai S., Zheng H., et al. (2006). Preliminary report on the biological effects of space flight on the producing strain of a new immunosuppressant. J. Industrial. Microbiol. Biotechnol. 33 707–712. 10.1007/s10295-006-0118-z - DOI - PubMedZongzhou Z., Yaping X. (2009). The impact of spaceborne on the microflora of Daqu. Food. Sci. 3 214–216. 来源：医学顾事
免责声明：本站系转载，并不代表本网赞同其观点和对其真实性负责。如涉及作品内容、版权和其它问题，请在30日内与本站联系，我们将在第一时间删除内容!