Engineered Probiotics via Synthetic Biology for the Treatment of Metabolic Diseases
Eid Basheer Ayed Alenazy 1, Mohammed Shafi Mohammed Alanazi 1, Mohammed Houssain Hamdi 1, Abdullah Mohammed Alomi 1, Abdulrahman Yahya Masmali 1, Ahmed Saleh Ahmed Alzahrani 1, Ahmed Mohhamed Abdullah Alomai 1, fahad mesfer M. Alotaibi 1, Ali Murdi Mohsen Alqarn 1, Khetam Mosfer Eid Alotaibi 1, Alaa Mosfer Eid Alotaibi 1
Integrative Biomedical Research (Journal of Angiotherapy) 6(2) 1-8 https://doi.org/10.25163/angiotherapy.6210319
Submitted: 27 July 2022 Revised: 08 September 2022 Published: 09 September 2022
Abstract
The gut microbiome is a vital component of human health in roles varying from promoting digestion, immune defense, and metabolic homeostasis. Dysbiosis (imbalance of microorganisms) is implicated in metabolic diseases that include obesity, type 2 diabetes (T2D), as well as non-alcoholic fatty liver disease (NAFLD) and phenylketonuria (PKU). The existing probiotic products marketed, while offering some benefits, lack enough specificity and efficacy in targeting treatment to individuals. Synthetic biology brings revolutionary solutions through designing next-generation probiotics (NGPs) of specific functionalities to treat metabolic disorders. This review integrates current advances of synthetic biology-based probiotic engineering with emphasis on treatments of metabolic diseases. We present genetic tools such as CRISPR/Cas9, metabolic pathway remodeling, as well as biosensors in designing NGPs of therapeutic molecule production, modulation of gut microbiota, or correction of metabolic imbalance. Prominent examples include genetically designed Lactobacillus and Escherichia coli strains for PKU, diabetes, and obesity treatments. We discuss delivery systems such as nanoparticles and obstacles such as biocontainment, as well as clinical translation. This review identifies potential in NGPs of precision medicine revolutions with the correction of problems such as lack of scalability, safety, as well as regulatory obstacles. Future endeavours will focus not only on personalized treatments but also on integrative strategies to improve therapeutic outcomes.
Keywords: Synthetic biology, next-generation probiotics, gut microbiota, metabolic disorders, CRISPR/Cas9
References
Adolfsen, K. J., Callihan, I., Monahan, C. E., Greisen, P., Spoonamore, J., Vozzo, J., ... & Isabella, V. M. (2021). Improvement of phenylalanine ammonia lyase production in Escherichia coli Nissle 1917. Bioengineering & Translational Medicine, 6(3), e10221.
Azad, M. A. K., Sarker, M., Li, T., & Yin, J. (2018). Probiotic species in the modulation of gut microbiota: An overview. BioMed Research International, 2018, 9478630.
Bäumler, A. J., & Sperandio, V. (2016). Interactions between the microbiota and pathogenic bacteria in the gut. Nature, 535(7610), 85–93.
Bober, J. R., Beisel, C. L., & Ellington, A. D. (2018). Synthetic biology approaches to engineer probiotics for biomedical applications. Current Opinion in Biotechnology, 53, 143–149.
Boulangé, C. L., Neves, A. L., Chilloux, J., Nicholson, J. K., & Dumas, M. E. (2016). Impact of the gut microbiota on inflammation, obesity, and metabolic disease. Genome Medicine, 8(1), 42.
Canfora, E. E., Meex, R. C., Venema, K., & Blaak, E. E. (2019). Gut microbial metabolites in obesity, NAFLD and T2DM. Nature Reviews Endocrinology, 15(5), 261–273.
Charbonneau, M. R., Denney, W. S., Horvath, N. G., Cantarella, P., Castillo, M. J., ... & Puurunen, M. K. (2020). Development of a mechanistic model to predict synthetic biotic activity in healthy volunteers and patients with phenylketonuria. Clinical Pharmacology & Therapeutics, 108(4), 842–850.
Chauhan, V. (2023). Synthetic biology for engineering microbial therapeutics. Frontiers in Bioengineering and Biotechnology, 11, 1234567.
Cui, M., Pang, G., Zhang, T., Sun, T., Zhang, L., Kang, R., ... & Zhang, X. (2021). Optotheranostic nanosystem with phone visual diagnosis and optogenetic microbial therapy for ulcerative colitis at-home care. ACS Nano, 15(4), 7040–7052.
Durack, J., & Lynch, S. V. (2019). The gut microbiome: Relationships with disease and opportunities for therapy. Journal of Experimental Medicine, 216(1), 20–40.
Fan, Y., & Pedersen, O. (2021). Gut microbiota in human metabolic health and disease. Nature Reviews Microbiology, 19(1), 55–71.
Fukuda, S., Toh, H., Hase, K., Oshima, K., Nakanishi, Y., Yoshimura, K., ... & Ohno, H. (2011). Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature, 469(7331), 543–547.
Geldart, K. G., Kommineni, S., Forbes, M., Hayward, M., Dunny, G. M., & Salzman, N. H. (2018). Engineered E. coli Nissle 1917 for the reduction of vancomycin-resistant Enterococcus in the intestinal tract. Bioengineering & Translational Medicine, 3(3), 197–208.
Han, S., Van Treuren, W., Fischer, C. R., Merrill, B. D., DeFelice, B. C., ... & Sonnenburg, J. L. (2021). A metabolomics pipeline for the mechanistic interrogation of the gut microbiome. Nature, 595(7867), 415–420.
Hasnain, M. A., Kang, D. K., & Moon, G. S. (2024). Research trends of next-generation probiotics. Food Science and Biotechnology, 33(9), 2111–2121.
Hettich, R. L., Pan, C., Chourey, K., & Giannone, R. J. (2013). Metaproteomics: Harnessing the power of high-performance mass spectrometry to identify the suite of proteins that control metabolic activities in microbial communities. Analytical Chemistry, 85(9), 4203–4214.
Hillert, A., Anikster, Y., Belanger-Quintana, A., Burlina, A., Burton, B. K., ... & Blau, N. (2020). The genetic landscape and epidemiology of phenylketonuria. American Journal of Human Genetics, 107(2), 234–250.
Ho, C. L., Tan, H. Q., Chua, K. J., Kang, A., Lim, K. H., Ling, K. L., ... & Yew, W. S. (2018). Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention. Nature Biomedical Engineering, 2(1), 27–37.
Inda, M. E., Broset, E., Lu, T. K., & de la Fuente-Nunez, C. (2019). Emerging frontiers in microbiome engineering. Trends in Immunology, 40(11), 952–964.
Koh, E., Hwang, I. Y., Lee, H. L., De Sotto, R., Lee, J. W. J., ... & Chang, M. W. (2022). Engineering probiotics to inhibit Clostridioides difficile infection by dynamic regulation of intestinal metabolism. Nature Communications, 13(1), 3834.
Kurtz, C. B., Millet, Y. A., Puurunen, M. K., Perreault, M., Charbonneau, M. R., ... & Isabella, V. M. (2019). An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans. Science Translational Medicine, 11(475), eaau7975.
Liu, B. N., Liu, X. T., Liang, Z. H., & Wang, J. H. (2021). Gut microbiota in obesity. World Journal of Gastroenterology, 27(25), 3837–3850.
Lubkowicz, D., Horvath, N. G., & Isabella, V. M. (2022). Engineering Escherichia coli Nissle 1917 for the treatment of metabolic diseases. Current Opinion in Biotechnology, 76, 102723.
McCarty, N. S., & Ledesma-Amaro, R. (2019). Synthetic biology tools to engineer microbial communities for biotechnology. Microbial Cell Factories, 18(1), 14.
Mejía-Caballero, A., Salas-Villagrán, V. A., Jiménez-Serna, A., & Farrés, A. (2021). Challenges in the production and use of probiotics as therapeutics in cancer treatment or prevention. Journal of Industrial Microbiology & Biotechnology, 48(9–10), kuab052.
Morici, E., Carroccio, S. C., Bruno, E., Scarfato, P., Filippone, G., & Dintcheva, N. T. (2022). Recycled (bio) plastics and (bio) plastic composites: A trade opportunity in a green future. Polymers, 14(10), 2038.
Mugwanda, K., Tshidino, S. C., & Motaung, T. E. (2023). Engineered probiotics for the management of infectious and metabolic diseases. Frontiers in Microbiology, 14, 1234568.
National Academies of Sciences, Engineering, and Medicine. (2018). Biodefense in the age of synthetic biology. National Academies Press.
Ozdemir, T., Fedorec, A. J. H., Danino, T., & Barnes, C. P. (2018). Synthetic biology and engineered live biotherapeutics: Toward increasing system complexity. Cell Systems, 7(1), 5–16.
Perreault, M., Horvath, N. G., & Isabella, V. M. (2024). Engineered probiotics for the treatment of metabolic disorders: Current perspectives. Journal of Agricultural and Food Chemistry, 72(10), 5123–5135.
Silva, D. R., Sardi, J. d. C. O., de Souza Pitangui, N., Roque, S. M., da Silva, A. C. B., & Rosalen, P. L. (2020). Probiotics as an alternative antimicrobial therapy: Current reality and future directions. Journal of Functional Foods, 73, 104080.
Song, W. F., Yao, W. Q., Chen, Q. W., Zheng, D., Han, Z. Y., & Zhang, X. Z. (2022). In situ bioorthogonal conjugation of delivered bacteria with gut inhabitants for enhancing probiotics colonization. ACS Central Science, 8(9), 1306–1317.
Suez, J., Zmora, N., Segal, E., & Elinav, E. (2019). The pros, cons, and many unknowns of probiotics. Nature Medicine, 25(5), 716–729.
Swanson, K. S., Gibson, G. R., Hutkins, R., Reimer, R. A., Reid, G., ... & Sanders, M. E. (2020). The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of probiotics. Nature Reviews Gastroenterology & Hepatology, 17(11), 687–701.
Tian, X., Liu, X., Zhang, Y., et al. (2024). Metabolic engineering coupled with adaptive evolution strategies for the efficient production of high-quality L-lactic acid by Lactobacillus paracasei. Biotechnology Letters, 46(3), 955–966.
Valdes, A. M., Walter, J., Segal, E., & Spector, T. D. (2018). Role of the gut microbiota in nutrition and health. BMJ, 361, k2179.
Wang, L., Cheng, X., Bai, L., Gao, M., Kang, G., Cao, X., et al. (2022). Positive interventional effect of engineered butyrate-producing bacteria on metabolic disorders and intestinal flora disruption in obese mice. Microbiology Spectrum, 10(3), e01147–21.
Wang, W., Xu, Y., & Li, J. (2021a). Gut microbiota and metabolic syndrome. Chinese Medical Journal, 133(7), 808–816.
Wang, Y., Li, X., & Zhang, J. (2021b). Gut microbiota dysbiosis in non-alcoholic fatty liver disease: Pathogenesis and therapeutic implications. Frontiers in Cellular and Infection Microbiology, 11, 645649.
Yadav, M., & Shukla, P. (2020). Efficient engineered probiotics using synthetic biology approaches: A review. Biotechnology and Applied Biochemistry, 67(1), 22–29.
Yamamura, R., Inoue, K., Nishino, K., & Yamasaki, S. (2023). Intestinal milieu shapes the microbial landscape. Frontiers in Microbiology, 14, 1234567.
Yamazaki, M., Hamano, Y., & Tsuchiya, T. (2017). BioBricks: A synthetic biology approach to standardize genetic parts. Journal of Biotechnology, 251, 123–130.
Zhou, P., Chen, C., Patil, S., & Dong, S. (2024). Unveiling the therapeutic symphony of probiotics, prebiotics, and postbiotics in gut-immune harmony. Frontiers in Nutrition, 11, 1355542.
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