Synthetic Biology and the Next Generation of Microbiota-Based Therapies

By Dr. Priyom Bose, Ph.D.Reviewed by Lily Ramsey, LLM

Microbiota-based therapies leverage gut microorganisms or their components to enhance human health.¹ Synthetic biology, a multidisciplinary field, facilitates the development of genetically engineered probiotics or microbial consortia designed to deliver targeted therapeutic effects.²

Recent advancements in genetic engineering tools, including CRISPR/Cas9, TALENs, and ZFNs, as well as innovations in computational modeling, have significantly expanded the potential for microbial manipulation in therapeutic applications.

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How did Synthetic Biology Empower Microbial Therapeutics?

The human microbiome is a community of microorganisms that are symbiotically present in different body sites, particularly the gastrointestinal (GI) tract.³ These microbes play a crucial role in regulating metabolic and immune responses, as well as neurological functions.

Any modification in gut microbial diversity, such as enhancement in gut microbiome through diet or drugs, could influence an individual's health. Considering gut microbial functions, scientists manipulate or restore gut microbial diversity to promote human health.⁴

Synthetic biology has played a pivotal role in microbial therapeutics by creating microbes with desirable traits. It employs the principles of computer science, biology, engineering, and other scientific domains to design and manipulate biological systems. It focuses on creating novel artificial biological systems or redesigning the existing ones to achieve targeted functions.⁵

When genetically modified microbes are introduced in the GI, they integrate with or influence the existing microbiota. Therefore, synthetic biology promotes the development of targeted interventions with unprecedented precision. For example, engineered probiotics contain genetically modified microbial strains that produce therapeutic compounds in the gut that can alleviate diseased conditions.²

In contrast to conventional therapies, microbial therapies, particularly bacterial therapies, present certain advantages, including self-replication, on-site synthesis and delivery of therapeutic agents, diagnostic functions via genetic circuits, avoidance of expensive downstream processes, and minimal side effects.⁶

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Synthetic Biology in Microbiota-Based Therapies

Synthetic biology provides innovative tools to develop microbes for therapeutic and diagnostic applications. For example, CRISPR-Cas9 is used to precisely modify bacterial genomes by removing specific genes, enhancing desirable traits, or reducing adverse effects.⁷

This approach enables the creation of microbes capable of producing valuable metabolites not synthesized by their wild-type counterparts. Artificial biosynthetic pathways, designed computationally, are used to produce essential compounds such as hormones, vitamins, and anti-inflammatory agents, contributing to improved health outcomes. This strategy is also applied to develop novel probiotics with enhanced health benefits.

Engineered probiotics are programmed to secrete anti-inflammatory cytokines, which can treat metabolic disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).⁸ These probiotics have also been developed for treating other conditions, including cancer and autoimmune diseases.

Microbes can be genetically engineered to selectively target pathogenic bacteria without harming beneficial species. This is achieved by enabling the production of specific antimicrobial peptides or enhancing the absorption of harmful metabolites. Removing pathogenic microbes helps restore the gut microbial community, which supports overall health.⁹

Synthetic biology also involves the creation of synthetic microbial communities that mimic or enhance natural microbiota functions. These synthetic consortia are meticulously designed to improve immune responses, increase short-chain fatty acid (SCFA) production, or regulate metabolic pathways. Enhanced SCFA production and improved bile acid metabolism have been shown to alleviate metabolic diseases such as diabetes and obesity. Additionally, engineered probiotics programmed to modulate immune responses show significant potential in treating autoimmune disorders like multiple sclerosis and rheumatoid arthritis.

Engineered microbes can also function as ingestible biosensors, capable of identifying clinical pathogens—both bacteria and viruses—with high accuracy. This strategy supports real-time monitoring of gut health and infections, facilitating timely interventions.¹⁰

Furthermore, bacteria can be engineered to release therapeutic agents in response to specific microenvironmental conditions, such as pH or biomarker presence, significantly enhancing therapeutic accuracy and efficacy.

Sustainability within Synthetic Biology

Challenges and Considerations

Despite the numerous benefits of synthetic biology, it faces stringent ethical regulations to ensure the safety and stability of engineered organisms. The introduction of genetically modified viable microorganisms into the environment presents risks, such as unwanted phenotypic changes and non-specific mutations.

To mitigate these risks, scientists involved in genetic engineering prioritize effective management of gene expression and synthetic pathways. Strict protocols are followed to prevent the accidental release of genetically modified organisms. Genetic safeguards, such as biocontainment mechanisms and kill switches, are employed to prevent horizontal gene transfer and environmental persistence.¹¹

Advanced gene editing techniques, such as CRISPR-Cas9, have enabled the precise development of synthetic microorganisms. These techniques are essential for minimizing off-target effects and non-specific mutations, ensuring safer applications.

Maintaining the genetic stability of engineered microorganisms remains a significant challenge.¹² For gastrointestinal (GI) diseases, researchers face difficulties in developing therapeutic microbes that are both stable and capable of surviving the harsh conditions of the GI tract. To address this, strategies such as encapsulation and biocontainment have been adopted to protect therapeutic formulations from adverse acidic conditions.

In cancer treatment, a primary challenge lies in the selective targeting of tumors while minimizing off-target effects of microbial formulations. While preliminary studies have shown promising results using engineered microbes to target tumor biomarkers, further research is needed to validate these findings.

The lack of standardized protocols for producing and ensuring the quality of microbial therapeutic products also poses a major obstacle for pharmaceutical companies. Overcoming this limitation will require collaborative efforts among scientists, industry stakeholders, and regulatory bodies to streamline the production and quality control processes.

Conclusion

In conclusion, synthetic biology is revolutionizing therapeutic and diagnostic applications by enabling precise genetic modifications and novel treatment strategies for conditions such as GI diseases, cancer, and autoimmune disorders. However, significant challenges remain, particularly in ensuring the safety, stability, and regulatory compliance of engineered microorganisms.

To overcome these barriers, advancements in precision tools like CRISPR-Cas9, robust biocontainment strategies, and standardized production protocols are essential. Collaborative efforts between scientists, industry stakeholders, and regulatory bodies will play a pivotal role in addressing these challenges while unlocking the full potential of synthetic biology.

With continued innovation and responsible implementation, synthetic biology has the potential to redefine modern medicine and improve global health outcomes.

References

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8. Mishra J, et al. Inflammatory Bowel Disease Therapeutics: A Focus on Probiotic Engineering. Mediators Inflamm. 2022;2022:9621668. doi: 10.1155/2022/9621668.
9. Mahdizade Ari M, et al. Genetically Engineered Microorganisms and Their Impact on Human Health. Int J Clin Pract. 2024;2024:6638269. doi: 10.1155/2024/6638269.
10. Tanniche I, Behkam B. Engineered live bacteria as disease detection and diagnosis tools. J Biol Eng. 2023;17(1):65. doi: 10.1186/s13036-023-00379-z.
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12. Son HI, Weiss A, You L. Design patterns for engineering genetic stability. Curr Opin Biomed Eng. 2021;19:100297. doi: 10.1016/j.cobme.2021.100297.

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