Developing a new class of engineered live bacterial therapeutics to treat human diseases

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Abstract

A complex interplay of metabolic and immunological mechanisms underlies many diseases that represent a substantial unmet medical need. There is an increasing appreciation of the role microbes play in human health and disease, and evidence is accumulating that a new class of live biotherapeutics comprised of engineered microbes could address specific mechanisms of disease. Using the tools of synthetic biology, nonpathogenic bacteria can be designed to sense and respond to environmental signals in order to consume harmful compounds and deliver therapeutic effectors. In this perspective, we describe considerations for the design and development of engineered live biotherapeutics to achieve regulatory and patient acceptance.

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Most cited references 63

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A microbial symbiosis factor prevents intestinal inflammatory disease.

Sarkis Mazmanian, June Round, Dennis Kasper (2008)

Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.

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The gut microbiome in health and in disease

Andrew Shreiner, John Kao, Vincent B. Young (2015)

Recent technological advancements and expanded efforts have led to a tremendous growth in the collective knowledge of the human microbiome. This review will highlight some of the important recent findings in this area of research.

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Synchronized cycles of bacterial lysis for in vivo delivery

M Omar Din, Tal Danino, Arthur Prindle … (2016)

The pervasive view of bacteria as strictly pathogenic has given way to an appreciation of the widespread prevalence of beneficial microbes within the human body 1–3 . Given this milieu, it is perhaps inevitable that some bacteria would evolve to preferentially grow in environments that harbor disease and thus provide a natural platform for the development of engineered therapies 4–6 . Such therapies could benefit from bacteria that are programmed to limit bacterial growth while continually producing and releasing cytotoxic agents in situ 7–10 . Here, we engineer a clinically relevant bacterium to lyse synchronously at a threshold population density and to release genetically encoded cargo. Following quorum lysis, a small number of surviving bacteria reseed the growing population, thus leading to pulsatile delivery cycles. We use microfluidic devices to characterize the engineered lysis strain and we demonstrate its potential as a drug delivery platform via co-culture with human cancer cells in vitro. As a proof of principle, we track the bacterial population dynamics in ectopic syngeneic colorectal tumors in mice. The lysis strain exhibits pulsatile population dynamics in vivo, with mean bacterial luminescence that remained two orders of magnitude lower than an unmodified strain. Finally, guided by previous findings that certain bacteria can enhance the efficacy of standard therapies 11 , we orally administer the lysis strain, alone or in combination with a clinical chemotherapeutic, to a syngeneic transplantation model of hepatic colorectal metastases. We find that the combination of both circuit-engineered bacteria and chemotherapy leads to a notable reduction of tumor activity along with a marked survival benefit over either therapy alone. Our approach establishes a methodology for leveraging the tools of synthetic biology to exploit the natural propensity for certain bacteria to colonize disease sites.

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Author and article information

Journal

Title: Nature Communications

Abbreviated Title: Nat Commun

Publisher: Springer Science and Business Media LLC

ISSN (Electronic): 2041-1723

Publication date Created: December 2020

Publication date (Electronic): April 8 2020

Publication date (Print): December 2020

Volume: 11

Issue: 1

Article

DOI: 10.1038/s41467-020-15508-1

SO-VID: 51a37a5d-5738-4efd-8a00-9306ceee8a36

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https://creativecommons.org/licenses/by/4.0

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Developing a new class of engineered live bacterial therapeutics to treat human diseases

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Most cited references 63

A microbial symbiosis factor prevents intestinal inflammatory disease.

The gut microbiome in health and in disease

Synchronized cycles of bacterial lysis for in vivo delivery

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