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      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.

          Abstract

          The role microbes play in human health and the ability of synthetic biology to engineer microbial properties opens up new ways of treating disease. In this perspective, the authors describe the design and development of these living therapeutics.

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          Most cited references63

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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.
              Article 0 comments Cited 230 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Caroline B. Kurtz:
                ORCID: http://orcid.org/0000-0001-7192-6116
                caroline@synlogictx.com
                Journal
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature Communications
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2041-1723
                Publication date (Electronic): 8 April 2020
                Publication date PMC-release: 8 April 2020
                Publication date Collection: 2020
                Volume: 11
                Electronic Location Identifier: 1738
                Affiliations
                GRID grid.460014.7, Synlogic, Inc., ; 301 Binney Street, Cambridge, MA 02142 USA
                Author information
                http://orcid.org/0000-0003-4893-8244
                http://orcid.org/0000-0001-7192-6116
                Article
                Publisher ID: 15508
                DOI: 10.1038/s41467-020-15508-1
                PMC ID: 7142098
                PubMed ID: 32269218
                SO-VID: 51a37a5d-5738-4efd-8a00-9306ceee8a36
                Copyright © © The Author(s) 2020
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 2 October 2019
                Date accepted : 13 March 2020
                Categories
                Subject: Perspective
                Custom metadata
                issue-copyright-statement © The Author(s) 2020

                ScienceOpen disciplines: Uncategorized
                Keywords: synthetic biology,microbiome,molecular medicine
                Data availability:
                ScienceOpen disciplines: Uncategorized
                Keywords: synthetic biology, microbiome, molecular medicine

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