Engineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut

Praveschotinunt, Pichet; Duraj-Thatte, Anna; Gelfat, Ilia; Bahl, Franziska; Chou, David B.; Joshi, Neel

doi:10.1038/s41467-019-13336-6

Cited by 238 publications

(172 citation statements)

References 67 publications

Supporting

Mentioning

164

Contrasting

Unclassified

Order By: Relevance

“…There is an increasing awareness of the roles of the gut microbiome in in uencing the response to and outcome of chemotherapy [19,31,32]. Reciprocal modi cation of the microbiota by chemotherapeutic agents is also increasingly appreciated.…”

Section: Discussionmentioning

confidence: 99%

A Synthetic Probiotic Engineered for Colorectal Cancer Therapy Modulates Gut Microbiota

Chung

Ryu

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Successful chemoprevention or chemotherapy is achieved through targeted delivery of prophylactic agents during initial phases of carcinogenesis or therapeutic agents to malignant tumors. Bacteria can be used as anticancer agents, but efforts to utilize attenuated pathogenic bacteria suffer from the risk of toxicity or infection. Lactic acid bacteria are safe to eat and often confer health benefits, making them ideal candidates for live vehicles engineered to deliver anticancer drugs.Results: In this study, we developed an effective bacterial drug delivery system for colorectal cancer (CRC) therapy using the lactic acid bacterium Pediococcus pentosaceus. It is equipped with dual gene cassettes driven by a strong inducible promoter that encode the therapeutic protein P8 fused to a secretion signal peptide and a complementation system. In an inducible CRC cell-derived xenograft mouse model, our synthetic probiotic significantly reduced tumor volume and inhibited tumor growth relative to the control. Mice with colitis-associated CRC induced by azoxymethane and dextran sodium sulfate exhibited polyp regression and recovered taxonomic diversity when the engineered bacterium was orally administered. Further, the synthetic probiotic modulated gut microbiota and alleviated the chemically induced dysbiosis. Correlation analysis demonstrated that specific bacterial taxa potentially associated with eubiosis or dysbiosis, such as Akkermansia or Turicibacter, have positive or negative relationships with other microbial members.Conclusions: Taken together, our work illustrates that an effective and stable synthetic probiotic composed of P. pentosaceus and the P8 therapeutic protein can reduce CRC and contribute to rebiosis, and the validity and feasibility of cell-based designer biopharmaceuticals for both treating CRC and ameliorating impaired microbiota.

show abstract

Section: Discussionmentioning

confidence: 99%

A Synthetic Probiotic Engineered for Colorectal Cancer Therapy Modulates Gut Microbiota

Chung

Ryu

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Recently, E. coli Nissle 1917 was engineered to produce an extracellular matrix containing all three trefoil factors to treat inflammation and help re-build the intestinal epithelium (Praveschotinunt et al, 2019). CsgA is the monomer unit for the curli fibers that make up the fibrous matrix.…”

Section: Inducible Systemsmentioning

confidence: 99%

Engineered Probiotics for Detection and Treatment of Inflammatory Intestinal Diseases

Barra

Danino

Garrido

2020

Front. Bioeng. Biotechnol.

View full text Add to dashboard Cite

Inflammatory intestinal diseases such as Crohn's disease and ulcerative colitis have seen an increase in their prevalence in developing countries throughout the current decade. These are caused by a combination of genetic and environmental factors, altered immune response, intestinal epithelium disruption and dysbiosis in the gut microbiome. Current therapies are mainly focused on treating symptoms and are often expensive and ineffective in the long term. Recently, there has been an increase in our understanding of the relevance of the gut microbiome and its impact on human health. Advances in the use of probiotics and synthetic biology have led to the development of intestinal biosensors, bacteria engineered to detect inflammation biomarkers, that work as diagnostic tools. Additionally, live biotherapeutics have been engineered as delivery vehicles to produce treatment in situ avoiding common complications and side effects of current therapies. These genetic constructs often express a therapeutic substance constitutively, but others could be regulated externally by specific substrates, making the production of their treatment more efficient. Additionally, certain probiotics detecting specific biomarkers in situ and responding by generating a therapeutic substance are beginning to be developed. While most studies are still in the laboratory stage, a few modified probiotics have been tested in humans. These advances indicate that live biotherapeutics could have great potential as new treatments for inflammatory intestinal diseases.

show abstract

“…In this way, distinct peptide tags have empowered curli amyloid fibers with metal coordination, nanoparticle templating, covalent protein immobilization, or affinity binding properties in vitro (53). The resulting bacterial biofilms exhibit self-regenerating hydrogel architectures (54) or electric conductivity (55) or can be used to program mouse microbiota to counteract inflammatory bowel disease (56). In these approaches, bacterial extracellular amyloids meet the assembly selectivity required for orthogonal ␤-strand functional scaffolding (57).…”

Section: How To Achieve Control On Amyloid Conversion Through Synbiomentioning

confidence: 99%

SynBio and the Boundaries between Functional and Pathogenic RepA-WH1 Bacterial Amyloids

Giraldo

2020

mSystems

View full text Add to dashboard Cite

Amyloids are protein polymers that were initially linked to human diseases. Across the whole Tree of Life, many disease-unrelated proteins are now emerging for which amyloids represent distinct functional states. Most bacterial amyloids described are extracellular, contributing to biofilm formation. However, only a few have been found in the bacterial cytosol. This paper reviews from the perspective of synthetic biology (SynBio) our understanding of the subtle line that separates functional from pathogenic and transmissible amyloids (prions). In particular, it is focused on RepA-WH1, a functional albeit unconventional natural amyloidogenic protein domain that participates in controlling DNA replication of bacterial plasmids. SynBio approaches, including protein engineering and the design of allosteric effectors such as diverse ligands and an optogenetic module, have enabled the generation in RepA-WH1 of an intracellular cytotoxic prion-like agent in bacteria. The synthetic RepA-WH1 prion has the potential to develop into novel antimicrobials.

show abstract

Engineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut

Cited by 238 publications

References 67 publications

A Synthetic Probiotic Engineered for Colorectal Cancer Therapy Modulates Gut Microbiota

A Synthetic Probiotic Engineered for Colorectal Cancer Therapy Modulates Gut Microbiota

Engineered Probiotics for Detection and Treatment of Inflammatory Intestinal Diseases

SynBio and the Boundaries between Functional and Pathogenic RepA-WH1 Bacterial Amyloids

Contact Info

Product

Resources

About