Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention

Ho, Chun Loong; Tan, Hui; Chua, Koon Jiew; Kang, Aram; Lim, Kiat Hon; Ling, Khoon Lin; Yew, Wen Shan; Lee, Yung Seng; Thiery, Jean Paul; Chang, Matthew Wook

doi:10.1038/s41551-017-0181-y

Cited by 226 publications

(152 citation statements)

References 42 publications

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“…Chemotherapy is still the mainstay of treatment for inoperable cancer, despite numerous shortcomings such as inadequate drug concentrations in tumors, occurrence of systemic toxicity (hematological, gastrointestinal, alopecia, heart, and skin toxicity) in many types of cancer, and almost inevitable induction of drug resistance . Neutropenia is one of the main manifestations of hematological toxicity.…”

Section: Combination Of Bacteriotherapy With Chemotherapymentioning

confidence: 99%

“…Some of the recent studies have investigated the positive effects of Lactobacillus brevis CD2 lozenges on the severity and prevalence of mucositis, as well as the tumor resistance to radiotherapy. It was observed that patients who received Lactobacillus during chemotherapy had fewer intestinal problems than the others, resulting in shortening the course of chemotherapy and lower doses . Another method to reduce the side effects of chemotherapy is the COBALT strategy (combination bacteriolytic therapy; simultaneous use of C novyi ‐ NT spores with conventional chemotherapeutic agents).…”

Section: Combination Of Bacteriotherapy With Chemotherapymentioning

confidence: 99%

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Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities

et al. 2019

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Successful treatment of cancer remains a challenge, due to the unique pathophysiology of solid tumors, and the predictable emergence of resistance. Traditional methods for cancer therapy including radiotherapy, chemotherapy, and immunotherapy all have their own limitations. A novel approach is bacteriotherapy, either used alone, or in combination with conventional methods, has shown a positive effect on regression of tumors and inhibition of metastasis. Bacteria‐assisted tumor‐targeted therapy used as therapeutic/gene/drug delivery vehicles has great promise in the treatment of tumors. The use of bacteria only, or in combination with conventional methods was found to be effective in some experimental models of cancer (tumor regression and increased survival rate). In this article, we reviewed the major advantages, challenges, and prospective directions for combinations of bacteria with conventional methods for tumor therapy.

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Section: Combination Of Bacteriotherapy With Chemotherapymentioning

confidence: 99%

Section: Combination Of Bacteriotherapy With Chemotherapymentioning

confidence: 99%

Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities

et al. 2019

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“…In a separate work, E. coli Nissile 1917 (Eda) was genetically engineered to treat colorectal cancer (CRC) locally in the GI tract . The authors considered the CRC microenvironment, such as surface receptors on cancer cells, and the GI tract environment, such as ingested food, to optimize their formulation.…”

Section: Preclinical Approaches To Improve Microbe‐deliverymentioning

confidence: 99%

“…In a separate work, E. coli Nissile 1917 (Eda) was genetically engineered to treat colorectal cancer (CRC) locally in the GI tract. 85 The authors considered the CRC microenvironment, such as surface receptors on cancer cells, and the GI tract environment, such as ingested food, to optimize their formulation. The final formulation (Figure 4a), dubbed Eda-I1-HlpA, was designed to target the surface of CRC cells (Figure 4bi), convert dietary glucosinolate to sulforaphane (a cancer inhibitor) at the CRC-site (Figure 4bii), and be released from the CRCsite following tumor eradication ( Figure 4biii).…”

Section: Formulation For Improved Deliverymentioning

confidence: 99%

Clinical translation of microbe‐based therapies: Current clinical landscape and preclinical outlook

Vargason

Anselmo

2018

Bioengineering & Transla Med

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Next generation microbe‐based therapeutics, inspired by the success of fecal microbiota transplants, are being actively investigated in clinical trials to displace or eliminate pathogenic microbes to treat various diseases in the gastrointestinal tract, skin, and vagina. Genetically engineered microbes are also being investigated in the clinic as drug producing factories for biologic delivery, which can provide a constant local source of drugs. In either case, microbe‐therapeutics have the opportunity to address unmet clinical needs and open new areas of research by reducing clinical side effects associated with current treatment modalities or by facilitating the delivery of biologics. This review will discuss examples of past and current clinical trials that are investigating microbe‐therapeutics, both microbiome‐modulating and drug‐producing, for the treatment of a range of diseases. We then offer a perspective on how preclinical approaches, both those focused on developing advanced delivery systems and those that use in vitro microbiome model systems to inform formulation design, will lead to the realization of next‐generation microbe‐therapeutics.

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“…All engineered probiotics described to date have been members of the bacterial domain of life due to their high numerical abundance in the gut 13, 14 and ease of engineering. 9, 15 For example, Escherichia coli Nissle 1917 has been engineered to treat diseases such as phenylketonuria (PKU) 15, 16 , hyperammonemia 17 , and cancer 18 , or eliminate pathogens such as Pseudomonas aeruginosa 19 . In addition to these advantages, the limitations to bacterial probiotics include susceptibility to antibiotics, 20 predation by bacteriophage known to be highly abundant in the human gut, 21 and difficulty in producing high levels of post-translationally-modified proteins 22 .…”

Section: Introductionmentioning

confidence: 99%

Establishing ProbioticSaccharomyces boulardiias a Model Organism for Synthesis and Delivery of Biomolecules

Durmusoglu

Al'Abri

Collins

et al. 2020

Preprint

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12Saccharomyces boulardii is a widely used yeast probiotic which can counteract various 13 gastrointestinal disorders 1 . As a relative of Saccharomyces cerevisiae, S. boulardii exhibits rapid 14 growth and is easy to transform 2 and thus represents a promising chassis for the engineered 15 secretion of biomolecules. To establish S. boulardii as a platform for delivery of biomolecules to 16 the mammalian gut, we measured the amount and variance in protein expression enabled by 17 promoters, terminators, selective markers, and copy number control elements in this organism. 18These genetic elements were characterized in plasmidic and genomic contexts, revealing 19 strategies for tunable control of gene expression and CRISPR-mediated genome editing in this 20 strain. We then leveraged this set of genetic parts to combinatorially assemble pathways 21 enabling a wide range of drug and vitamin titers. Finally, we measured S. boulardii's residence 22 time in the gastrointestinal tracts of germ-free and antibiotic-treated mice, revealing the 23 relationships between dosing strategy and colonization level. This work establishes S. boulardii 24 as a genetically tractable commensal fungus and provides a set of strategies for engineering S. 25 boulardii to synthesize and deliver biomolecules during gut colonization. 26 27 abundant in the human gut, 21 and difficulty in producing high levels of post-translationally-42 modified proteins 22 . 43 44In addition to bacteria, a diverse fungal population also exists in the human gastrointestinal tract 45 (GIT) [23][24][25][26] . While the numerical abundance of fungal cells in the GIT is much lower than bacterial 46 cells, fungal cells are on average 100-fold larger, indicating that their biomass and role in the gut 47 may be larger than metagenomic surveys indicate 25,27 . Recent studies have shown that while 48 3 commensal fungi play important roles in the development of inflammatory bowel diseases, they 49 also provide protective heterologous immunity to pathogenic organisms by training the immune 50 system 28,29 . Furthermore, fungi are not susceptible to bacteriophage predation and are easily 51 engineered to secrete high titers of proteins that are post-translationally modified. Thus, in this 52 study, we established a pipeline to engineer the only eukaryotic probiotic that is approved by the 53 FDA: Saccharomyces boulardii 30 . 54 55 S. boulardii is a non-pathogenic yeast that was originally isolated from lychee and mangosteen in 56 1923 and has since been used to treat ulcerative colitis, diarrhea, and recurrent Clostridium 57 difficile infection 1,31 . S. boulardii is closely related to the famous budding yeast Saccharomyces 58 cerevisiae, indicating that it may be similarly amenable to engineering for the production of 59 biomolecules, including biologics requiring post-translational modifications 2,32 . Supporting this, 60 S. cerevisiae expression vectors can be transformed and propagated in S. boulardii, and 61 CRISPR/Cas9-mediated genome editing is functional in both ...

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Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention

Cited by 226 publications

References 42 publications

Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities

Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities

Clinical translation of microbe‐based therapies: Current clinical landscape and preclinical outlook

Establishing ProbioticSaccharomyces boulardiias a Model Organism for Synthesis and Delivery of Biomolecules

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