Construction of a sustainable 3-hydroxybutyrate-producing probiotic Escherichia coli for treatment of colitis

Yan, Xu; Liu, Xin-Yi; Zhang, Dian; Zhang, Yudian; Li, Zihua; Liu, Xu; Wu, Fuqing; Chen, Guo‐Qiang

doi:10.1038/s41423-021-00760-2

Cited by 83 publications

(40 citation statements)

References 75 publications

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“…The probiotic bacterium Escherichia coli Nissle 1917 (EcN) has recently been engineered for use as a therapeutic microorganism to sense and respond to disease biomarkers ( Daeffler et al, 2017 ; Riglar et al, 2017 ; McKay et al, 2018 ; Lynch et al, 2022 ) and treat diseases in the gastrointestinal tract, such as metabolic disease ( Isabella et al, 2017 ; Isabella et al, 2018 ) and inflammatory bowel disease ( Praveschotinunt et al, 2019 ; Yan et al, 2021 ). The EcN strain has been used in a multitude of clinical trials ( Sonnenborn and Schulze 2009 ; Ou et al, 2016 ; Sonnenborn 2016 ) and has the generally recognized as safe designation from the U.S. FDA, making it a suitable choice to use as an engineered living diagnostic or therapeutic bacterium.…”

Section: Introductionmentioning

confidence: 99%

Surveying the Genetic Design Space for Transcription Factor-Based Metabolite Biosensors: Synthetic Gamma-Aminobutyric Acid and Propionate Biosensors in E. coli Nissle 1917

Lebovich

Andrews

2022

Front. Bioeng. Biotechnol.

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Engineered probiotic bacteria have been proposed as a next-generation strategy for noninvasively detecting biomarkers in the gastrointestinal tract and interrogating the gut-brain axis. A major challenge impeding the implementation of this strategy has been the difficulty to engineer the necessary whole-cell biosensors. Creation of transcription factor-based biosensors in a clinically-relevant strain often requires significant tuning of the genetic parts and gene expression to achieve the dynamic range and sensitivity required. Here, we propose an approach to efficiently engineer transcription-factor based metabolite biosensors that uses a design prototyping construct to quickly assay the gene expression design space and identify an optimal genetic design. We demonstrate this approach using the probiotic bacterium Escherichia coli Nissle 1917 (EcN) and two neuroactive gut metabolites: the neurotransmitter gamma-aminobutyric acid (GABA) and the short-chain fatty acid propionate. The EcN propionate sensor, utilizing the PrpR transcriptional activator from E. coli, has a large 59-fold dynamic range and >500-fold increased sensitivity that matches biologically-relevant concentrations. Our EcN GABA biosensor uses the GabR transcriptional repressor from Bacillus subtilis and a synthetic GabR-regulated promoter created in this study. This work reports the first known synthetic microbial whole-cell biosensor for GABA, which has an observed 138-fold activation in EcN at biologically-relevant concentrations. Using this rapid design prototyping approach, we engineer highly functional biosensors for specified in vivo metabolite concentrations that achieve a large dynamic range and high output promoter activity upon activation. This strategy may be broadly useful for accelerating the engineering of metabolite biosensors for living diagnostics and therapeutics.

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Section: Introductionmentioning

confidence: 99%

Surveying the Genetic Design Space for Transcription Factor-Based Metabolite Biosensors: Synthetic Gamma-Aminobutyric Acid and Propionate Biosensors in E. coli Nissle 1917

Lebovich

Andrews

2022

Front. Bioeng. Biotechnol.

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“…Researchers engineered ECN to express interleukin-10 (IL-10), ketone body (R)-3-hydroxybutyrate (3HB) and Schistosoma immunomodulatory protein Sj16 and other substances. These substances can protect the intestinal mucosa by promoting the growth of probiotics, inhibiting the growth of harmful bacteria, improving the intestinal microenvironment, and downregulating inflammatory response-related cells or proteins, so as to achieve the purpose of treating and relieving the symptoms of intestinal inflammation [ 12 , 19 , 28 ]. However, these studies have only made progress in mouse models.…”

Section: Research and Application Of Engineered Probioticsmentioning

confidence: 99%

Engineered probiotics

Lyu

Liu

et al. 2022

Microb Cell Fact

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Engineered probiotics are a kind of new microorganisms produced by modifying original probiotics through gene editing. With the continuous development of tools and technology progresses, engineering renovation of probiotics are becoming more diverse and more feasible. In the past few years there have been some advances in the development of engineered probiotics that will benefit humankind. This review briefly introduces the theoretical basis of gene editing technology and focuses on some recent engineered probiotics researches, including inflammatory bowel disease, bacterial infection, tumor and metabolic diseases. It is hoped that it can provide help for the further development of genetically modified microorganisms, stimulate the potential of engineered probiotics to treat intractable diseases, and provide new ideas for the diagnosis of some diseases or some industrial production.

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“…Recently, some probiotics, such as Bacillus subtilis and lactobacillus , have been engineered to produce PHA of high production yield ( Singh et al, 2009 ; Monilola and Makinde, 2020 ). Interestingly, Yan et al showed proven success in colitis treatment by engineering the synthesis pathway of 3HB, the natural unit of PHB, in probiotic Escherichia coli Nissle 1917 ( Yan et al, 2021 ). It is thus possible to construct different PHA synthetic pathways in other bacterial hosts of interest, especially in probiotics used for in vivo therapeutic, making PHA granules as versatile building blocks for various therapeutic applications in the coming future.…”

Section: Discussionmentioning

confidence: 99%

A Polyhydroxyalkanoates-Based Carrier Platform of Bioactive Substances for Therapeutic Applications

Zhang

Liu

Hao

et al. 2022

Front. Bioeng. Biotechnol.

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Bioactive substances (BAS), such as small molecule drugs, proteins, RNA, cells, etc., play a vital role in many therapeutic applications, especially in tissue repair and regeneration. However, the therapeutic effect is still a challenge due to the uncontrollable release and instable physico-chemical properties of bioactive components. To address this, many biodegradable carrier systems of micro-nano structures have been rapidly developed based on different biocompatible polymers including polyhydroxyalkanoates (PHA), the microbial synthesized polyesters, to provide load protection and controlled-release of BAS. We herein highlight the developments of PHA-based carrier systems in recent therapeutic studies, and give an overview of its prospective applications in various disease treatments. Specifically, the biosynthesis and material properties of diverse PHA polymers, designs and fabrication of micro- and nano-structure PHA particles, as well as therapeutic studies based on PHA particles, are summarized to give a comprehensive landscape of PHA-based BAS carriers and applications thereof. Moreover, recent efforts focusing on novel-type BAS nano-carriers, the functionalized self-assembled PHA granules in vivo, was discussed in this review, proposing the underlying innovations of designs and fabrications of PHA-based BAS carriers powered by synthetic biology. This review outlines a promising and applicable BAS carrier platform of novelty based on PHA particles for different medical uses.

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Construction of a sustainable 3-hydroxybutyrate-producing probiotic Escherichia coli for treatment of colitis

Cited by 83 publications

References 75 publications

Surveying the Genetic Design Space for Transcription Factor-Based Metabolite Biosensors: Synthetic Gamma-Aminobutyric Acid and Propionate Biosensors in E. coli Nissle 1917

Surveying the Genetic Design Space for Transcription Factor-Based Metabolite Biosensors: Synthetic Gamma-Aminobutyric Acid and Propionate Biosensors in E. coli Nissle 1917

Engineered probiotics

A Polyhydroxyalkanoates-Based Carrier Platform of Bioactive Substances for Therapeutic Applications

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