Engineered Probiotics for Detection and Treatment of Inflammatory Intestinal Diseases

Abstract

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.

Synthetic Biology Approaches in the Development of Engineered Therapeutic Microbes

“…However, the production of therapeutic molecules in microbes needs to be carefully controlled because constant production of therapeutics is not only a burden to the endogenous metabolism of microbes but can also cause side effects in the host [ 10 ]. One way to solve these problems is to use biosensors that detect specific biomarkers representing or related to disease occurrence and its progression [ 26 ]. Biomarkers are available in various forms, such as gases, ions, chemical compounds and biomolecules [ 27 ].…”

Interplay between Regulatory RNAs and Signal Transduction Systems during Bacterial Infection

“…This inhibition impacts bacterial pathogenicity in vitro and in vivo but not cell growth [ 250 ]. Because of their function to sense the host conditions, TCSs together with transcriptional regulators are central actors in the design of engineered probiotics [ 251 , 252 ]. As a proof of concept to treat bacterial infection, the probiotic E. coli Nissle has been engineered to sense tetrathionate, a molecule produced in the inflamed gut during Salmonella infection, through the TtrS/R TCS.…”

Using Probiotics to Mute Salmonella enteric Serovar Typhimurium: An Opinion

“…Besides the traditional application of wild-type probiotics, GM probiotics are also studied. Although there are safety issues, GM probiotics attracted much interest due to their extra advantages and strengthened effects (Barra et al, 2020). Two different approaches are used to construct advanced GM probiotics: mutation and overexpression.…”

“…These toolboxes, including genetic circuits, different delivery systems, and a large number of genome-editing tools, successfully accelerated the development of advanced GM probiotics (Bober et al, 2018;Ozdemir et al, 2018). Live therapeutic GM probiotics can be constructed to function potentially as biosensors, regulators, delivery devices, and others for fighting against ST (Pedrolli et al, 2019;Barra et al, 2020). As applied for sensing and killing Pseudomonas aeruginosa and reducing vancomycinresistant Enterococcus by GM probiotic E. coli Nissle 1917, similar approaches might be also promising for ST prevention (Hwang et al, 2017;Geldart et al, 2018).…”