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Efficient treatment of a preclinical inflammatory bowel disease model with engineered bacteria.

ABSTRACT: We developed an orally administered, engineered, bacterium-based, RNA interference-mediated therapeutic method to significantly reduce the symptoms in the most frequently used animal model of inflammatory bowel disease. This bacterium-mediated RNA interference strategy was based on the genomically stable, non-pathogenic E. coli MDS42 strain, which was engineered to constitutively produce invasin and the listeriolysin O cytolysin. These proteins enabled the bacteria first to invade the colon epithelium and then degrade in the phagosome. This allowed the delivery of a plasmid encoding small hairpin RNA (shRNA) targeting tumor necrosis factor (TNF) into the cytoplasm of the target cells. The expression levels of TNF and other cytokines significantly decreased upon this treatment in dextran sulfate sodium (DSS)-induced colitis, and the degree of inflammation was significantly reduced. With further safety modifications this method could serve as a safe and side effect-free alternative to biologicals targeting TNF or other inflammatory mediators.

SUBMITTER: Ferenczi S

PROVIDER: S-EPMC7782194 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Efficient treatment of a preclinical inflammatory bowel disease model with engineered bacteria.

Ferenczi Szilamer S Solymosi Norbert N Horváth István I Szeőcs Natália N Grózer Zsuzsanna Z Kuti Dániel D Juhász Balázs B Winkler Zsuzsanna Z Pankotai Tibor T Sükösd Farkas F Stágel Anikó A Paholcsek Melinda M Dóra Dávid D Nagy Nándor N Kovács Krisztina J KJ Zanoni Ivan I Szallasi Zoltan Z

Molecular therapy. Methods & clinical development 20201120

We developed an orally administered, engineered, bacterium-based, RNA interference-mediated therapeutic method to significantly reduce the symptoms in the most frequently used animal model of inflammatory bowel disease. This bacterium-mediated RNA interference strategy was based on the genomically stable, non-pathogenic <i>E. coli</i> MDS42 strain, which was engineered to constitutively produce invasin and the listeriolysin O cytolysin. These proteins enabled the bacteria first to invade the col ...[more]

PMID: 33426148

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Project description:BackgroundMany preclinical studies have demonstrated the effectiveness of genetically modified probiotics (gm probiotics) in animal models of inflammatory bowel disease (IBD).ObjectiveThis systematic review was performed to investigate the role of gm probiotics in treating IBD and to clarify the involved mechanisms.MethodsPubMed, Web of Science, Cochrane Library, and Medline were searched from their inception to 18 September 2022 to identify preclinical and clinical studies exploring the efficacy of gm probiotics in IBD animal models or IBD patients. Two independent researchers extracted data from the included studies, and the data were pooled by the type of study; that is, preclinical or clinical.ResultsForty-five preclinical studies were included. In these studies, sodium dextran sulfate and trinitrobenzene sulfonic acid were used to induce colitis. Eleven probiotic species have been genetically modified to produce therapeutic substances, including IL-10, antimicrobial peptides, antioxidant enzymes, and short-chain fatty acids, with potential therapeutic properties against colitis. The results showed generally positive effects of gm probiotics in reducing disease activity and ameliorating intestinal damage in IBD models; however, the efficacy of gm probiotics compared to that of wild-type probiotics in many studies was unclear. The main mechanisms identified include modulation of the diversity and composition of the gut microbiota, production of regulatory metabolites by beneficial bacteria, reduction of the pro- to anti-inflammatory cytokine ratio in colonic tissue and plasma, modulation of oxidative stress activity in the colon, and improvement of intestinal barrier integrity. Moreover, only one clinical trial with 10 patients with Crohn's disease was included, which showed that L. lactis producing IL-10 was safe, and a decrease in disease activity was observed in these patients.ConclusionsGm probiotics have a certain efficacy in colitis models through several mechanisms. However, given the scarcity of clinical trials, it is important for researchers to pay more attention to gm probiotics that are more effective and safer than wild-type probiotics to facilitate further clinical translation.

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Efficient treatment of a preclinical inflammatory bowel disease model with engineered bacteria.

Publications

Efficient treatment of a preclinical inflammatory bowel disease model with engineered bacteria.

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