Second-generation Probiotics Producing IL-22 Increase Survival of Mice After Total Body Irradiation

Abstract

Background/Aim: Intestinal damage induced by total body irradiation (TBI) reduces leucine-rich repeatcontaining G-protein-coupled receptor 5 (Lgr5)-expressing stem cells, goblet, and Paneth cells, breaching the epithelial lining, and facilitating bacterial translocation, sepsis, and death. Materials and Methods: Survival was measured after TBI in animals that received wild-type or recombinant bacteria producing interleukin-22 (IL-22). Changes in survival due to microbially delivered IL-22 were measured. Lactobacillus reuteri producing IL-22, or Escherichia coli-IL-22 were compared to determine which delivery system is better. Results: C57BL/6 mice receiving IL-22 probiotics at 24 h after 9.25 Gy TBI, demonstrated green fluorescent protein-positive bacteria in the intestine, doubled the number of Lgr5+ intestinal stem cells, and increased 30-day survival. Bacteria were localized to the jejunum, ileum, and colon. Conclusion: Second-generation probiotics appear to be valuable for mitigation of TBI, and radiation protection during therapeutic total abdominal irradiation.

Secretion of Recombinant Interleukin-22 by Engineered Lactobacillus reuteri Reduces Fatty Liver Disease in a Mouse Model of Diet-Induced Obesity

“…In this study, we demonstrated the proof of concept that engineered L. reuteri can secrete biologically active mIL-22, which reduced markers related to liver disease in a model of diet-induced obesity. We believe that our study, combined with recent studies demonstrating the efficacy of recombinant L. reuteri in animal disease models of total body irradiation and alcohol-induced liver disease (11,18), reveals the potential to develop L. reuteri as a next-generation probiotic to treat disease in the clinic.…”

“…Alternative approaches may therefore be more efficient. For example, we recently demonstrated that activation of native prophages in L. reuteri can lyse the cell and subsequently release a recombinant mature protein that has accumulated inside the cell; this approach has proven successful in preclinical disease models (11,18). Using bacterial lysis to release mature proteins also has the advantage that lysis can be optimized to contribute to containment.…”

Acute Radiation Syndrome and the Microbiome: Impact and Review

“…Second-generation probiotics are also being developed to take advantage of the natural properties of these bacteria, using microbial-mediated delivery of drugs to target the gut. Researchers have engineered probiotics that produce IL-22 ( Zhang et al, 2020 ), a cytokine with anti-inflammatory properties known to stabilize both intestinal Paneth cells and Lgr5+ intestinal stem cells ( Zha et al, 2019 ). In this study, C57BL/6 mice were exposed to 9.25-Gy TBI and then treated with Lactobacillus reuteri –producing IL-22 strains postirradiation via oral gavage.…”

“…A 30% improvement in survival was noted, as compared to animals dosed only with the IL-22 protein. Time of administration of the bacteria was also examined, and a survival advantage could be seen even when dosed at 72-h postirradiation, with the highest benefit seen at 24 h (85%) and 48 h (70%) postirradiation administration ( Zhang et al, 2020 ).…”

Space Radiation Protection Countermeasures in Microgravity and Planetary Exploration

“…Some forms of combined injury may elevate or exacerbate the same cellular death pathways involved in irradiation cell killing and necessitate modifying the dose of a radioprotector to be administered. Space radiation protectors and mitigators will likely also include the use of novel orally administered second-generation probiotics and other nutraceuticals [ 124 ].…”