Development of targeted microbiome therapeutics and dietary interventions for potent intestinal barrier promotion to minimize GI-ARS

摘要

ABSTRACT Exposure to total body irradiation (TBI) produced by nuclear accidents, premeditated nuclear, or terrorist attack causes gastrointestinal (GI) acute radiation syndrome (GI-ARS), a state of severe intestinal mucosal barrier damage, loss of tissue integrity, and translocation of the luminal content. Measures to counteract the effect of such detrimental exposure are critical for the survival and well-being of those impacted. The gastrointestinal microbiome (bacteria and metabolites) plays a crucial role in the maintenance of tissue homeostasis. Multiple studies have implicated specific microbiome clades as responsible for promoting intestinal barrier function and consequent resistance against infections and inflammatory conditions. The central hypothesis of this project is that targeted microbiome supplementation with specific subsets of intestinal bacteria or probiotics engineered to produce barrier function-promoting metabolites and their enhancement via precise dietary intervention actively improves barrier homeostasis in the intestinal epithelium, creating an environment that reduces GI-ARS. In Aim 1, we will develop novel live biotherapeutic products that minimize GI-ARS by promoting barrier function through the potent induction of functional epithelial surface P-glycoprotein expression. Additionally, we will uncover the broader distribution of this receptor system within clinical, metagenomic samples. In Aim 2, we will develop a novel genetically engineered strain of the probiotic E. coli Nissle 1917 that minimizes GI-ARS by promoting barrier function through the potent constitutive production of succinate. Lastly, in Aim 3 we will evaluate the effect of prebiotics-enriched diets in promoting GI-ARS limitation by barrier-enhancing intestinal bacteria. Cumulatively, this work will generate novel microbiome therapeutic agents that, by specifically targeting intestinal barrier function, minimize GI-ARS and increase survival after total body irradiation.