Mitigation of GI-ARS by Lactobacillus species

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Public radiation exposure due to large-scale radiation incidents is a rising global concern. Gastrointestinal Acute Radiation Syndrome (GI-ARS) is associated with high morbidity and mortality. However, FDA- approved therapeutics for GI-ARS are unavailable. Therefore, outlining the mechanisms of radiation injury to develop targeted medical countermeasures (MCMs) is a high priority. The gut microbiome is highly susceptible to ionizing radiation, and an altered microbiome is a major contributing factor in the pathogenesis of GI-ARS. The gap in this field is that the precise mechanisms by which radiation causes dysbiosis of gut microbiota and its impact on radiation injury are poorly defined. The long-term goal of our research is to identify the radiation-sensitive microbiota in the gut and develop gut microbiome-targeted MCMs to mitigate radiation injury. Our preliminary studies have identified that: 1) Lactobacillus casei and plantarum mitigate radiation-induced epithelial tight junction (TJ) disruption and barrier dysfunction by distinct cellular mechanisms. 2) Depletion of Paneth cell α-defensins plays a pivotal role in the mechanism of radiation- induced microbiota dysbiosis. 3) When administered in diet 24 hours after irradiation, L. casei and L. plantarum mitigate radiation-induced α-defensin depletion, microbiota dysbiosis, gut barrier dysfunction, endotoxemia, and systemic inflammation. These findings form the scientific premise and support the central hypothesis that “L. casei and L. plantarum synergistically mitigate GI-ARS by reversing dysbiosis of gut microbiota and epithelial barrier dysfunction, leading to attenuation of endotoxemia and systemic inflammation.” We will test this hypothesis by determining that 1) L. plantarum mitigates radiation-induced epithelial TJ disruption by EGFR-mediated inhibition of c-Jun N-terminal kinase-2 (JNK2)/c-Src/protein tyrosine phosphorylation, 2) L. casei mitigates radiation-induced remodeling of the actin cytoskeleton and mucosal barrier dysfunction in the intestinal epithelium by a PKC-dependent mechanism, 3) L. casei and L. plantarum synergistically mitigate radiation-induced intestinal barrier dysfunction, 4) Radiation downregulates intestinal Paneth cell α-defensins by HDAC3-mediated histone deacetylation, 5) HDAC3 and α-defensin downregulation play crucial roles in radiation-induced dysbiosis of gut microbiota, 6) L. casei and L. plantarum, and their 3KDF fractions mitigate radiation-induced HDAC3 expression, α-defensin depletion, and gut microbiota dysbiosis, 7) Identifying the lowest effective doses of L. casei, L. plantarum, and 3KDF fractions for mitigating GI-ARS, 8) Determining the ideal time window for the effectiveness of L. casei, L. plantarum, and 3KDF fractions, and 9) Determining the most effective doses of L. casei and L. plantarum, and the ideal time window for increasing the survival rate after lethal dose irradiation. Completing this project will establish a significant causative relation of intestinal Lactobacillus depletion with radiation injury. Furthermore, these studies will validate Lactobacillus-based probiotic therapy as a novel microbiome-targeted MCM for GI-ARS under the Animal-Rule guidance.