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Principal Investigator: RADHAKRISHNA RAO
Organization: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
Fiscal Year: 2024
Award: $497,663
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <ASVSRC1><Actins><Acute Radiation Syndrome><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Animal Model><Animal Models and Related Studies><Anti-Bacterial Agents><Bacteria><Biological><Biology><C-jun Amino-Terminal Kinase><C-jun Kinase-1><C-jun N-Terminal Kinase 1><CaCo2><Caco-2 Cells><Calcium Phospholipid-Dependent Protein Kinase><Calcium-Activated Phospholipid-Dependent Kinase><Cancer Patient><Cancer Radiotherapy><Cell Body><Cells><Cellular Matrix><Colon><Cyclic AMP-Dependent Protein Kinases><Cytoskeletal System><Cytoskeleton><Data><Diet><Dose><Down-Regulation><Dysfunction><EGF Receptor><EGFR><ERBB Protein><Effectiveness><Endotoxemia><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epithelium><Exhibits><Exposure to><FDA approved><Filtration><Filtration Fractionation><Functional disorder><GI microbiome><GI microbiota><Gastrointestinal microbiota><Goals><Gut Epithelium><HDAC><HDAC Proteins><HER1><Histone Deacetylase><Histone Deacetylation><Hour><Human><Intestinal><Intestinal Mucosa><Intestines><Ionizing Electromagnetic Radiation><Ionizing radiation><JN Kinase><JNK><JNK Mitogen-Activated Protein Kinases><JNK1><JNK1 Kinase><JNK1 protein><JNK1A2><JNK21B1/2><KO mice><Knock-out Mice><Knockout Mice><L casei><L plantarum><L. casei><L. plantarum><Lactic acid><Lactobacillus><Lactobacillus casei><Lactobacillus plantarum><MAP Kinase 8><MAP Kinase 8 Gene><MAPK8><MAPK8 Mitogen-Activated Protein Kinase><MAPK8 gene><Mediating><Mice><Mice Mammals><Mitogen-Activated Protein Kinase 8><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Mouse Strains><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Nuclear Accidents><Null Mouse><Occluding Junctions><Oral Administration><Oral Drug Administration><Organoids><Outcome Study><PKA><PRKM8><Paneth Cells><Pathogenesis><Peptides><Phospholipid-Sensitive Calcium-Dependent Protein Kinase><Physiopathology><Play><Predisposition><Probiotics><Protein Kinase A><Protein Kinase C><Proteins><Qualifying><Radiation><Radiation Accidents><Radiation Enteritis><Radiation Injuries><Radiation Toxicity><Radiation exposure><Radiation-Ionizing Total><Radiotoxicity><Research><Role><SAP Kinase-1><SAPK/JNK><SAPK1 Mitogen-Activated Protein Kinase><SAPK1/JNK><SRC Family Gene><SRC gene><Stress-Activated Protein Kinase JNK1><Stress-Activated Protein Kinase gamma><Survival Rate><Susceptibility><TGF-alpha Receptor><Testing><Therapeutic><Tight Junctions><Time><Transforming Growth Factor alpha Receptor><Tyrosine Phosphorylation><Urogastrone Receptor><Zonula Occludens><alpha-Defensins><alter microbiome><analyze microbiome><animal rule><anti-bacterial><attenuation><biologic><bowel><c src><c-erbB-1><c-erbB-1 Protein><c-jun N-Terminal Kinase><c-src Genes><c-src Proto-Oncogenes><cAMP-Dependent Protein Kinases><cancer radiation therapy><defensin A><diets><digestive tract microbiome><dysbacteriosis><dysbiosis><dysbiotic><enteric microbial community><enteric microbiome><enteric microbiota><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><gastrointestinal><gastrointestinal epithelium><gastrointestinal microbial flora><gastrointestinal microbiome><gut commensal><gut community><gut dysbiosis><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><insect defensin A><intestinal barrier><intestinal biome><intestinal epithelium><intestinal flora><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal mucosal barrier><intestinal tract microflora><intracellular skeleton><intraoral drug delivery><ionizing output><irradiation><irradiation injury><irradiation response><jun-NH2-Terminal Kinase><knockout gene><medical countermeasure><microbial consortia><microbial flora><microbial imbalance><microbiome><microbiome adaptation><microbiome alteration><microbiome analysis><microbiome perturbation><microbiota><microbiota composition><microflora><model of animal><monolayer><mortality><mouse model><multispecies consortia><murine model><novel><nuclear disaster><nuclear event><nuclear incident><pathophysiology><probiotic therapeutic><probiotic therapy><probiotic treatment><protein kinase C receptor><proto-oncogene protein c-erbB-1><radiation disaster><radiation event><radiation incident><radiation mitigation><radiation poisoning><radiation response><radiological accident><radiological disaster><radiological event><radiological incident><radiological mitigation><radiomitigation><receptors for activated C kinase><response to radiation><social role><stress-activated protein kinase 1><systemic inflammation><systemic inflammatory response><v-SRC Avian Sarcoma (Schmidt-Ruppin A-2) Viral Oncogene Homolog><α-Defensins>