Mitigation of GI-ARS by Lactobacillus species

乳酸菌物种缓解 GI-ARS

• 批准号: 10570082
• 负责人: RADHAKRISHNA RAO
• 金额: $ 48.78万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-22 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570082
• 关键词: Actins; Animal Model; Anti-Bacterial Agents; Bacteria; Biological; Biology; Caco-2 Cells; Cancer Patient; Cells; Colon; Cyclic AMP-Dependent Protein Kinases; Cytoskeleton; Data; Diet; Dose; Down-Regulation; Effectiveness; Endotoxemia; Epidermal Growth Factor Receptor; Epithelium; Exhibits; Exposure to; FDA approved; Filtration; Functional disorder; Goals; Histone Deacetylase; Histone Deacetylation; Hour; Human; Intestinal Mucosa; Intestines; Ionizing radiation; Knockout Mice; Lactic acid; Lactobacillus; Lactobacillus casei; Lactobacillus plantarum; MAPK8 gene; Mediating; Molecular; Morbidity - disease rate; Mouse Strains; Mucous Membrane; Mus; Nuclear Accidents; Oral Administration; Organoids; Outcome Study; Paneth Cells; Pathogenesis; Peptides; Play; Predisposition; Probiotics; Protein Kinase C; Proteins; Qualifying; Radiation; Radiation Accidents; Radiation Enteritis; Radiation Injuries; Radiation Toxicity; Radiation exposure; Research; Role; SRC gene; Survival Rate; Testing; Therapeutic; Tight Junctions; Time; Tyrosine Phosphorylation; alpha-Defensins; animal rule; attenuation; cancer radiation therapy; dysbiosis; gastrointestinal; gastrointestinal epithelium; gut dysbiosis; gut microbiome; gut microbiota; insect defensin A; intestinal barrier; intestinal epithelium; irradiation; knockout gene; medical countermeasure; microbiome; microbiome alteration; microbiome analysis; microbiota; monolayer; mortality; mouse model; novel; probiotic therapy; radiation mitigation; radiation response; receptors for activated C kinase; systemic inflammatory response

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.

大规模辐射事故引起的公共辐射暴露是一个日益受到全球关注的问题。胃肠道 急性辐射综合征(GI-ARS)具有较高的发病率和死亡率。然而，FDA- 已批准的治疗GI-ARS的药物还不可用。因此，概述辐射损伤的机制 制定有针对性的医疗对策(MCM)是当务之急。肠道微生物群高度发达 对电离辐射敏感，微生物群的改变是发病的主要因素 GI-ARS。这一领域的空白是辐射导致肠道生物失调的确切机制 微生物区系及其对辐射损伤的影响还没有明确的定义。我们研究的长期目标是 确定肠道中对辐射敏感的微生物区系，并开发肠道微生物组靶向MCM以缓解 辐射损伤。我们的初步研究发现：1)干酪乳杆菌和植物乳杆菌可减轻 辐射诱导的上皮紧密连接(TJ)断裂和屏障功能障碍 机制。2)潘氏细胞α-防御素的耗竭在辐射损伤机制中起着关键作用。 诱导的微生物区系失调。3)照射后24小时饲喂干酪乳杆菌和植物乳杆菌 减轻辐射引起的α防御素耗竭、微生物区系失调、肠道屏障功能障碍、内毒素血症、 和全身炎症。这些发现形成了科学前提，并支持了中心假设 干酪乳杆菌和植物乳杆菌通过逆转肠道微生物区系的失调和 上皮屏障功能障碍，导致内毒素血症和全身炎症的减轻。我们 将通过确定1)植物乳杆菌减轻辐射诱导的上皮TJ破坏来检验这一假说 通过EGFR介导的抑制c-jun氨基末端激酶-2(JNK2)/c-Src/蛋白酪氨酸磷酸化，2)L. 酪蛋白减轻辐射诱导的肌动蛋白细胞骨架重塑和粘膜屏障功能障碍 3)干酪乳杆菌和植物乳杆菌协同缓解肠道上皮损伤 辐射诱导的肠屏障功能障碍，4)辐射下调肠道潘氏细胞α-防御素 通过HDAC3介导组蛋白去乙酰化，5)HDAC3和α-防御素下调在 6)干酪乳杆菌和植物乳杆菌及其3KDF组分对辐射诱导的肠道微生物区系失调的缓解作用 辐射诱导的HDAC3表达、α-防御素耗竭和肠道微生物区系失调，7)鉴定 酪乳杆菌、植物乳杆菌和3KDF组分缓解GI-ARS的最低有效剂量，8)测定 酪乳杆菌、植物乳杆菌和3KDF组分的有效作用的理想时间窗口，以及9)确定 干酪乳杆菌和植物乳杆菌的最有效剂量和提高存活率的理想时间窗 在致死剂量照射后。完成这一项目将建立一个重要的肠道致病关系 乳酸菌枯竭与辐射损伤。此外，这些研究将验证基于乳酸菌的 动物法则指导下的益生菌治疗GI-ARS的新型微生物群靶向MCM。