Impact of Stress on Alcohol-Associated Gut Injury and Systemic Response

压力对酒精相关肠道损伤和全身反应的影响

• 批准号: 10485363
• 负责人: RADHAKRISHNA RAO
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10485363
• 关键词: Alcohol consumption; Alcoholic beverage heavy drinker; Alcohols; Anti-Bacterial Agents; Attenuated; Behavior Therapy; Brain; Cell secretion; Cellular biology; Chronic; Chronic stress; Clinical; Corticosterone; Defensins; Disease; Down-Regulation; Endotoxemia; Ethanol; Exposure to; Feedback; Functional disorder; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Human; In Vitro; Injury; Intestinal permeability; Intestines; Knock-out; Knockout Mice; Link; Liver; Mediating; Messenger RNA; Microinjections; Military Personnel; Molecular; Mucositis; Mus; NR3C1 gene; Organ; Outcome; Outcome Study; Paneth Cells; Patients; Peptides; Post-Traumatic Stress Disorders; Preventive; Production; Proteomics; Qualifying; Recovery; Regulation; Reporter; Research; Role; Stress; Symptoms; T-Cell Receptor; Therapeutic; Veterans; alcohol misuse; alpha-Defensins; clinically significant; combat; comorbidity; dysbiosis; experience; fecal transplantation; global health; gut dysbiosis; gut microbiota; host microbiome; in vivo Model; insect defensin A; intestinal epithelium; knockout gene; liver injury; microbiota; military veteran; multiorgan injury; neuroinflammation; novel; novel therapeutic intervention; pathobiont; prevent; receptor; response; restraint stress; stress disorder; systemic inflammatory response; therapeutic target; tissue injury; transcription factor; traumatic stress; treatment strategy; young man

Alcohol-associated diseases and disorders (AAD) account for over 5% of global health problems. AAD is more common among veterans, and more than 30% of young men in the military are heavy drinkers, twice as much as their civilian counterparts. Alcohol misuse is high in veterans exposed to combat-related traumatic stress or experiencing post-traumatic stress disorder (PTSD). AAD and PTSD symptoms feedback into one another and impede the recovery from both disorders. Therefore, treating AAD patients comorbid with PTSD is complicated and requires a deeper understanding of the cross-talk between alcohol and stress. Behavioral intervention is not efficacious in moderate to heavy alcohol drinkers, and its benefit in PTSD is inconsistent. The common conditions associated with AAD and PTSD are endotoxemia and systemic inflammation. Clinical and experimental evidence indicates that intestinal dysbiosis (depleted beneficial species, increased pathobionts, and decreased diversity) is necessary for developing endotoxemia and systemic inflammation. Therefore, dysbiosis is a crucial therapeutic target for treating AAD and PTSD. The critical barrier in this field is that the mechanisms involved in alcohol and stress-induced dysbiosis are poorly defined. There is no treatment with clear evidence of efficacy available for treating AAD or AAD comorbid with PTSD. Our long-term goal is to describe the pathophysiology of AAD-stress comorbidity and develop novel therapeutic strategies by targeting the gut microbiota. Our preliminary studies have identified that: 1) chronic restraint stress (CRS) and corticosterone exacerbate ethanol (EtOH)-induced gut barrier dysfunction, endotoxemia, systemic inflammation, liver damage, and neuroinflammation in mice. 2) Corticosterone reinforces EtOH-induced dysbiosis and depletion of Paneth cell a-defensin mRNA. 3) Deleting intestinal glucocorticoid receptor (GR) prevents corticosterone and EtOH-induced gut permeability and systemic response. 4) Knockout of intestinal NR3C1 (encoding GR) prevents corticosterone and EtOH-induced defensin mRNA depletion and dysbiosis. 5) Corticosterone and EtOH reduce intestinal mRNA for T-cell receptor 4 (TCF4), the transcription factor required for a-defensin production. These findings form the scientific premise and support the central hypothesis that the Paneth cell GR drives stress and alcohol-associated dysbiosis, gut permeability, and systemic responses by suppressing a-defensin production. Our overall objective is to define the role of Paneth cell GR and the downstream mechanism in stress and alcohol-associated organ damage and identify the therapeutic potential of a-defensins in treating AAD comorbid with chronic stress. This objective will be achieved by determining that 1) Paneth cell GR is required for stress and alcohol-induced TCF4 down- regulation, a-defensin depletion, and microbiota dysbiosis. 2) TCF4 down-regulation mediates GR's role in stress and alcohol-induced a-defensin depletion and dysbiosis. 3) GR-mediated TCF4 regulation in Paneth cells plays a role in stress and alcohol-induced gut permeability and systemic response. 4) GR-regulated microbiota composition reinforces alcohol-induced gut permeability and systemic response. 5) HD5 and HD6 attenuate stress and alcohol-induced intestinal dysbiosis and systemic response. 6) Stress and alcohol-induced dysbiosis and multi-organ injury is reversed by HD5 and HD6. The proposed research will utilize novel in vitro and in vivo models to identify GR, a-defensins, and dysbiosis as therapeutic targets for AAD and PTSD.

酒精相关疾病和失调 (AAD) 占全球健康问题的 5% 以上。亚德 这种情况在退伍军人中更为常见，超过 30% 的军队年轻人酗酒，是军人的两倍 就像他们的民用同行一样。遭受战斗相关创伤的退伍军人滥用酒精的比例很高 压力或经历创伤后应激障碍 (PTSD)。 AAD 和 PTSD 症状反馈合二为一 另一个并阻碍这两种疾病的康复。因此，治疗合并 PTSD 的 AAD 患者是 复杂，需要更深入地了解酒精和压力之间的相互作用。行为方面 干预对于中度至重度饮酒者无效，并且其对 PTSD 的益处也不一致。这 与 AAD 和 PTSD 相关的常见病症是内毒素血症和全身炎症。临床和 实验证据表明肠道菌群失调（有益物种减少、致病生物增加、 和多样性降低）对于发生内毒素血症和全身炎症是必要的。所以， 生态失调是治疗 AAD 和 PTSD 的重要治疗靶点。该领域的关键障碍是 酒精和压力引起的生态失调的机制尚不清楚。没有治疗方法 治疗 AAD 或 AAD 合并 PTSD 的疗效有明确的证据。我们的长期目标是 描述 AAD 应激合并症的病理生理学并通过靶向开发新的治疗策略 肠道微生物群。我们的初步研究表明：1）慢性束缚压力（CRS）和 皮质酮会加剧乙醇 (EtOH) 引起的肠道屏障功能障碍、内毒素血症、全身炎症、 小鼠的肝脏损伤和神经炎症。 2) 皮质酮会加剧乙醇引起的生态失调 潘氏细胞 a-防御素 mRNA 的耗尽。 3) 删除肠道糖皮质激素受体 (GR) 可预防 皮质酮和乙醇诱导的肠道通透性和全身反应。 4) 肠道NR3C1的敲除 （编码 GR）可防止皮质酮和乙醇诱导的防御素 mRNA 耗竭和生态失调。 5） 皮质酮和乙醇减少肠道 T 细胞受体 4 (TCF4) 的 mRNA，这是所需的转录因子 用于生产α-防御素。这些发现构成了科学前提和支持 中心假设是潘氏细胞GR驱动压力和酒精相关的生态失调，肠道 通过抑制α-防御素的产生来调节渗透性和全身反应。我们的总体目标是定义 潘氏细胞 GR 的作用及其下游机制在压力和酒精相关器官损伤中的作用 确定α-防御素在治疗伴有慢性应激的 AAD 中的治疗潜力。这一目标将 通过确定 1) 压力和酒精诱导的 TCF4 下调需要潘氏细胞 GR 来实现 调节、α-防御素耗竭和微生物群失调。 2）TCF4下调介导GR在应激中的作用 以及酒精引起的α-防御素耗竭和生态失调。 3）GR介导的TCF4在潘氏细胞中的调节作用 在压力和酒精引起的肠道通透性和全身反应中发挥作用。 4) GR调节的微生物群 成分增强酒精诱导的肠道通透性和全身反应。 5）HD5和HD6衰减 压力和酒精引起的肠道菌群失调和全身反应。 6）压力和酒精引起的生态失调 HD5和HD6可逆转多器官损伤。拟议的研究将利用新颖的体外和体内 确定 GR、α-防御素和生态失调作为 AAD 和 PTSD 治疗靶点的模型。