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（AAD）占全球健康问题的5%以上。AAD 在退伍军人中更为常见，军队中超过30%的年轻人酗酒，是退伍军人的两倍。 就像他们的平民同行一样。酒精滥用在暴露于与战斗有关的创伤的退伍军人中很高 压力或经历创伤后应激障碍（PTSD）。AAD和PTSD症状反馈为一体 另一个，并阻碍从这两种疾病的恢复。因此，治疗与PTSD共病的AAD患者， 这很复杂，需要更深入地了解酒精和压力之间的相互作用。行为 干预对中度至重度饮酒者无效，其对PTSD的益处也不一致。的 与AAD和PTSD相关的常见病症是内毒素血症和全身性炎症。临床和 实验证据表明肠道生态失调（耗尽有益物种，增加致病菌， 和多样性下降）是发生内毒素血症和全身炎症所必需的。因此，我们认为， 生态失调是治疗AAD和PTSD的关键治疗靶点。这一领域的关键障碍是， 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， 有明确的证据表明AAD或AAD合并PTSD治疗有效。我们的长期目标是 描述AAD-应激并发症的病理生理学，并通过靶向治疗开发新的治疗策略。 肠道菌群我们的初步研究已经确定：1）慢性束缚应激（CRS）， 皮质酮加重乙醇（EtOH）诱导肠屏障功能障碍、内毒素血症、全身炎症， 肝脏损伤和神经炎症。2)皮质酮加强EtOH诱导的生态失调， 潘氏细胞α-防御素mRNA的耗竭。3)删除肠道糖皮质激素受体（GR）， 皮质酮和乙醇诱导的肠道通透性和全身反应。4)肠NR 3C 1基因敲除 （编码GR）防止皮质酮和EtOH诱导的防御素mRNA消耗和生态失调。第五章） 皮质酮和乙醇减少T细胞受体4（TCF 4）的肠道mRNA， 用于α-防御素的生产。这些发现构成了科学前提和支持 潘氏细胞GR驱动压力和酒精相关的生态失调的中心假设， 渗透性和通过抑制α-防御素产生的全身反应。我们的总体目标是定义 潘氏细胞GR及其下游机制在应激和酒精相关器官损伤中的作用， 鉴定α-防御素在治疗与慢性应激共病的AAD中的治疗潜力。这一目标将 通过确定1）潘氏细胞GR是压力和酒精诱导的TCF 4下降所必需的， 调节、α-防御素耗竭和微生物群生态失调。2)TCF 4下调介导GR在应激中的作用 以及酒精诱导的α-防御素耗竭和生态失调。3)GR介导的Paneth细胞中TCF 4的调节作用 在应激和酒精诱导的肠道通透性和全身反应中的作用。4)GR调节微生物群 组合物增强了酒精诱导的肠道渗透性和全身反应。5)HD 5和HD 6减弱 应激和酒精诱导肠道生态失调和全身反应。6)压力和酒精引起的生态失调 HD 5和HD 6可逆转多器官损伤。拟议的研究将利用新的体外和体内 模型来鉴定GR、α-防御素和生态失调作为AAD和PTSD的治疗靶标。