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

酒精相关疾病和紊乱(AAD)占全球健康问题的5%以上。AAD 在退伍军人中更常见，军队中超过30%的年轻男性是酗酒者，是 就像他们的文职同行一样。酒精滥用在暴露于战斗相关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症状反馈合二为一 另一种是阻碍从这两种疾病中恢复的。因此，治疗合并创伤后应激障碍的AAD患者 这很复杂，需要对酒精和压力之间的相互作用有更深的理解。行为 干预对中到重度饮酒者无效，其对创伤后应激障碍的益处也不一致。这个 与AAD和PTSD相关的常见情况是内毒素血症和全身炎症。临床和 实验证据表明，肠道生物失调(有益物种枯竭，致病菌增加， 和多样性降低)是发展内毒素血症和全身炎症所必需的。因此， 生物失调是治疗AAD和PTSD的重要靶点。这一领域的关键障碍是 酒精和压力导致的生物失调的机制还不是很清楚。没有治疗的方法 治疗AAD或AAD合并创伤后应激障碍有效的明确证据。我们的长期目标是 描述AAD-应激共病的病理生理学机制，并通过靶向开发新的治疗策略 肠道微生物区系。我们的初步研究发现：1)慢性束缚应激(CRS)和 皮质酮加重乙醇(EtoH)诱导的肠屏障功能障碍、内毒素血症、全身炎症、 小鼠的肝脏损伤和神经炎症。2)皮质酮增强乙醇诱导的生态失调 Paneth细胞a-防御素基因的缺失。3)删除肠糖皮质激素受体(GR)可防止 皮质酮和乙醇诱导的肠道通透性和全身反应。4)肠道NR3C1基因敲除 (编码GR)防止皮质酮和乙醇诱导的防御素mRNA枯竭和生物失调。5) 皮质酮和乙醇减少肠道T细胞受体4(TCF4)的mRNA，这是必需的转录因子 用于生产a-防御素。这些发现构成了科学的前提和支持 潘氏细胞GR驱动压力和酒精相关的生物失调的中心假设是肠道 通透性，以及通过抑制α-防御素产生的全身反应。我们的总体目标是定义 Paneth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 确定α-防御素在治疗慢性应激并发的AAD中的治疗潜力。这一目标将 通过确定1)应激和酒精诱导的TCF4下降需要Paneth细胞GR- 调节、α-防御素耗竭和微生物区系失调。2)TCF4下调介导GR在应激中的作用 以及酒精引起的α-防御素耗竭和生物失调。3)GR介导的TCF4在Paneth细胞中的调节作用 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调节的微生物区系 组合物增强酒精诱导的肠道通透性和全身反应。5)HD5和HD6衰减 应激和酒精引起的肠道生态失调和全身反应。6)应激和酒精所致的生物失调 HD5和HD6可逆转多器官损伤。拟议的研究将利用新的体外和体内研究 确定糖皮质激素受体、α-防御素和生物失调作为治疗AAD和PTSD靶点的模型。

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.