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，军队中有30％以上的年轻人是饮酒者，是两倍的 和他们的平民一样。滥用酒精的退伍军人很高，暴露于战斗有关的创伤 压力或经历创伤后应激障碍（PTSD）。 AAD和PTSD症状反馈成一个 另一个并阻碍了这两种疾病的恢复。因此，治疗AAD患者与PTSD合并 复杂，需要更深入地了解酒精与压力之间的串扰。行为 干预措施在中度至重酒精饮用者中没有有效，其在PTSD中的好处是不一致的。这 与AAD和PTSD相关的常见疾病是内毒素血症和全身性炎症。临床和 实验证据表明，肠道营养不良（耗尽的有益物种，病原体增加， 多样性下降）对于发展内毒素血症和全身性炎症是必要的。所以， 营养不良是治疗AAD和PTSD的关键治疗靶点。该领域的关键障碍是 涉及酒精和压力引起的营养不良的机制的定义很差。没有治疗 可用于与PTSD处理AAD或AAD合并症的明确证据。我们的长期目标是 描述AAD应力合并症的病理生理学，并通过靶向发展新型的治疗策略 肠道菌群。我们的初步研究已经确定：1）慢性约束压力（CRS）和 皮质酮加剧乙醇（ETOH）诱导的肠道屏障功能障碍，内毒素血症，全身性炎症， 肝损伤和小鼠的神经炎症。 2）皮质酮增强EtOH诱导的营养不良和 Paneth细胞A-防御素mRNA的耗竭。 3）删除肠道糖皮质激素受体（GR）可防止 皮质酮和ETOH诱导的肠道渗透性和全身反应。 4）肠NR3C1的敲除 （编码GR）防止皮质酮和ETOH诱导的防御蛋白mRNA耗竭和营养不良。 5） 皮质酮和ETOH降低了T细胞受体4（TCF4）的肠道mRNA，所需的转录因子 用于A-Defensin的生产。这些发现构成了科学前提和支持 中心假设，即泛元细胞GR驱动压力和酒精相关的营养不良，肠道 渗透性和全身反应通过抑制A-防御素的产生。我们的总体目标是定义 Paneth Cell GR和下游机制在压力和酒精相关器官损伤中的作用以及 鉴定A-防御素在治疗慢性应激的合并症中的治疗潜力。这个目标将 可以通过确定1）应力和酒精诱导的TCF4下降所必需的paneth Cell GR。 调节，A-防御素的耗竭和微生物群营养不良。 2）TCF4下调介导GR在压力中的作用 和酒精诱导的A-防御素的耗竭和营养不良。 3）Paneth细胞中GR介导的TCF4调节 在压力和酒精引起的肠道渗透性和全身反应中的作用。 4）GR调节的微生物群 组成增强了酒精引起的肠道渗透性和全身反应。 5）HD5和HD6衰减 压力和酒精引起的肠道营养不良和全身反应。 6）压力和酒精引起的营养不良 HD5和HD6逆转了多器官损伤。拟议的研究将利用新颖的体外和体内 鉴定GR，A-抗原蛋白和营养不良的模型是AAD和PTSD的治疗靶标。