Role of intestinal serotonin transporter in post traumatic stress disorder

肠道血清素转运蛋白在创伤后应激障碍中的作用

• 批准号: 10590033
• 负责人: Ravinder K Gill
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590033
• 关键词: Affect; Age; Aggressive behavior; Alleles; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Bacteria; Behavior; Biological Assay; Brain; Brain-Derived Neurotrophic Factor; CCL2 gene; CXCL1 gene; Cells; Chronic; Data; Desulfovibrio; Development; Disease Management; Disease model; Enteral; Epithelial Cells; Epithelium; Exhibits; FDA approved; Female; Fright; Functional disorder; Genes; Genetic Polymorphism; Genetic study; Health; Hippocampus; Hormones; Human Genetics; Impulsive Behavior; Individual; Intestines; Knock-in; Laboratories; Link; Measures; Medical; Mental Depression; Mental disorders; Microbe; Modeling; Molecular; Mood Disorders; Morbidity - disease rate; Mus; Neurons; Neurotransmitters; Occupational; Outcome Study; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Post-Traumatic Stress Disorders; Pre-Clinical Model; Predisposition; Regulatory Pathway; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Services; Sex Differences; Social isolation; Stress; Structure; Sulfate; Tissues; Transgenic Model; Trauma; Treatment outcome; Tryptophan 5-monooxygenase; Veterans; antimicrobial peptide; bench to bedside; conditioned fear; disability; disability payment; effective therapy; extracellular; fecal transplantation; gastrointestinal epithelium; gut bacteria; gut microbes; gut microbiota; gut-brain axis; ileum; insight; intestinal epithelium; liquid chromatography mass spectrometry; male; microbial; microbial based therapy; microbiota; microbiota-gut-brain axis; mind control; mouse model; neuroinflammation; novel; novel therapeutics; overexpression; resilience; response; reuptake; serotonin receptor; serotonin transporter; severe mental illness; sex; single-cell RNA sequencing; social; stress related disorder; stressor; suicidal behavior; sulfate reducing bacteria; transcriptome; traumatic stress

Post traumatic stress disorder (PTSD) a devastating psychiatric disorder and one of the most difficult service- related disabilities in Veterans, nonetheless without a consistently effective therapy. The only FDA-approved drugs for the treatment of PTSD are the selective serotonin reuptake inhibitors (SSRIs); the response rate to these drugs, however, is relatively small requiring development of more specific and individually effective therapies. In this regard, the neurotransmitter and hormone, serotonin (5-HT) is well-recognized for its role in depression, anxiety, aggression, impulsivity, and suicidal behaviors, which are frequently found in PTSD patients. Serotonin transporter, (SERT; SLC6A4), regulates the extracellular availability of 5-HT, and is a common target for SSRIs. Linkage of the short allele of the SERT gene polymorphism has been implicated in increasing the vulnerability to develop PTSD and predicting poor treatment outcome. In this regard, SERT is abundantly expressed in the gut and its dysfunction has been shown to cause gut microbiota alterations; albeit its role in the predisposition or progression of PTSD is not fully understood. To gain insights into the role of gut- microbiota and SERT interactions in PTSD, we utilized our recently developed novel transgenic model with inducible overexpression of SERT restricted to intestinal epithelial cells (SOEIEC) that exhibits low fecal 5-HT levels (LC/MS). The mouse model of protracted social isolation (SI), was used as chronic stressor important to elicit PTSD-like increased aggression in resident intruder assays. Interestingly, males with SOEIEC under SI exhibited increase in aggression while females were resilient as compared to wild type counterparts. To understand the sex-dependent differences, we correlated the aggression with structure of gut microbial communities. The data demonstrated a strong negative association of aggression with genus Desulfovibrio (sulfate reducing bacteria) and positive associations with Bacteroidales, Gastranaerophilales, and genus- Anaerotruncus. How 5-HT pools in the gut impact upstream factors affecting gut microbiota and triggers downstream factors in the gut and brain leading to PTSD like behavior in a sex-dependent manner is not known. Thus, our proposed studies will use cell specific SOE (in IEC and in neurons) to further elucidate PTSD related fear conditioning responses and aggression behavior and elucidate the underlying molecular mechanisms across gut-brain axis (Aim 1). Additional studies utilizing SOE and SERT KO are needed to assess the causal role of SERT induced gut-microbiota changes in predisposing mice (M/F) to fear deficits/increased aggression (Aim 2). This will be achieved by fecal microbial transplant and assessing the functional role of gut microbial changes by integrating the PTSD-like behavior with downstream targets (single cell RNA seq) and selected metabolites along gut-brain axis. The outcome of the studies will provide novel insights into the role of intestinal SERT in PTSD predisposition and will pave the way for microbial based therapeutics for PTSD management.

创伤后应激障碍（PTSD）是一种毁灭性的精神疾病，也是最困难的服务之一 - 退伍军人的相关残疾，尽管如此，却没有持续有效的治疗方法。唯一获得 FDA 批准的 治疗创伤后应激障碍（PTSD）的药物是选择性血清素再摄取抑制剂（SSRIs）；的响应率 然而，这些药物相对较小，需要开发更具体和单独有效的药物 疗法。在这方面，神经递质和激素血清素 (5-HT) 因其在 抑郁、焦虑、攻击性、冲动和自杀行为，这些都是 PTSD 中常见的症状 患者。血清素转运蛋白（SERT；SLC6A4）调节细胞外 5-HT 的可用性，是一种 SSRIs 的共同目标。 SERT 基因多态性的短等位基因的连锁涉及 增加患创伤后应激障碍（PTSD）的脆弱性并预测不良的治疗结果。在这方面，SERT 在肠道中大量表达，其功能障碍已被证明会导致肠道微生物群改变；尽管 它在 PTSD 易感性或进展中的作用尚不完全清楚。为了深入了解肠道的作用 PTSD 中微生物群和 SERT 相互作用，我们利用我们最近开发的新型转基因模型 仅限于肠上皮细胞 (SOEIEC) 的 SERT 诱导性过度表达，粪便 5-HT 水平较低 水平（LC/MS）。长期社交隔离（SI）的小鼠模型被用作重要的慢性压力源 在常驻入侵者检测中引发类似 PTSD 的攻击性增加。有趣的是，SI 下具有 SOEIEC 的男性 与野生型相比，雌性表现出攻击性的增加，而雌性则具有弹性。到 了解性别依赖性差异后，我们将攻击性与肠道微生物的结构相关联 社区。数据表明攻击性与脱硫弧菌属呈强烈负相关 （硫酸盐还原菌）与拟杆菌目、嗜胃杆菌目和属呈正相关 厌氧菌。肠道中的 5-HT 池如何影响影响肠道微生物群和触发因素的上游因素 肠道和大脑中以性别依赖性方式导致 PTSD 样行为的下游因素尚不清楚。 因此，我们提出的研究将使用细胞特异性 SOE（在 IEC 和神经元中）来进一步阐明 PTSD 相关的 恐惧条件反应和攻击行为，并阐明潜在的分子机制 穿过肠-脑轴（目标 1）。需要利用 SOE 和 SERT KO 进行更多研究来评估因果关系 SERT 诱导肠道微生物群变化对易感小鼠 (M/F) 恐惧缺陷/攻击性增加的作用 （目标 2）。这将通过粪便微生物移植和评估肠道微生物的功能作用来实现 通过将 PTSD 样行为与下游目标（单细胞 RNA seq）整合并选择来改变 沿着肠脑轴的代谢。研究结果将为肠道的作用提供新的见解 SERT 治疗 PTSD 易感性，将为基于微生物的 PTSD 治疗治疗铺平道路。