Microbiome-mediated weight, anxiety, and stress dysregulation in anorexia nervosa

神经性厌食症中微生物介导的体重、焦虑和压力失调

• 批准号: 9297384
• 负责人: Ian Michael Carroll
• 金额: $ 70.64万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9297384
• 关键词: Acute; Adolescent; Age; Animal Model; Anorexia Nervosa; Anxiety; Bacteria; Behavior; Behavioral; Body Weight; Body Weight decreased; Body mass index; Chronic Disease; Clinical; Clostridium difficile; Colitis; Comorbidity; Complex; Data; Disease; Distress; Dropout; Enteral; Etiology; Exhibits; Fatty acid glycerol esters; Feces; Female; Functional disorder; Genetic; Germ-Free; Goals; Guidelines; High-Throughput Nucleotide Sequencing; Human; Individual; Intervention; Intestines; Investigation; Maintenance; Malnutrition; Measures; Mediating; Mental disorders; Mesentery; Metabolic syndrome; Metabolism; Microbe; Mus; Neurotransmitters; Obesity; Pain; Patients; Pattern; Phase; Phosphate Buffer; Polyunsaturated Fatty Acids; Public Health; Recovery; Regulation; Relapse; Role; Saline; Sampling; Science; Starvation; Sterility; Stress; Testing; Therapeutic; Transplantation; Treatment outcome; Tryptophan; Volatile Fatty Acids; Weight; Work; abdominal fat; base; effective therapy; evidence base; fecal transplantation; gastrointestinal; ghrelin; gut microbiota; improved; innovation; microbial community; microbiome; microbiota; molecular marker; mortality; non-genetic; novel; novel strategies; public health relevance; rRNA Genes; restoration; severe psychiatric disorder; sex; stress reactivity; study population; trait

 DESCRIPTION (provided by applicant): Anorexia nervosa (AN), a psychiatric disorder characterized by extreme weight dysregulation commonly presents with comorbid anxiety. Therapeutic renourishment in AN is based primarily on clinical opinion and guidelines, with a weak evidence base. Compelling data implicate the intestinal microbiota in the regulation of adiposity and behavior, providing a strong rationale for exploring the role of this complex microbial community in the emergence and maintenance of, and recovery from AN. Our overarching goal is to understand the precise mechanism(s) by which intestinal bacteria contribute to dysregulation of adiposity, BMI, anxiety, and stress in patients with AN. We hypothesize that intestinal microbiotas that arise from prolonged starvation contribute to increases in adiposity upon refeeding and to persistently elevated anxiety and stress in individuals with AN. To test our hypothesis we propose 3 specific aims. In aim 1, we will identify the enteric bacterial groups associated with adiposity, BMI, anxiety, and stress in AN patients. We will characterize the intestinal microbiota in acutely low weight AN patients (T1), in the same patients following weight restoration (T2), and in healthy controls (HC) via high throughput sequencing of the 16S rRNA gene. We will compare the abundances of specific enteric taxa with adiposity, BMI and behavior (anxiety and stress) in this study population. In aim 2, we will characterize the functional impact of the intestinal microbiota of AN patients on adiposity and BMI when transplanted into germ free (GF) mice. We will transplant uncultured microbiotas from AN patients (at T1 and T2) and HC into GF mice and assess the impact of enteric microbes on adiposity. In aim 3, we will characterize the functional impact of the intestinal microbiota of AN patients on anxiety and stress, and molecular biomarkers of these behaviors, when transplanted into GF mice. We will transplant uncultured microbiotas from T1 AN patients and HC into GF mice and assess the impact of enteric microbes on anxiety and stress. GF mice gavaged with sterile phosphate buffer saline will be used as controls in aims 2 and 3. The proposed science is significant in pioneering the combination of large scale 16S rRNA gene sequencing-based studies of intestinal microbiotas in AN with exploration of their functional influence on adiposity and behavioral traits associated with AN. Our results will provide direction on how best to test adjunct interventions for AN with pre-, pro-, anti-, or syn-biotics to enhance current approaches to therapeutic weight restoration and improve treatment outcome. The science is highly innovative as it will investigate an entirely novel factor in AN, the intestinal microbiota, and us a novel approach to identify enteric microbes that impact adiposity and behavior in this devastating illness. Additionally, we will investigate an entirely novel factor (namely, the intestinal microbiota) as a contributor to the underlying pathophysiology of AN.

 描述（应用程序提供）：厌食症（AN），一种以极端体重失调为特征的精神疾病，通常表现出合并症的焦虑症。 AN中的治疗疗法主要基于临床意见和指南，证据基础较弱。令人信服的数据暗示了肠道微生物群在调节肥胖和行为中，这为探索这种复杂的微生物群落在出现和维持和从AN中恢复中的作用提供了有力的理由。我们的总体目标是了解肠道细菌的精度机制，导致AN的患者的肥胖，BMI，动画和压力的失调。我们假设由长时间饥饿引起的肠道微生物群有助于参考时肥胖的增加，并持续升高为患有AN的人的动画和压力。提案3特定目标。在AIM 1中，我们将确定患者中与肥胖，BMI，焦虑和压力相关的肠细菌组。我们将通过16S rRNA基因的高吞吐量测序在体重恢复后（T2）和健康对照（HC）中表征急性低体重A（T1）患者（T1）的肠道菌群（T1）。我们将在这项研究人群中比较特定的肠群和肥胖，BMI和行为（焦虑和压力）的丰富性。在AIM 2中，我们将表征患者肠道菌群对肥胖和BMI的功能影响，当时将其移植到无胚膜（GF）小鼠中。我们将从患者（AT T1和T2）和HC中移植未养殖的微生物群，并评估促进微生物对肥胖的影响。在AIM 3中，当移植到GF小鼠中时，我们将表征患者肠菌群对焦虑和压力的功能影响，以及这些行为的分子生物标志物。我们将从T1 A A和HC中移植未养殖的微生物群，并评估增强微生物对焦虑和压力的影响。 GF小鼠用无菌磷酸盐缓冲液盐水刺入的GF小鼠将用作目标2和3中的对照。拟议的科学在开创了基于大规模的16S rRNA基因测序研究的肠道微生物群的研究，并探索了其对脂肪的功能影响， 和与An相关的行为特征。我们的结果将提供有关如何最好地测试使用预，抗，抗或同步药物的辅助干预措施的方向，以增强当前的治疗体重恢复和改善治疗结果的方法。该科学具有很高的创新性，因为它将研究AN，肠道菌群的一个完全新颖的因素，并且我们采用了一种新的方法来识别影响这种毁灭性疾病中肥胖和行为的肠子微生物。此外，我们将研究一个完全新颖的因素（即肠道菌群），作为促成AN的潜在病理生理学的贡献者。