Sex related differences in Brain Gut Microbiome Interactions in Irritable Bowel Syndrome

肠易激综合症中脑肠微生物组相互作用的性别相关差异

• 批准号: 10461213
• 负责人: Lin Chang
• 金额: $ 154.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10461213
• 关键词: Address; Affective; Anatomy; Anxiety; Arousal; Bile Acids; Biological; Biological Markers; Brain; Brain Stem; Brain imaging; Brain region; Cell Nucleus; Characteristics; Chronic; Chronic Disease; Clinical; Clinical effectiveness; Cognitive; Cognitive Therapy; Consensus; Constipation; Data Analyses; Diffusion; Digestive System Disorders; Disease; Doctor of Philosophy; Effectiveness; Emotional; Estrogens; Female; Functional Gastrointestinal Disorders; Functional disorder; Funding; Gastrointestinal Diseases; Generations; Goals; Gonadal Steroid Hormones; Image; Intestinal Diseases; Irritable Bowel Syndrome; Lead; Leadership; Luteal Phase; Mediating; Mediator of activation protein; Menopause; Menstruation; Outcome; Pain; Pathway interactions; Patients; Perception; Physiological; Play; Pontine structure; Postmenopause; Premenopause; Prevalence; Progress Reports; Public Health; Publications; Reproducibility; Research; Research Personnel; Rest; Role; Sensory; Severities; Sex Differences; Signal Transduction; Structure; Subgroup; Symptoms; System; Time; Treatment Effectiveness; Treatment outcome; Tryptophan; Visceral; Volatile Fatty Acids; Woman; base; bioinformatics tool; career; clinical phenotype; comorbidity; computerized data processing; coping; experience; female sex hormone; gut microbiome; gut-brain axis; imaging modality; improved; insight; male; men; microbial; microbiome analysis; neuromelanin; noradrenergic; novel; perimenstrual; response; sex; therapeutically effective; therapy outcome; tool; treatment response; treatment strategy

ABSTRACT Irritable bowel syndrome (IBS) and chronic normal transit constipation (CC) are prevalent intestinal disorders which are more common in women. In addition, female IBS patients experience more pain during low estrogen states, e.g. during the luteal phase of the menstrual period and post menopause. Until recently, there was no consensus about the pathophysiology of these disorders, no satisfactory long term treatments, and no reliable biomarkers for guiding treatment decisions. However, there is increasing evidence that disturbances at different levels of the brain-gut microbiome (BGM) axis play a central role in the pathophysiology of IBS and possibly CC. This proposal is based on the general hypothesis that female sex hormones and gut microbial metabolites play an important modulatory role on brain gut microbiome interactions, and that ascending arousal systems originating in the brainstem may in part responsible for the altered cognitive, affective and sensory processing function resulting in increased perception of visceral and other sensory signals, maladaptive coping, and comorbid anxiety characteristic for patient with functional GI disorders. Therefore, the overall goal of this proposal is to identify the sex-specific effect of gut microbial metabolites, and estrogen levels on ascending arousal pathways originating in distinct brainstem nuclei to change the activity and connectivity of brain networks involved in symptom generation. Using advanced brain imaging methods, gut microbiome analyses, and detailed clinical phenotyping, as well as state of the art statistical and bioinformatics tools, this proposal is addressing the hypothesis in 3 synergistic and closely related Projects, assisted by a Leadership Administrative Core and a Data Processing and Analysis Core. Project 1 aims to study the influence of natural low estrogen states and microbial metabolites on BGM interactions in female IBS patients with IBS and CC in the luteal phase, and after menopause. Project 2 aims to clearly identify the brainstem nuclei giving rise to ascending noradrenergic and serotonergic projections to limbic and cortical brain regions, determine the influence of gut microbial metabolites on these arousal systems and determine differences in these effects between male and female patients. Project 3 aims to evaluate the biological mechanisms within the BGM axis that mediate the clinical effectiveness of cognitive behavioral therapy (CBT) in male and female IBS patients, and identify possible predictors and mediators of outcome.The information garnered from this study could reveal novel insight into the involvement of different levels of the brain gut microbiome axis in IBS pathophysiology, and provide a powerful clinical tool for identifying the most effective therapeutic strategies for women and men with functional GI disorders.

摘要