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Neonatal Antibiotic Therapy, The Pulmonary Microbiome, and theCholinergic Anti-inflammatory Pathway

新生儿抗生素治疗、肺部微生物组和胆碱能抗炎途径

基本信息

批准号：
9198756
负责人：
JOY A. PHILLIPS
金额：
$ 22.54万
依托单位：
SAN DIEGO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198756
关键词：
Acetyl Coenzyme A Acetylcholine Acute Address Adult Agonist Alzheimer&apos s Disease Anti-Cholinergics Anti-Inflammatory Agents Anti-inflammatory Antibiotic Therapy Antibiotics Area Arthritis Asthma B-Lymphocytes Binding Biological Biological Markers Brain CD4 Positive T Lymphocytes Cells Cholecystokinin Choline Choline O-Acetyltransferase Chronic Data Development Diabetes Mellitus Disease Disease model Endothelium Endotoxemia Environment Enzymes Exploratory/Developmental Grant Exposure to Generations Greater sac of peritoneum Half-Life Health Heart Diseases Hemorrhagic Shock Homeostasis Human Hypersensitivity Immunity Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inflammatory Response Pathway Interleukin-1 beta Interleukin-6 Intestines Ischemia Life Link Lung Lung diseases Lymphocyte Lymphocyte Activation Mechanics Mediating Mediator of activation protein Memory Metabolic syndrome Mucositis Mucous Membrane Mus Muscarinic Acetylcholine Receptor Neonatal Nerve Nervous system structure Neuroglia Neurotransmitters Pathway interactions Peritoneal Phenotype Play Pleural cavity Population Production Pulmonary Inflammation Reflex action Regulation Reporter Risk Role Sepsis Signal Transduction Spleen Stimulus T-Lymphocyte TNF gene Therapeutic Agents Tissues Translations Ulcerative Colitis Up-Regulation Vagus nerve structure airway inflammation alpha-bungarotoxin receptor cholinergic cohort cytokine design follow-up functional disability gut microbiome in vivo macrophage microbial microbiome neutrophil novel peptide hormone potential biomarker programs public health relevance respiratory response transcriptome

项目摘要

DESCRIPTION (provided by applicant): It is well established that the microbiome plays a role in regulating systemic and mucosal inflammation, but the mechanism underlying this recognized phenomena remains unclear. Diseases associated with microbiome disruptions including allergies and asthma, diabetes and metabolic syndrome, heart disease, arthritis, ulcerative colitis, sepsis, and Alzheimer's disease. Increased cytokine-driven inflammation is also believed to play a causative role in these same diseases. We propose that these two phenomena are linked by the function of acetylcholine-producing lymphocytes, which develop in response to interactions with byproducts of the microbiome and which act to regulate inflammatory cytokines. Inflammatory cytokine production is regulated by the brain via the cholinergic anti-inflammatory pathway. Secreted acetylcholine binds to α7 nicotinic acetylcholine receptors, inhibiting NF-κB activation and downregulating synthesis and release of inflammatory cytokines, primarily TNF, IL-1β, and IL-6. There is growing recognition that the acetylcholine in the cholinergic anti-inflammatory pathway is not secreted directly by the nervous system. In the spleen and peritoneal cavity, the critical acetylcholine-secreting cells are lymphocytes. Splenic CD4 T cells and peritoneal B-1 and B-2 cells secrete acetylcholine in response to signals from the vagal nerve, controlling the inflammatory response to factors as varied as TLR agonists, hemorrhagic shock, and tissue ischemia. Loss of these cholinergic lymphocytes leads to uncontrolled inflammation in response to inflammatory stimuli. These cholinergic (i.e., acetylcholine-producing) lymphocytes develop post- natally, in response to interaction with byproducts of the intestinal microbiome. The cholinergic anti- inflammatory pathway also functions in the lungs, but the mechanics of acetylcholine secretion in response to inflammation is unknown. We propose that the pulmonary compartment possesses a cohort of cholinergic lymphocytes similar to those of the peritoneal cavity. We further propose that these pulmonary cholinergic lymphocytes are regulated in response to interactions with byproducts of the recently-described pulmonary microbiome. Finally, we propose that early life disruption of the mucosal microbiome by neonatal antibiotic therapy leads to permanent disruption of these critical cholinergic lymphocytes. Using antibiotic treatment to reduce intestinal and systemic microbial load, TNF as a biomarker of inflammation, and LPS stimulation as the prototypic inflammatory stimulus, we propose to confirm cholinergic lymphocytes as the link between neonatal antibiotic treatment and inflammatory-associated disorders in adulthood.

描述（由申请人提供）：已经确定微生物组在调节全身和粘膜炎症中起作用，但这种公认现象的机制仍不清楚。与微生物组破坏相关的疾病，包括过敏和哮喘、糖尿病和代谢综合征、心脏病、关节炎、溃疡性结肠炎、败血症和阿尔茨海默病。增加的尼古丁驱动的炎症也被认为在这些相同的疾病中起致病作用。我们认为这两种现象与产生乙酰胆碱的淋巴细胞的功能有关，这些淋巴细胞响应于与微生物组副产物的相互作用而发展，并起到调节炎症细胞因子的作用。炎症性细胞因子的产生由大脑通过胆碱能抗炎途径调节。分泌的乙酰胆碱与α7烟碱型乙酰胆碱受体结合，抑制NF-κB活化并下调炎性细胞因子（主要是TNF、IL-1β和IL-6）的合成和释放。越来越多的人认识到，胆碱能抗炎途径中的乙酰胆碱不是由神经系统直接分泌的。在脾脏和腹腔中，关键的乙酰胆碱分泌细胞是淋巴细胞。脾CD 4 T细胞和腹膜B-1和B-2细胞响应来自迷走神经的信号分泌乙酰胆碱，控制对TLR激动剂、出血性休克和组织缺血等多种因素的炎症反应。这些胆碱能淋巴细胞的丢失导致对炎症刺激的不受控制的炎症。这些胆碱能（即，产生乙酰胆碱的）淋巴细胞在出生后发育，以响应与肠道微生物组的副产物的相互作用。胆碱能抗炎途径也在肺中起作用，但乙酰胆碱分泌对炎症的反应机制尚不清楚。我们认为，肺隔室具有类似于腹膜腔的胆碱能淋巴细胞的队列。我们进一步提出，这些肺胆碱能淋巴细胞响应于与最近描述的肺微生物组的副产物的相互作用而受到调节。最后，我们提出，新生儿抗生素治疗对粘膜微生物组的早期破坏导致这些关键胆碱能淋巴细胞的永久破坏。使用抗生素治疗，以减少肠道和全身的微生物负荷，TNF作为炎症的生物标志物，LPS刺激作为原型炎症刺激，我们建议确认胆碱能淋巴细胞之间的联系新生儿抗生素治疗和炎症相关疾病在成年期。