Project 3

项目3

• 批准号: 10270980
• 负责人: Kumi Nagamoto-Combs
• 金额: $ 25.39万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-13 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270980
• 关键词: 16S ribosomal RNA sequencing; Address; Adoptive Transfer; Affect; Affective; Age; Allergens; Anxiety; Attenuated; Bacteria; Behavior; Behavior Disorders; Behavioral; Behavioral Symptoms; Bile Acids; Biogenic Amines; Blood; Blood - brain barrier anatomy; Blood Circulation; Brain; Cattle; Cells; Chronic; Cognition Disorders; Cognitive; Consultations; Development; Disease; Encephalitis; Endotoxins; Etiology; Exhibits; Extravasation; Feces; Female; Food Hypersensitivity; Gliosis; Gut Mucosa; Health; Homeostasis; Homing; IgE; Immune; Immunologics; Immunotherapy; Impairment; Individual; Infiltration; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Integrins; Intervention; Intestinal Mucosa; Intestines; Knowledge; Lead; Link; Mediating; Mental Health; Mental disorders; Metabolic; Microbe; Milk Hypersensitivity; Mood Disorders; Mucous body substance; Mus; Obesity; Outcome Study; Pathogenicity; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Pharmacology; Physiology; Probiotics; Proteins; Quality of life; Reporting; Resistance; Risk; Role; Self-Injurious Behavior; Structure; Substance abuse problem; Supplementation; Synapses; Testing; Therapeutic; Thinness; Tight Junctions; Tumor-infiltrating immune cells; Volatile Fatty Acids; Whey Protein; antibody immunotherapy; anxiety-like behavior; behavior change; behavior test; brain behavior; chemokine; comorbidity; cost effective; cytokine; dietary; dysbiosis; fecal microbiota; fecal transplantation; functional disability; gut bacteria; gut microbiota; gut-brain axis; host-microbe interactions; inflammatory disease of the intestine; inflammatory milieu; integrin alpha4beta7; intestinal barrier; intestinal epithelium; intestinal homeostasis; male; microbiota; microbiota-gut-brain axis; microorganism; mouse model; neuroinflammation; neurological pathology; neuron loss; neuropsychiatric disorder; neuroregulation; neurotrophic factor; novel; oral supplementation; pathogen; pathogenic bacteria; prevent; probiotic supplementation; recruit; young adult

Project Summary Altered intestinal microbiota has been found in patients with a variety of chronic conditions including food allergy (FA), obesity, and inflammatory bowel disease, as well as with affective and cognitive disorders. Interestingly, some of these conditions, for example, FA and anxiety, are often reported comorbid, suggesting that dysbiosis may be a common pathology that links the two distinct disorders. Using a mouse model of mild cow’s milk allergy (CMA), we have previously shown that sensitization to a bovine whey protein, β-lactoglobulin (BLG; Bos d 5) results in intestinal pathology and neuroinflammation that were associated with behavioral changes in male mice. Furthermore, BLG sensitization also altered gut microbiota, elevating cytokine and chemokine levels in the circulation. However, it is not clear how microbiota is altered during sensitization and subsequently affects intestine, brain. We hypothesize that the inflammatory milieu produced by allergen-sensitized intestinal immune cells favors enrichment of pathogenic bacteria and decreases capacity of the gut microbial community to support structural and metabolic homeostasis of the intestines. We will first examine the effect of FA-activated host immune cells on gut bacteria by adoptively transferring immune cells from BLG-sensitized donor mice to naïve mice and assessing changes in microbiota, intestinal barrier function, and neuroinflammation in the recipient mice. Some recipient mice will also be simultaneously treated with anti-α4β7 integrin antibody immunotherapy to determine whether homing of FA-activated immune cells to the intestines is critical for the development of dysbiosis. Next, we will test the ability of CMA-associated microbiota to elicit intestinal barrier impairment and neuroinflammation by transplanting fecal microbiota from BLG-sensitized mice to naïve recipient mice. Lastly, we will assess the protective role and therapeutic potential of Verrucomicrobia Akkermansia muciniphila, a commensal species shown to be beneficial for gut mucosa and found to be decreased in BLG-sensitized mice. We expect that FA-induced inflammatory environment due to activation and infiltration of gut immune cells will facilitate loss of beneficial bacteria while allowing overgrowth of pathogenic bacteria. Furthermore, the resulting alteration in the gut microbiota composition will impair intestinal barrier function and trigger intestinal and brain inflammation and structural pathology development. We also expect that the treatment with anti-α4β7 integrin antibody immunotherapy or a probiotic treatment with A. muciniphila will attenuate CMA-associated pathologies. This proposed study is significant because it investigates the role of host immune cells in the development of dysbiosis in FA individuals and the sequelae that are under-recognized, particularly in individuals who are at risk of repeated allergen exposure. Providing the evidence for a contributory role of FA in mental health via microbiota will also offer new strategies to treat neuropsychiatric disorders with immunotherapy, probiotics and dietary consultation that are safer and more cost-effective than currently available behavior-modifying medications.

项目概要 在患有包括食物过敏在内的多种慢性疾病的患者中发现了肠道微生物群的改变 (FA)、肥胖、炎症性肠病以及情感和认知障碍。 其中一些情况，例如 FA 和焦虑，经常被报告为共病，这表明生态失调 可能是一种常见的病理学，使用轻度牛奶过敏的小鼠模型来联系这两种不同的疾病。 (CMA)，我们之前已经证明对牛乳清蛋白、β-乳球蛋白（BLG；Bos d 5）过敏 导致与雄性小鼠行为变化相关的肠道病理和神经炎症。 此外，BLG 致敏还改变了肠道微生物群，提高了肠道中细胞因子和趋化因子的水平。 然而，尚不清楚微生物群在致敏过程中如何改变并随后产生影响。 我们勇敢地面对过敏原敏感的肠道免疫产生的炎症环境。 细胞有利于病原菌的富集，并降低肠道微生物群落的支持能力 我们将首先检查 FA 激活宿主的影响。 通过将 BLG 致敏供体小鼠的免疫细胞过继转移至幼稚小鼠体内，对肠道细菌产生免疫细胞作用 小鼠并评估受体的微生物群、肠道屏障功能和神经炎症的变化 一些受体小鼠还将同时接受抗α4β7整合素抗体免疫治疗。 确定 FA 激活的免疫细胞归巢至肠道是否对于疾病的发展至关重要 接下来，我们将测试 CMA 相关微生物群引起肠道屏障损伤和 通过将 BLG 致敏小鼠的粪便微生物移植到幼稚受体小鼠中来抑制神经炎症。 我们将评估 Verrucomicrobia Akkermansia muciniphila（一种 共生物种被证明对肠道粘膜有益，并且发现在 BLG 致敏小鼠中减少。 我们预计，由于肠道免疫细胞的激活和浸润，FA 诱导的炎症环境将 促进有益细菌的损失，同时允许病原菌过度生长。 肠道微生物群组成的改变会损害肠道屏障功能并触发肠道和大脑 我们还期望用抗α4β7整合素进行治疗。 抗体免疫疗法或益生菌治疗可减轻 CMA 相关病理。 这项拟议的研究意义重大，因为它研究了宿主免疫细胞在免疫细胞发育中的作用。 FA 个体的菌群失调以及未得到充分认识的后遗症，特别是处于危险之中的个体 为 FA 通过微生物群对心理健康做出贡献提供证据。 还将提供通过免疫疗法、益生菌和饮食治疗神经精神疾病的新策略 比目前可用的行为改变药物更安全、更具成本效益的咨询。