Project 3

项目摘要 在包括食物过敏在内的各种慢性疾病的患者中发现肠道微生物区系改变。 (FA)、肥胖和炎症性肠病，以及情感和认知障碍。有趣的是， 这些情况中的一些，例如FA和焦虑，经常被报道为并存，这表明生物失调 可能是一种常见的病理，将这两种不同的疾病联系在一起。使用轻度牛奶过敏的小鼠模型 (Cma)，我们之前已经证明了对牛乳清蛋白β-乳球蛋白(Blg；bos d 5)的敏化。 结果与雄性小鼠的行为改变有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区系，提高了动物体内细胞因子和趋化因子的水平。 发行量。然而，目前还不清楚微生物区系在致敏过程中是如何改变的，并随后影响 肠，脑。我们假设过敏原致敏的肠道免疫所产生的炎性环境 细胞有利于病原菌的聚集，降低肠道微生物群落支持的能力 肠道结构和代谢的动态平衡。我们将首先检查FA激活的宿主的效果 过继转移BLG致敏供体小鼠的免疫细胞到幼稚的肠道细菌上的免疫细胞 并评估受者的微生物区系、肠道屏障功能和神经炎症的变化 老鼠。一些受体小鼠也将同时接受抗α4β7整合素抗体免疫治疗 为了确定FA激活的免疫细胞归巢到肠道是否对糖尿病的发展至关重要 生物失调。接下来，我们将测试CMA相关微生物区系诱导肠屏障损害和 将BLG致敏小鼠的粪便微生物区系移植到幼稚受体小鼠的神经炎症。最后， 我们将评估马鞭草的保护作用和治疗潜力。 共生物种显示对肠道粘膜有益，在BLG致敏的小鼠中发现减少。 我们预计，FA通过激活和渗透肠道免疫细胞而诱导的炎症环境将 促进有益细菌的流失，同时允许病原菌过度生长。此外，由此产生的 肠道微生物区系组成的改变会损害肠道屏障功能，并引发肠道和大脑 炎症和结构病理学的发展。我们还预计抗α4β7整合素的治疗 抗体免疫治疗或益生菌治疗将减轻CMA相关的病理。 这项拟议的研究具有重要意义，因为它调查了宿主免疫细胞在慢性粒细胞白血病发生发展中的作用。 FA患者的生物失调和未被充分认识的后遗症，特别是处于危险中的个人 反复接触过敏原。通过微生物区系为FA在精神健康中的贡献作用提供证据 还将提供治疗神经精神疾病的新策略，包括免疫疗法、益生菌和饮食 咨询比目前可用的行为矫正药物更安全、更具成本效益。

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.