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.

项目总结