Studying the Gut-Brain inflammatory interaction

研究肠-脑炎症相互作用

• 批准号: 10291246
• 负责人: Sang Hoon Rhee
• 金额: $ 43.06万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10291246
• 关键词: Address; Alzheimer' s Disease; Animals; Blood; Brain; C57BL/6 Mouse; CASP1 gene; CD14 Antigen; Cardiovascular system; Caspase; Chronic; Colitis; Cytosol; Data; Disease; Environment; Exhibits; Goals; HMGB1 Protein; Hippocampus (Brain); Homeostasis; Human; Imaging Techniques; Impaired cognition; Incidence; Indigenous; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-1; Interleukin-10; Knockout Mice; Knowledge; Lipopolysaccharides; Magnetic Resonance Imaging; Manganese; Measures; Mediating; Mental Depression; Microglia; Modeling; Molecular; Mus; Necrosis; Nerve Degeneration; Neurodegenerative Disorders; Nuclear Protein; Parkinson Disease; Pathologic; Patients; Physiological; Physiology; Play; Prevalence; Production; Public Health; Research; Risk; Role; Serum; Sex Differences; Signal Transduction; Sodium Dextran Sulfate; Testing; Tissues; Travel; bioimaging; blood-brain barrier permeabilization; cell injury; dextran sulfate sodium induced colitis; extracellular; gut microbiota; gut-brain axis; in vivo; inflammatory disease of the intestine; long term memory; macrophage; microbial; neuroinflammation; novel therapeutics; response; sex

Project Summary Emerging evidence indicates that the risk of neurodegenerative disease such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) is substantially increased in inflammatory bowel diseases (IBD) patients without sex differences. Therefore, it is believed that chronic gut inflammation may change brain physiology. However, there is no direct evidence that gut inflammation elicits a pathological condition in the brain; its underlying molecular mechanism remains elusive. Accordingly, the goal of this application is (1) to demonstrate that chronic gut inflammation alters the brain function using “manganese-enhanced magnetic resonance imaging” (MEMRI) in mice and (2) to uncover its underlying mechanism. Using the MEMRI technique that is an excellent non-invasive, in vivo bio-imaging technique to measure the brain activity in living animals, we discovered that C57BL/6 mice suffering from multicycle DSS-induced chronic colitis exhibit reduced brain activity in the hippocampus compared to that of healthy mice. Accordingly, long-term memory is declined in chronic colitis mice. Neuroinflammatory responses, including IL-1 levels and the activation of caspase-1 and caspase-11, are elevated in the hippocampus of chronic colitis mice compared to those of controls. HMGB1 levels are substantially increased both in the blood serum and in the hippocampus of chronic colitis mice, while LPS levels remain at low levels without significant changes in these tissues. The permeability of the blood brain barrier is markedly increased in chronic colitis mice. Given the fact that HMGB1 transports extracellular LPS into the cytosol to trigger caspase-11-medaited pyroptosis in macrophages, our central hypothesis is, therefore, that in chronic gut inflammatory conditions, HMGB1 is released and travels to the brain. Then, elevated levels of HMGB1, in conjunction with a low level of indigenous LPS, are capable of activating caspase-11-mediated inflammatory responses in microglial cells; thereby, causing the inflammation in the brain. To study this hypothesis, we propose the aims: (Aim 1) examine whether HMGB1 mediates the inflammatory response in the brain of chronic colitis mice, and (Aim 2) examine whether IL-10-ko mice with chronic colitis exhibit altered brain activity.

项目总结

项目成果

Lactobacillus plantarum Metabolites Elicit Anticancer Effects by Inhibiting Autophagy-Related Responses.

• DOI: 10.3390/molecules28041890
• 发表时间: 2023-02-16
• 期刊: MOLECULES
• 影响因子: 4.6
• 作者: Jeong, Sihyun;Kim, Yuju;Park, Soyeong;Lee, Doyeon;Lee, Juho;Hlaing, Shwe Phyu;Yoo, Jin-Wook;Rhee, Sang Hoon;Im, Eunok
• 通讯作者: Im, Eunok

Chronic intestinal inflammation suppresses brain activity by inducing neuroinflammation in mice.

• DOI: 10.1016/j.ajpath.2021.09.006
• 发表时间: 2021-10
• 期刊: The American journal of pathology
• 作者: Jonathon Mitchell;S. Kim;Cody S. Howe;Seulah Lee;J. Her;M. Patel;Gayoung Kim;Jaewon Lee;E. Im;S. Rhee

Atractylodin Ameliorates Colitis via PPARα Agonism.

• DOI: 10.3390/ijms24010802
• 发表时间: 2023-01-02
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Heo, Gwangbeom;Kim, Yuju;Kim, Eun-La;Park, Soyeong;Rhee, Sang Hoon;Jung, Jee H. H.;Im, Eunok
• 通讯作者: Im, Eunok