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    Injured Brain, Disrupted Gut: Bidirectional Brain-Gut Interactions and Chronic Pathologies following Traumatic Brain Injury

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    Author
    Ma, Elise L.
    Advisor
    Faden, A. I.
    Shea-Donohue, Terez
    Date
    2017
    Type
    dissertation
    
    Metadata
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    Abstract
    Traumatic brain injury (TBI) has complex effects on the gastrointestinal tract that are associated with TBI-related mortality and morbidities, including susceptibility to peripheral infections and septicemia. Although human and animal studies have established a link between TBI and intestinal dysfunction during acute stages of injury, long-term consequences of TBI in the gut are vastly unknown. First, mucosal properties, enteric glial cells, and microbiota in the gut were examined after experimental TBI in mice. Then, the interaction between TBI and peripheral challenge in the intestinal tract was assessed by examining the effects of Citrobacter rodentium (Cr) infection - an enteric murine pathogen similar to human E. coli - on both gut and brain after chronic TBI. Finally, potential mechanisms of bidirectional brain-gut communication during the chronic phase of TBI were explored. Moderate-level TBI in adult male C57BL/6 mice was induced by controlled cortical impact (CCI; 6 m/sec, 2mm depth). Moderate CCI led to delayed, chronic changes in colon morphology, including increased mucosal hyperplasia and smooth muscle thickening. At day 28 post-CCI, increased paracellular mucosal permeability associated with decreased claudin-1 mRNA and protein expression were observed in the absence of inflammation in the colon. Activated enteric glial cells (GFAP+, Sox10+) were significantly increased 28 days after CCI. Moreover, chronic CCI altered gut microbiome composition, including specific increases in pathology-associated microbes Peptostreptococcacea and Bacteroides in the colon. After CCI, mice demonstrated delayed changes in autonomic balance and adaptability, which were associated with pro-inflammatory priming of peripheral macrophages. When challenged with enteric Cr infection 28 days post-CCI, host Th1/Th17 immune responses in the colon were unaffected by CCI; however, colonic paracellular flux and enteric glial cell activation were significantly increased. Importantly, Cr infection in chronically-injured mice worsened TBI neuropathology and increased neuroinflammatory responses (GFAP+ astrocytes, CD68+ microglia/m?) in the cortex. These Cr-induced changes were associated with increased circulating IP-10 levels and decreased serum miR-223 expression. These findings provide significant and novel insights into the bidirectional brain-gut axis and its clinical implications on long-term consequences and outcomes after TBI.
    Description
    University of Maryland, Baltimore. Neuroscience. Ph.D. 2017
    Keyword
    brain-gut axis
    enteric glial cells
    mucosal barrier function
    neuroinflammation
    Brain Injuries, Traumatic
    Citrobacter rodentium
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/7069
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    Theses and Dissertations School of Medicine
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