Skip to main content
ARS Home » Northeast Area » Beltsville, Maryland (BHNRC) » Beltsville Human Nutrition Research Center » Diet, Genomics and Immunology Laboratory » Research » Publications at this Location » Publication #339349

Research Project: Dietary Regulation of Immunity and Inflammation

Location: Diet, Genomics and Immunology Laboratory

Title: Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

Author
item Ma, Elise - University Of Maryland
item Smith, Allen
item Desai, Neemesh - University Of Maryland
item Cheung, Lumei
item Hanscom, Marie - University Of Maryland
item Stoica, Bogdan - University Of Maryland
item Loane, David - University Of Maryland
item Shea-donohue, Terez - University Of Maryland
item Faden, Alan - University Of Maryland

Submitted to: Brain Behavior and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/30/2017
Publication Date: 7/1/2017
Citation: Ma, E.L., Smith, A.D., Desai, N., Cheung, L., Hanscom, M., Stoica, B.A., Loane, D.J., Shea-Donohue, T., Faden, A.I. 2017. Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice. Brain Behavior and Immunity. pii: S0889-1591(17)30207-6. doi: 10.1016/j.bbi.2017.06.018.

Interpretive Summary: Traumatic brain injury (TBI) can affect the gastrointestinal tract and has been associated with TBI-related illness and death. We examined changes in gut barrier function and specialized cells in the gut, called enteric glial cells (EGC), after experimental TBI in mice, as well as effects of a gut bacterial infection caused by Citrobacter rodentium (Cr) on both the gut and brain after injury. Moderate-level TBI was induced in C57BL/6 mice. The function of the gut barrier was assessed by measuring transepithelial resistance, fluorescent-labeled dextran flux, and quantification of tight junction proteins, all of which measure if the gut barrier function has changed. EGC activation, a measure of inflammation, was assessed by measuring the amount of a specific protein found that increases when EGC cells are activated, and the number of EGCs by measuring the expression of Sox10, another protein found in these cells. Other groups of mice were infected with Cr and the host immune response, barrier integrity, EGC reactivity, and progression of brain injury were assessed. Permeability in the colon was chronically increased at 28 days post-TBI and was associated with decreased expression of a protein, claudin-1, that is important for maintaining the gut barrier. Colonic GFAP and Sox10 expression were significantly increased 28 days after brain injury indicating that increased inflammation was present. The host immune responses to the bacterial infection caused by Cr was not changed by TBI in mice. However, other gut functions were changed. The gut barrier became leaky, allowing greater transport of molecules across the gut barrier. GFAP expression, a measure of inflammation, increased after Cr infection in TBI-injured mice. Importantly, brain lesions were significantly greater and neuroinflammation was increased in TBI-injured mice infected with Cr compared to TBI-injured mice alone. These experimental studies demonstrate that TBI can affect how the gut functions and changes in the gut, such as infection, can change the response in the brain to TBI, which may negatively impact late outcomes after brain injury.

Technical Abstract: Traumatic brain injury (TBI) has complex effects on the gastrointestinal tract that are associated with TBI-related morbidity and mortality. We examined changes in mucosal barrier properties and enteric glial cell response in the gut after experimental TBI in mice, as well as effects of the enteric pathogen Citrobacter rodentium (Cr) on both gut and brain after injury. Moderate-level TBI was induced in C57BL/6 mice by controlled cortical impact (CCI). Mucosal barrier function was assessed by transepithelial resistance, fluorescent-labelled dextran flux, and quantification of tight junction proteins. Enteric glial cell number and activation were measured by Sox10 expression and GFAP reactivity, respectively. Separate groups of mice were challenged with Cr infection during the chronic phase of TBI, and host immune response, barrier integrity, enteric glial cell reactivity, and progression of brain injury and inflammation were assessed. Chronic CCI induced changes in colon morphology, including increased mucosal depth and smooth muscle thickening. At day 28 post-CCI, increased paracellular permeability and decreased claudin-1 mRNA and protein expression were observed in the absence of inflammation in the colon. Colonic glial cell GFAP and Sox10 expression were significantly increased 28 days after brain injury. Clearance of Cr and upregulation of Th1/Th17 cytokines in the colon were unaffected by CCI; however, colonic paracellular flux and enteric glial cell GFAP expression were significantly increased. Importantly, Cr infection in chronically-injured mice worsened the brain lesion injury and increased astrocyte- and microglia- mediated inflammation. This study demonstrates the impact of chronic brain injury on the gut and of gut inflammation on the resolution of chronic brain injury.