Saturday, November 23, 2024
11/23/2024
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.
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