CHRONIC COLITIS ALTERS BRAIN ACTIVITY BY INDUCING HMGB1-MEDIATED PYROPTOSIS IN MICE

Chronic gut inflammation such as inflammatory bowel diseases is thought as being associated with neurodegenerative diseases in humans. The direct evidence for and the underlying mechanism of this brain-gut interaction, however, remain elusive.

We used manganese-enhanced magnetic resonance imaging (MEMRI) to assess brain functional activity from awake and freely moving mice. As a mouse model of chronic colitis, mice were treated with three cycles of dextran sulfate sodium. We performed the passive avoidance test, which is a fear-motivated test that assesses short-term and long-term memory. Mouse hippocampus tissues and microglial cells were subjected to GC-MS, immunofluorescence staining, ELISA, and immunoblotting analysis to examine how the inflamed gut is linked to the brain pathology.

We found that manganese ion uptake, indicative of Ca²⁺ influx into neuronal cells, and accumulation are dramatically reduced in the hippocampus of chronic colitis mice compared to control mice. Long-term memory is declined in chronic colitis mice. Neuroinflammatory signals, including IL-1β production and the activation of Caspase-1, Caspase-11, and Gasdermin (GSDM), are induced in the hippocampus of chronic colitis mice. High-mobility group box 1 (HMGB1) level is elevated both in the serum and in the hippocampus of chronic colitis mice; however, lipopolysaccharide (LPS) levels remain at low levels without significant changes in these samples. The blood-brain barrier permeability is increased in chronic colitis mice. In the presence of LPS, accordingly, HMGB1 treatment induces the activation of Caspase-11 and GSDM in mouse microglial cell line SIM-A9.

Our findings suggest that HMGB1 released from the inflamed intestine may move to the brain through the blood circulatory system; in conjunction with a low level of endogenous LPS, elevated HMGB1 can subsequently activate Caspase-mediated inflammatory responses in the brain. This study implies that chronic gut inflammation may alter brain activity in mice.