Chronic Intestinal Inflammation Suppresses Brain Activity by Inducing Neuroinflammation in Mice.

Chronic gut inflammation such as inflammatory bowel disease is believed to be associated with neurodegenerative diseases in humans. However, the direct evidence for and the underlying mechanism of this brain-gut interaction remain elusive. In this study, manganese-enhanced magnetic resonance imaging was used to assess functional brain activity from awake and freely moving mice with chronic colitis. Manganese ion uptake (indicative of Ca2+ influx into neuronal cells) and accumulation were reduced in the hippocampus of chronic colitis mice compared with control mice. Long-term memory declined and neuroinflammatory signals, including IL-1ß production and activation of caspase-1, caspase-11, and gasdermin, were induced. High-mobility group box 1 (HMGB1) levels were elevated both in the serum and in the hippocampus; however, lipopolysaccharide (LPS) levels remained at low levels without significant changes in these samples. The blood-brain barrier permeability was increased in chronic colitis mice. In the presence of LPS, HMGB1 treatment induced the activation of caspase-11 and gasdermin in the mouse microglial cell line SIM-A9. These 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.

Blockage of protease-activated receptor 2 exacerbates inflammation in high-fat environment partly through autophagy inhibition.

Protease-activated receptor 2 (PAR2) regulates inflammatory responses and lipid metabolism. However, its precise role in colitis remains unclear. In this study, we aimed to investigate the function of PAR2 in high-fat diet-fed mice with colitis and its potential role in autophagy. PAR2+/+ and PAR2-/- mice were fed a high-fat diet (HFD) for 7 days before colitis induction with dextran sodium sulfate. Deletion of PAR2 and an HFD significantly exacerbated colitis, as shown by increased mortality, body weight loss, diarrhea or bloody stools, colon length shortening, and mucosal damage. Proinflammatory cytokine levels were elevated in HFD-fed PAR2-/- mice and in cells treated with the PAR2 antagonist GB83, palmitic acid (PA), and a cytokine cocktail (CC). Damaging effects of PAR2 blockage were associated with autophagy regulation by reducing the levels of YAP1, SIRT1, PGC-1α, Atg5, and LC3A/B-I/II. In addition, mitochondrial dysfunction was demonstrated only in cells treated with GB83, PA, and CC. Reduced cell viability and greater induction of apoptosis, as shown by increased levels of cleaved caspase-9, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP), were observed in cells treated with GB83, PA, and CC but not in those treated with only PA and CC. Collectively, protective effects of PAR2 were elucidated during inflammation accompanied by a high-fat environment by promoting autophagy and inhibiting apoptosis, suggesting PAR2 as a therapeutic target for inflammatory bowel disease co-occurring with metabolic syndrome.NEW & NOTEWORTHY Deletion of PAR2 with high-fat diet feeding exacerbates colitis in a murine colitis model. Proinflammatory effects of PAR2 blockage in a high-fat environment were associated with an altered balance between autophagy and apoptosis. Increased colonic levels of PAR2 represent as a therapeutic strategy for IBD co-occurring with metabolic syndrome.