Chronic Intestinal Inflammation Suppresses Brain Activity by Inducing Neuroinflammation in Mice

Am J Pathol. 2022 Jan;192(1):72-86. doi: 10.1016/j.ajpath.2021.09.006. Epub 2021 Oct 5.


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-1β 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Blood-Brain Barrier / pathology
  • Brain / diagnostic imaging
  • Brain / pathology*
  • Brain / physiopathology
  • Caspases / metabolism
  • Cell Line
  • Chronic Disease
  • Colitis / blood
  • Colitis / pathology
  • Cytokines / metabolism
  • HMGB1 Protein / metabolism
  • Hippocampus / enzymology
  • Hippocampus / pathology
  • Inflammation / blood
  • Inflammation / diagnostic imaging
  • Inflammation / pathology*
  • Inflammation / physiopathology
  • Intestines / pathology*
  • Lipopolysaccharides
  • Magnetic Resonance Imaging
  • Memory, Long-Term
  • Mice
  • Mice, Inbred C57BL
  • Microglia / metabolism
  • Microglia / pathology
  • Permeability
  • Pore Forming Cytotoxic Proteins / metabolism
  • Pyroptosis


  • Cytokines
  • Gsdma protein, mouse
  • HMGB1 Protein
  • Lipopolysaccharides
  • Pore Forming Cytotoxic Proteins
  • Caspases