Abstract
Inflammatory bowel disease (IBD) patients frequently suffer from anxiety disorders and depression, indicating that altered gut-brain axis signalling during gastrointestinal inflammation is a risk factor for psychiatric disease. Microglia, immune cells of the brain, is thought to be involved in a number of mental disorders, but their role in IBD is largely unknown. In the current work, we investigated whether colitis induced by dextran sulphate sodium (DSS), a murine model of IBD, alters microglial phenotypes in the brain. We found that colitis caused a reduction of Iba-1 and CD68 immunoreactivity, microglial activation markers, in specific brain regions of the limbic system such as the medial prefrontal cortex (mPFC), while other areas remained unaffected. Flow cytometry showed an increase of monocyte-derived macrophages during colitis and gene expression analysis in the mPFC showed pronounced changes of microglial markers including cluster of differentiation 86 (CD86), tumour necrosis factor-α, nitric oxide synthase 2, CD206 and chitinase-like protein 3 consistent with both M1 and M2 activation. Taken together, these findings suggest that experimental colitis-induced inflammation is propagated to the brain altering microglial function.
Highlights
Inflammatory bowel disease (IBD) patients frequently suffer from anxiety disorders and depression, indicating that altered gut-brain axis signalling during gastrointestinal inflammation is a risk factor for psychiatric disease
We evaluated microglial polarization in the medial prefrontal cortex, a brain area which showed pronounced ionized calcium-binding adapter molecule 1 (Iba-1) alterations using markers for M1 status (CD86, nitric oxide synthase 2 (Nos2), tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β)) as well as M2 status (CD206, arginase 1 (Arg1), chitinase-like 3 (Chil3))
Given the accumulating evidence of altered gut-brain axis signalling in the course of visceral inflammation[26,27] and the well-established role of microglia in response to peripheral immune challenge and stress[17,28,29,30], the current study set out to investigate whether dextran sulphate sodium (DSS)-induced colitis, an animal model of IBD, and WAS, a mild psychological stressor, would alter the brain’s microglia phenotype
Summary
Inflammatory bowel disease (IBD) patients frequently suffer from anxiety disorders and depression, indicating that altered gut-brain axis signalling during gastrointestinal inflammation is a risk factor for psychiatric disease. Flow cytometry showed an increase of monocytederived macrophages during colitis and gene expression analysis in the mPFC showed pronounced changes of microglial markers including cluster of differentiation 86 (CD86), tumour necrosis factor-α, nitric oxide synthase 2, CD206 and chitinase-like protein 3 consistent with both M1 and M2 activation Taken together, these findings suggest that experimental colitis-induced inflammation is propagated to the brain altering microglial function. Dextran sulphate sodium (DSS)-induced colitis, an animal model of IBD7,8, has been shown to disrupt emotional-affective behaviour in rodents, effects which are significantly modulated in the presence of psychological stress[9,10,11,12] These behavioural changes are accompanied by altered neuronal activation in the corticolimbic system[13], increased brain excitability[12] as well as brain region-specific changes in neuropeptide and inflammatory marker gene expression[9,11], demonstrating that gastrointestinal inflammation alters neuronal function. We hypothesized that experimental colitis and psychological stress are able to alter microglial phenotype in various limbic brain areas
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