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, 16 (4), 422-433

From Gut to Brain: Alteration in Inflammation Markers in the Brain of Dextran Sodium Sulfate-induced Colitis Model Mice

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From Gut to Brain: Alteration in Inflammation Markers in the Brain of Dextran Sodium Sulfate-induced Colitis Model Mice

Jongho Do et al. Clin Psychopharmacol Neurosci.

Abstract

Objective: Neuropsychiatric manifestations like depression and cognitive dysfunction commonly occur in inflammatory bowel disease (IBD). In the context of the brain-gut axis model, colitis can lead to alteration of brain function in a bottom-up manner. Here, the changes in the response of the hypothalamic-pituitary-adrenal axis and inflammation-related markers in the brain in colitis were studied.

Methods: Dextran sodium sulfate (DSS) was used to generate a mouse model of colitis. Mice were treated with DSS for 3 or 7 days and sacrificed. We analyzed the gene expression of brain-derived neurotrophic factor (BDNF), cyclooxygenase 2 (COX-2), and glial fibrillary acidic protein (GFAP), and the expression of GFAP, in the hippocampus, hypothalamus, and amygdala. Additionally, the levels of C-reactive protein (CRP) and serum cortisol/corticosterone were measured.

Results: Alteration of inflammatory-related markers varied depending on the brain region and exposure time. In the hippocampus, COX-2 mRNA, GFAP mRNA, and GFAP expression were upregulated during exposure to DSS. However, in the hypothalamus, COX-2 mRNA was upregulated only 3 days after treatment. In the amygdala, BDNF and COX-2 mRNAs were downregulated. CRP and corticosterone expression increased with DSS treatment at day 7.

Conclusion: IBD could lead to neuroinflammation in a bottom-up manner, and this effect varied according to brain region. Stress-related hormones and serum inflammatory markers, such as CRP, were upregulated from the third day of DSS treatment. Therefore, early and active intervention is required to prevent psychological and behavioral changes caused by IBD, and region-specific studies can help understand the precise mechanisms by which IBD affects the brain.

Keywords: Brain-derived neurotrophic factor; Cyclooxygenase 2; Dextran sodium sulfate; Glial fibrillary acidic protein; Inflammatory bowel disease; Neuroinfalmmation.

Figures

Fig. 1
Fig. 1
Chemically induced colitis elevated serum C-reactive protein (CRP) levels and activation of the hypothalamic-pituitary-adrenal (HPA) axis. The graph displays the effect of dextran sodium sulfate (DSS) on serum CRP levels (A), and the effect of DSS treatment on HPA axis (B–C). (B) Cortisol concentration at 0 day, 3 days, and 7 days after DSS treatment. (C) Corticosterone concentration at 0 day, 3 days, and 7 days after DSS treatment. *Significant difference (p<0.05).
Fig. 2
Fig. 2
Dextran sodium sulfate (DSS)-induced colitis led to brain-derived neurotrophic factor (BDNF) mRNA changes in different brain regions. Graphs show the effects of DSS-induced colitis in mice on BDNF mRNA levels (A) in the hippocampus, (B) in the amygdala, and (C) in the hypothalamus after exposure to 3 and 7 days of DSS. The values are expressed as fold changes normalized to the untreated control group. The values represent mean±standard error of mean; *p<0.05.
Fig. 3
Fig. 3
Dextran sodium sulfate (DSS)-induced colitis caused cyclooxygenase 2 (COX-2) mRNA changes in different brain regions. Graphs show the effects of DSS-induced colitis in mice on COX-2 mRNA levels (A) in the hippocampus, (B) in the amygdala, and (C) in the hypothalamus after exposure to 3 and 7 days of DSS. The values are expressed as fold changes normalized to the untreated control group. The values represent means±standard error of mean; *p<0.05.
Fig. 4
Fig. 4
Dextran sodium sulfate (DSS)-induced colitis lead to glial fibrillary acidic protein (GFAP) mRNA changes in different brain regions. Graphs show the effects of DSS-induced colitis in mice on GFAP mRNA levels (A) in the hippocampus, (B) in the amygdala, and (C) in the hypothalamus after exposure to 3 and 7 days of DSS. The values are expressed as fold changes normalized to the untreated control group. The values represent means±standard error of mean; *p<0.05.
Fig. 5
Fig. 5
Glial fibrillary acidic protein (GFAP) expression patterns in the hippocampus, amygdala and hypothalamus after exposure to dextran sodium sulfate (DSS). These are representative photomicrographs of the hippocampus (A–F), the amygdala (G–L) and the hypothalamus (M–R) from our study. Representative histology of the hippocampus was stained with hematoxylin and eosin (H&E) at untreated (control) (A), 3 days (C), and 7 days (E) after exposed to DSS. GFAP expression in hippocampus tissue was increased compared to (B) control group after exposed to DSS at (D) 3 days, and (F) 7 days, as shown by immunohistochemistry (IHC). Representative histology of the amygdala was also stained with H&E at (G) untreated (control), (I) 3 days, and (K) 7 days after exposed to DSS. IHC of GFAP expression in the amygdala showed no significant difference between the (H) control group, (J) the 3-day treatment group, and (L) the 7-day treatment group. (M) Hypothalamus tissue stained with H&E at untreated (control), (O) 3 days, and (Q) 7 days after exposed to DSS. IHC of GFAP expression in the hypothalamus did not show any significant difference between (N) the control group, (P) the 3-day treatment group, and (R) the 7-day treatment group.
Fig. 6
Fig. 6
Quantification of changes in glial fibrillary acidic protein (GFAP) expression in different brain regions. GFAP expression in the hippocampus and amygdala was quantified (ImageJ software; NIH, Bethesda, MD, USA) and expressed as a percentage of tissue area. (A) GFAP expression changes in hippocampus. (B) GFAP expression changes in amygdala. (C) GFAP expression changes in hypothalamus. Like mRNA expression changes in hippocampus, GFAP expression pattern changed after dextran sodium sulfate exposure. *Significance (p<0.05).

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