Dysregulation of cellular metabolism within the gut-brain axis is associated with behavioural changes in chronic intestinal inflammation.

Abstract

Background: Inflammatory bowel disease (IBD) is a chronic debilitating condition significantly affecting patient quality of life. Although the exact aetiology remains unknown, accumulating evidence has shown that disruption of the gut-brain axis may be related to the occurrence and development of chronic intestinal inflammation. Psychological disorders are highly prevalent in patients with IBD. However, an association between altered behaviour and dysregulated metabolic pathways within the gut-brain axis is yet to be explored.

Methods: Metabolic multiplexed phenotyping system involving indirect calorimetry and flow-through respirometry monitors was used to assess energy metabolism in Winnie mice with spontaneous chronic colitis and C57BL/6 littermates. Depressive and anxiety-like behaviours were evaluated with light dark, open field, grooming, elevated plus maze, and forced swimming tests. To investigate underlying mechanisms of the metabolic changes in Winnie mice, glycolysis/gluconeogenesis, fatty acid ß-oxidation, tricarboxylic acid cycle and oxidative phosphorylation gene expressions were determined by transcriptome analysis using high-throughput sequencing of mRNA extracted from the distal colon and brain samples.

Results: Our findings showed that energy metabolism and spontaneous activity were reduced in Winnie mice corresponding to alterations in the expression of cellular metabolism-associated genes in the distal colon. Winnie mice displayed depressive and anxiety-like behaviours reflecting downregulation of glycolysis/gluconeogenesis, fatty acid ß-oxidation, tricarboxylic acid cycle and oxidative phosphorylation in the distal colon and brain. Subsequent analyses showed pro-inflammatory cytokine expression was upregulated in the Winnie mouse brain.

Conclusions: These data provide evidence that the dysregulation of cellular metabolism within the gut-brain axis underlies changes in behaviour and energy metabolism in chronic intestinal inflammation.