Abstract
Inflammatory bowel diseases (IBD) are chronic intestinal diseases affecting over 1.4 million Americans. Children and adolescents typically have more severe disease and are more likely to display extra-intestinal effects, including psychosocial deficits, compared to adult patients. Unfortunately, the mechanism(s) through which these extra-intestinal deficits develop is unknown and murine models of pediatric IBD do not exist. Our overall goal was to develop a model of pediatric IBD and assess the microbiota-gut-brain axis in adolescent mice. We hypothesized that induction of colitis at weaning would lead to long-lasting effects on the microbiota-gut-brain axis, including behavior. Colonic inflammation was induced by administration of dextran sodium sulfate (DSS), a chemical colitogen with anticoagulant properties known to cause colitis in rodents. DSS (2% w/v) was given to weanling mice (P21) in drinking water for 5 days and then allowed to recover, modeling acute colitis. Behavior (cognition and anxiety) and inflammation (colon and hippocampus) was assessed at 6-8 weeks of age. In adult mice anxiety (light/dark box) and cognition (novel object recognition [NOR] task) were performed, and tissue samples collected for analysis by qPCR. Compared to control mice, DSS-treated mice showed impaired object recognition and increased anxiety-like behaviors. Gene expression was assessed in the colon and showed increased expression of the pattern recognition receptors nucleotide-binding oligomerization domain Nod1 andNod2 (as well as increased expression of the anti-inflammatory cytokine, interleukin 10 (Il10), and genes involved in NF-κB signaling (IκB) in DSS-treated mice compared to controls. Finally, gene expression in the hippocampus showed increased expression of nod1, nod2, and brain derived neurotropic factor (Bdnf) in DSS-treated mice compared to sham-treated controls. Taken together, these results indicate that acute DSS-induced colitis in early adolescence can have long-lasting effects on the microbiota-gut-brain axis in adulthood.
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