Characterizing the microbiota‐gut‐brain axis in a murine model of pediatric inflammatory bowel disease

Abstract

Background Inflammatory bowel diseases (IBD) are chronic intestinal diseases affecting over 1.4 million Americans. Pediatric patients are especially vulnerable to the psychiatric effects seen in IBD as they are still undergoing brain maturation and neuroplasticity during periods of significant GI inflammation. A murine model of pediatric IBD and the mechanism(s) in which the microbiota‐gut‐brain axis is altered during this developmental time have yet to be identified. Aim Our goal was to develop a pediatric model of IBD and assess the effect on the microbiota‐gut‐brain axis at adulthood. Hypothesis We hypothesized that induction of ulcerative colitis by dextran sodium sulfate (DSS) at weanling mice (P21) would lead to lasting effects on the microbiota‐gut‐brain axis into adulthood, including behavioral deficits. Methods C57BL/6 mice (male and female) were weaned (P21) and treated with 2% DSS (or vehicle) for 5 days in the drinking water. In early adulthood (6–8 weeks of age), behavioral tests were performed (novel object recognition task [NOR], light/dark [L/D] box and open field test [OFT]) and tissue samples collected for PCR, immunofluorescence and microbiota analysis. Results DSS‐treated mice showed impaired object recognition and increased anxiety‐like behaviors compared to vehicle controls. Hippocampal gene expression showed increased expression of the pattern recognition receptors (Nod1 and Nod2), inflammatory cytokines (IL17ar, IL23 and IL22) along with a decreased expression of the neuronal activation markers (cFOS). Cell proliferation in the hippocampal dentate gyrus as quantified by doublecortin (DCX) staining showed significantly less DCX than vehicle controls. Finally, microbiota assessment identified persistent dysbiosis in DSS‐treated mice on alpha diversity, taxa abundance and phylum abundance compared to vehicle controls. Conclusions 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. Future studies will assess whether administration of probiotics can ameliorate these colitis‐induced microbiota‐gut‐brain axis deficits. Support or Funding Information Funding provided by Crohn’s & Colitis Foundation (CCFA)