Examining the brain's response to intestinal permeability and inflammation in the dextran sulfate sodium-induced colitis model.
The gut and brain are increasingly linked in human disease, with neuropsychiatric conditions classically long attributed to the brain showing an involvement of the intestine and inflammatory bowel diseases displaying an ever-lengthening list of neurological comorbidities. To identify molecular systems that underpin this gut-brain connection and thus discover therapeutic targets, experimental models of gut dysfunction must be evaluated for brain effects. In the present study, we examine disturbances along the gut-brain axis in a widely used murine model of colitis, the dextran sodium sulfate (DSS) model, using high-throughput transcriptomics and an unbiased network analysis strategy coupled with standard outcome measures, yielding a comprehensive approach to identify key disease processes in both colon and brain. We examine the reproducibility of colitis induction with this model and its resulting genetic programs during different phases of disease, finding that DSS-induced colitis is largely reproducible with a few site-specific molecular features. We focus on the circulating immune system, which exhibits an activation of pro-inflammatory innate immunity during colitis, as the vessel between gut and brain. Our unbiased approach provides supporting evidence for immune activation in the brain during colitis, suggests that myelination may be a vulnerable system with intestinal permeability, and identifies a possible role for oxidative stress and brain oxygenation. Overall, we provide a comprehensive evaluation of multiple systems in a prevalent experimental model of intestinal permeability, which will inform future studies using this model and others, assist in the identification of druggable targets, and contribute to our understanding of the concomitance of intestinal and neuropsychiatric dysfunction. Overall design: C57Bl6/J mice were treated with 2.5% DSS, assigned to various treatment schedules to create a time-series as follows: untreated controls, 5d DSS, 7d DSS, 7d DSS + 2d recovery, 7d DSS + 5d recovery, 7d DSS + 7d recovery, and 7d DSS + 14d recovery. After their respective schedules, mice were euthanized via rapid decapitation and tissues were harvested. Distal and proximal segments of the colon were taken to assess molecular processes associated with colitis and evaluate the reproducibility of these systems. From the brain, cortex, hippocampus, ventral midbrain, and striatum were taken to examine both global and regionally-specific transcriptomic perturbances that emerge in response to gut leakiness. All tissues were assayed with high-throughput RNA sequencing.