A leaky gut dysregulates gene networks in the brain associated with immune activation, oxidative stress, and myelination in a mouse model of colitis.

Autor:	Boles JS; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Krueger ME; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Jernigan JE; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Cole CL; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Neighbarger NK; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Huarte OU; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA., Tansey MG; Department of Neuroscience, College of Medicine, University of Florida, Gainesville, FL, USA.; Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, FL, USA.; McKnight Brain Institute, University of Florida, Gainesville, FL, USA.; Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Aug 13. Date of Electronic Publication: 2023 Aug 13.
DOI:	10.1101/2023.08.10.552488
Abstrakt:	The gut and brain are increasingly linked in human disease, with neuropsychiatric conditions classically attributed to the brain showing an involvement of the intestine and inflammatory bowel diseases (IBDs) displaying an ever-expanding 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 biochemical outcome measures to achieve 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 as the intermediary between the gut and brain, which exhibits an activation of pro-inflammatory innate immunity during colitis. Our unbiased transcriptomics analysis provides supporting evidence for immune activation in the brain during colitis, suggests that myelination may be a process vulnerable to increased 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 in the gut-brain axis, and contribute to our understanding of the concomitance of intestinal and neuropsychiatric dysfunction. Competing Interests: Conflict of interest The authors declare no conflicts.
Databáze:	MEDLINE
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