Gut dysbiosis preceding immune imbalances has also been shown in human schizophrenia cases ( Severance et al., 2013, 2016). Dietary immunomodulation issues ( Verlaet et al., 2014), allergic sensitization ( de Theije et al., 2014), and reductions in microbiome alpha diversity are seen in young patients with attention deficit hyperactivity disorder (ADHD Prehn-Kristensen et al., 2018). For example, intestinal complications ( de Magistris et al., 2010), changes in microbial composition ( Louis, 2012), and food allergies ( de Theije et al., 2014) have been documented in pediatric patients with autism spectrum disorders (ASD). There is an abundance of clinical evidence suggesting that dysfunction of the GBA is a common culprit underlying a wide spectrum of neurodevelopmental disorders. Because the gut is a major source of microorganisms (i.e., bacteria, viruses, fungi, and protozoa), along with their collective genetic materials (i.e., microbiome), alterations in diversity or composition of gut microbiota can impact the brain thus resulting in the modern nomenclature of gut microbiota-brain axis or brain-gut microbiome axis defining a reciprocal relationship ( Martin et al., 2018 Morais et al., 2021). Studies providing evidence of the therapeutic importance of the GBA were historically seeded by observations of psychological stress as a comorbidity in human patients with inflammatory bowel disease ( Mawdsley and Rampton, 2005 Cámara et al., 2009 Cryan and O’Mahony, 2011 Kennedy et al., 2012). The gut-brain axis (GBA) is one example of such crosstalk inclusive of a bidirectional network fostering communication between the central nervous system (CNS), autonomic nervous system (ANS), enteric nervous system (ENS), and hypothalamic pituitary adrenal (HPA) axis ( Carabotti et al., 2015). Though the brain serves as the master regulator of the body, it is heavily influenced by other systems with hubs located in distant compartments. Our findings indicate that microbiota plays a critical role in promoting WM development during early life when the brain is vulnerable to environmental insults that can result in an array of disabilities manifesting later in life. We find significant region-specific reductions, and sexually dimorphic trends, in WM volume, oligodendrogenesis, and mature oligodendrocyte numbers in germ-free piglets during a key postnatal epoch of myelination. Here, we develop and validate a neonatal germ-free swine model to address these issues, as piglets share key similarities in WM volume, developmental trajectories, and distribution to humans. Microbial colonization of the gut aligns with ongoing postnatal processes of oligodendrogenesis and the peak of brain myelination in humans however, the influence of microbiota on gyral WM development remains elusive. In addition, gut dysbiosis is common in preterm birth patients who often display diffuse WM injury and delayed WM maturation in critical tracts including those within the PFC and corpus callosum. The influence of microorganisms on brain development has recently been brought into the clinical and research spotlight as alterations in commensal microbiota are implicated in such disorders, including autism spectrum disorders, schizophrenia, depression, and anxiety via the gut-brain axis.
8Department of Human Development and Family Science, Virginia Tech, Roanoke, VA, United StatesĪbnormalities in the prefrontal cortex (PFC), as well as the underlying white matter (WM) tracts, lie at the intersection of many neurodevelopmental disorders.7Biomedical Engineering and Mechanics, Virginia Tech, Blacksburg, VA, United States.6Fralin Biomedical Research Institute at Virginia Tech Carilion (VTC), Virginia Tech, Roanoke, VA, United States.5School of Neuroscience, Virginia Tech, Blacksburg, VA, United States.4Molecular Microbiology and Immunology, University of Missouri, Columbia, MO, United States.3Virginia Tech Graduate Program in Translational Biology, Medicine and Health, Virginia Tech, Roanoke, VA, United States.
2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States.1Graduate Studies in Biomedical and Veterinary Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA, United States.Pickrell 5 Maosen Wang 6 Stephen LaConte 6,7 Brittany R. Henry 2 Julia Mykins 2 Aditya Ravipati 2 Aryn Booker 2 Jing Ju 1 Hanzhang Ding 3 Ashwin K.
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