Early Influences of Microbiota on White Matter Development in Germ-Free Piglets.

Sadia Ahmed,Ashwin K Ramesh,Stephen Laconte,Sierrah D Travis,Brittany R Howell,Alicia M Pickrell,Sara N Henry,Hanzhang Ding,Julia Mykins,Jing Ju,Francisca V Díaz-Bahamonde,Aryn Booker,Demisha D L Porter,Lijuan Yuan,Maosen Wang,Paul D Morton,Aditya Ravipati

doi:10.3389/fncel.2021.807170

Abstract

Abnormalities in the prefrontal cortex (PFC), as well as the underlying white matter (WM) tracts, lie at the intersection of many neurodevelopmental disorders. 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. 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. 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. 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. 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. 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.

Highlights

Though the brain serves as the master regulator of the body, it is heavily influenced by other systems with hubs located in distant compartments
In accordance with the findings that OL proliferation is not affected by GF conditions in the subventricular zone (SVZ), but OL numbers and OL maturation are significantly lower in prefrontal cortex (PFC), corpus callosum (CC)-Genu, CCBody, and CC-Splenium, we considered the underlying cause may be a reduction in local pools of oligodendrocyte progenitor cells (OPC) within these white matter (WM) tracts
A significant reduction in proliferating OLs (Olig2+ Ki67+) was seen in prefrontal cortical white matter (PFCWM) of GF piglets compared with controls (Figures 6A,C). These findings indicate a halt in cell proliferation in PFCWM at birth, when the gut is initially colonized with microbiota, resulting in less mature OLs to build upon key WM tracts

Summary

Introduction

Though the brain serves as the master regulator of the body, it is heavily influenced by other systems with hubs located in distant compartments. 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. There is an abundance of clinical evidence suggesting that dysfunction of the GBA is a common culprit underlying a wide spectrum of neurodevelopmental disorders. 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). 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; PrehnKristensen et al, 2018). Gut dysbiosis preceding immune imbalances has been shown in human schizophrenia cases (Severance et al, 2013, 2016)

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Results

Conclusion