Does Autism Develop in the Womb? A Million Dollar Question


Autism is a neurodevelopmental disorder that remains largely unexplored despite rapidly increasing numbers of patients. Immune abnormalities, now considered to be the cause of many diseases, also play a role in the development of autism. Brain swelling and peripheral immune system disturbances are commonly seen in autistic patients. In addition, immune abnormalities are accompanied by abnormalities in the gut microbiota, which is also thought to be involved in disease pathogenesis through the gut-brain axis. However, the essential mechanisms behind these immune abnormalities remain to be elucidated.

Given the critical developmental stages of immune insults and the extensive involvement of the immune system in the development of autism, the research team hypothesized that a common etiology underlies widespread immune dysregulation and originates from different types of progenitor cells. The analysis focused on hematopoietic cells from which immune cells are derived, as well as the yolk sac and aorta-gonad-mesonephros, which are involved in hematopoiesis during the fetal stage. These results look for a common ancestor of inflammation in the brain and abnormalities in the peripheral immune system. BTBR mice were used as an idiopathic model for autism for this study.

Results of this Research

  • HDAC1 has been identified as the etiology of immune abnormalities through single-cell RNA-seq analysis of AGM blood cells in BTBR mice, an animal model of autism.
  • A single-cell RNA-seq analysis of yolk sac hematopoietic cells also identified HDAC1 as the etiology of microglial developmental abnormalities.
  • Regulation of HDAC activity during the fetal stage ameliorated brain inflammation and immune dysregulation in BTBR mice.
  • Changes were found in the gut environment, especially in the immune system, and lead to abnormalities in the gut microbiota of BTBR mice.

Findings of the Research

Single-cell RNA sequencing of BTBR mice traced the origin of immune abnormalities back to the yolk sac and aorta-gonad-mesonephros embryonic stages and identified where the macrophages (microglia) and the peripheral ones differ. Definitive hematopoiesis successfully identified pathological mechanisms at the molecular level within rare progenitor cells at early stages of development. That is, a common mechanism of transcriptional regulation through HDAC1, a histone deacetylase, underlying these pathologies has been found.

We have also shown that manipulation of epigenetic mechanisms during specific developmental stages can restore immune abnormalities in the brain and peripheral tissues. That is, the histone deacetylase HDAC1 has been identified as a common mechanism. Administration of inhibitors of this histone (sodium butyrate or Romidepsin) during the fetal stage in BTBR mice suppressed elevated inflammatory cytokines and microglial activation.

Furthermore, dysregulated immunity can determine gut dysbiosis of specific profiles in autistic model mice, making potential biomarkers of Treg and gut dysbiosis a means of categorizing the immunodysregulated autism spectrum disorder subtype.

From the above, it is clear that abnormalities in the brain and peripheral organs (such as the intestines) seen in autism are caused by epigenetic abnormalities in the hematopoietic stem cell lineage, the ancestor of immune cells.

Source: Medindia

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