Does autism start in the womb?

Summary: Researchers have found that idiopathic autism occurs as a result of epigenetic abnormalities in blood-forming cells during fetal development, leading to immune dysregulation in the brain and gut.

Source: Kobe University

Autism (autism spectrum disorder) is a neurodevelopmental disorder that remains largely unexplored despite the rapid increase in the number of patients. Immune abnormalities, now thought to be the cause of many diseases, also play an important role in the development of autism.

Cerebral inflammation and disturbances of the peripheral immune system are frequently observed in autistic patients. Moreover, immune abnormalities are accompanied by abnormalities of the intestinal microbiota, which would also be involved in the pathogenesis of the disease via the brain-gut axis.

However, the essential mechanisms underlying these immune abnormalities remain to be elucidated.

Given the critical developmental stages of immune insults and the significant 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 (YS) and aorta-gonad-mesonephros (AGM), which are involved in hematopoiesis at the stage fetal.

These findings search for a common ancestor of inflammation in the brain and peripheral immune system abnormalities. In this study, BTBR mice were used as an idiopathic model for autism.

search results

Single-cell RNA sequencing (sc-RNA seq) of BTBR mice traced the origin of immune abnormalities back to the embryonic yolk sac (YS) and aorta-gonad-mesonephros (AGM) stages and identified where macrophages (microglia) and peripheral immune cells differentiate.

Definitive hematopoiesis in YS and AGM single-cell level analysis has successfully identified pathological mechanisms at the molecular level in rare progenitor cells at early stages of development. Namely, we found a common mechanism of transcriptional regulation via HDAC1, a histone deacetylase, underlying these pathologies.

We have also shown that manipulating epigenetic mechanisms during specific developmental stages can restore immune abnormalities in brain and peripheral tissues. Namely, we identified histone deacetylase HDAC1 as a common mechanism.

Administration of this histone inhibitors (sodium butyrate or romidepsin) at the fetal stage in BTBR mice suppressed elevated inflammatory cytokines and microglial activation.

The study results revealed that in autism, there are immune abnormalities that can be seen in the brain and gut. Image is in public domain

We further demonstrated that dysregulated immunity can determine gut dysbiosis of specific patterns in autistic mouse models, making potential biomarkers of Treg and gut dysbiosis a means to categorize the immunosupregulated ASD subtype.

From the above, it is clear that the abnormalities of 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. .

Perspectives

Our findings not only provide the missing piece to solve the long-standing puzzle of systemic immune dysregulation in autism, but also suggest the role of epigenetic disruption as a common etiology among different risk factor models of autism. environmental.

Moreover, to develop precision medicine for ASDs in the future, subtyping ASDs based on the mechanism of pathogenesis is a key first step to resolve the heterogeneity of ASDs and open a new avenue for treatment. of ASDs.

About this autism research news

Author: Townsend Truth
Source: Kobe University
Contact: Verity Townsend – Kobe University
Picture: Image is in public domain

Original research: Free access.
“An epigenetic mechanism common to different cellular origins underlies systemic immune dysregulation in an idiopathic autistic mouse model” by Toru Takumi et al. Molecular psychiatry


Abstract

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An epigenetic mechanism common to different cellular origins underlies systemic immune dysregulation in a mouse model of idiopathic autism

Immune dysregulation plays a key role in the pathogenesis of autism. Changes occurring at the systemic level, ranging from brain inflammation to disturbed innate/adaptive immunity at the periphery, are frequently observed in autistic patients; however, the intrinsic mechanisms behind them remain elusive.

We hypothesize that a common etiology may lie in progenitors of different types underlying widespread immune dysregulation. By single-cell RNA sequencing (sc-RNA seq), we trace the developmental origins of immune dysregulation in a mouse model of idiopathic autism.

It was found that in aorta-gonad-mesonephros (AGM) and yolk sac (YS) progenitors, HDAC1-mediated dysregulation of the epigenetic machinery alters definitive hematopoiesis during embryogenesis and regulates to the decrease in the expression of the AP-1 complex for the development of microglia.

Subsequently, these changes result in dysregulation of the immune system, resulting in gut dysbiosis and overactive microglia in the brain.

We further confirm that dysregulated immune profiles are associated with a specific microbiota composition, which can serve as a biomarker to identify autism of immunosupregulated subtypes.

Our findings elucidate a common mechanism underlying brain-to-gut immune dysregulation in autism and provide new insights to dissect the heterogeneity of autism, as well as the therapeutic potential of subtype targeting. immune dysregulated autism.

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