Does Autism Begin in the Womb?

Summary: Researchers found idiopathic autism occurs as the result of epigenetic abnormalities in hematopoietic cells during fetal development, leading to immune dysregulation in the brain and gut.

Source: Kobe University

Autism (autism spectrum disorder) is a developmental neurological disorder that remains largely unexplored despite the rapidly increasing number of patients. Immune abnormalities, now considered the cause of many diseases, also play an important role in the development of autism.

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

However, the essential mechanisms behind these immune abnormalities have yet 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 the widespread immune dysregulation and originates in different types of progenitor cells.

The analysis focused on the hematopoietic cells from which immune cells are derived, as well as on the yolk sac (YS) and the aorta-gonad-mesonephros (AGM), which are involved in hematopoiesis during the fetal stage.

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

Research Findings

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

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

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

Administrating inhibitors of this histone (sodium butyrate or Romidepsin) during the fetal stage in BTBR mice suppressed elevated inflammatory cytokines and microglial activation.

This shows a pregnant woman's belly
The results of the study revealed that in autism, there are immune abnormalities which can be seen in the brain and gut. Image is in the public domain

We further demonstrated that dysregulated immunity can determine gut dysbiosis of specific profiles in autistic model mice, which make the potential biomarkers of Treg and gut dysbiosis a means to categorize the immune-dysregulated ASD subtype.

From the above, it is clear that the 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.

Perspectives

Our findings not only provide the missing piece to solve the long-time puzzle of systemic immune dysregulation in autism, but also hint the role of epigenetic disturbance as common etiology among different autism models of environmental risk factors.

Furthermore, to develop precision medicine for ASD in the future, ASD subtyping according to the pathogenesis mechanism is a key first step to resolve the heterogeneity of ASD and to open up a new avenue for ASD treatment.

About this autism research news

Author: Verity Townsend
Source: Kobe University
Contact: Verity Townsend – Kobe University
Image: The image is in the public domain

Original Research: Open access.
A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model” by Toru Takumi et al. Molecular Psychiatry


Abstract

A common epigenetic mechanism across different cellular origins underlies systemic immune dysregulation in an idiopathic autism mouse model

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

We hypothesize 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 is found that both in aorta-gonad-mesonephros (AGM) and yolk sac (YS) progenitors, the dysregulation of HDAC1-mediated epigenetic machinery alters definitive hematopoiesis during embryogenesis and downregulates the expression of the AP-1 complex for microglia development.

Subsequently, these changes result in the dysregulation of the immune system, leading to gut dysbiosis and hyperactive microglia in the brain.

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

Our findings elucidate a shared mechanism for the origin of immune dysregulation from the brain to the gut in autism and provide new insight to dissecting the heterogeneity of autism, as well as the therapeutic potential of targeting immune-dysregulated autism subtypes.

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  1. I often wonder if exposure to PFAS/PFOA has anything to do with this as forever chemicals have immune system effects. Would be an interesting case study.

  2. I have a child with a form of autism. I worked for an allergist who tested and treatment a large number of autistic children who improved once food allergies were determined and dietary changes occurred. All had some improvements, some more then others. Since this finding connects autism to development and what’s behind it, my question is… could this change be connected to the chemicals and pesticides in our foods? What we ingest is passed on from generation to generation in our genetics and over time they build on one another and mutate and overload our bodies. Autism has been on the rise since the foods we eat have been chemically ultered. This needs to be investigated to confirm there is a connection. Don’t just treat the symptoms or in this case the ulteration, find the source of what’s causing the ulteration and fix that to permanently take care of the problem.

    1. Because the for profit only USA operates entirely for financial gain, this will never happen here. We can hope the UK may take up such a study. They’re light years ahead of us in healthcare, treatments, health and food safety.

  3. Again, another complete miss in autism research, presenting it as a disease and/or abnormality and looking for answers in mice.
    Yes, autism starts in the womb. No, it’s not abnormal. It’s a naturally occurring divergence with very specific traits that has clear evolutionary basis.
    I only see researchers here fishing in the dark when an obvious answer is staring them in the face. If nothing else, at least try using Occam’s razor.

  4. this is a fascinating research development, but y’all should really avoid using such pathologizing language in talking about Autistic people. I’m proudly Autistic, don’t consider myself remotely diseased for being so, and would never even want to imagine a life in which I wasn’t Autistic. I consider allistic people disabled; the profound limits of their imagination and comprehension just seem so sad and unfulfilling to me. caring more about what popular opinion dictates than their own authentic passions and insights is a road to nothing but toxic feedback loops and mob rule.

    we are an essential, advantageous, and immutable aspect of human neurodiversity, and despite being systematically disenfranchised and treated as a problem by rigidly allistic and eugenic power structures, we continue to create the artistic, scientific, and philosophical advances that allow for better and more fulfilling lives for all of humanity.

    be better. we already are. you’re all welcome.

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