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A study from the tummy to the brain

Autism spectrum disorder (ASD) finds more and more understanding as a condition that extends beyond neurological differences, frequently co-occurring with a range of chronic physical health challenges. Gastrointestinal (GI) issues stand out for their prevalence and complexity. Emerging research highlights a potential link between neurodevelopmental and immune dysregulation, shedding light on the co-morbidity of ASD and GI inflammation. Understanding this connection is critical for addressing the multifaceted healthcare needs of autistic individuals.

A recent Harvard Medical School and Massachusetts Institute of Technology (MIT) study offers compelling insights into the mechanisms underpinning the co-occurrence of ASD and GI inflammation. Utilizing mouse models, the researchers demonstrated that infections during pregnancy could have profound effects on offspring. Specifically, maternal infections elevate the inflammatory signaling molecule interleukin-17a (IL-17a). This molecule, already implicated in altering fetal brain development and contributing to autism-like behaviors, was also shown to influence the maternal microbiome, priming the immune systems of offspring for heightened inflammatory responses postnatally.

The study, published in Immunity, builds on a series of findings since 2016 by co-senior authors Gloria Choi of MIT and Jun Huh of Harvard. Their work has traced how elevated IL-17a during pregnancy affects fetal brain development, resulting in autism-like social deficits in mice. The new findings expand on this, revealing that IL-17a-mediated changes in the maternal microbiome during pregnancy can predispose offspring to gut inflammation when exposed to inflammatory stimuli later in life. These findings underscore a shared environmental driver for the central nervous and immune system dysregulation observed in individuals with ASD.

The researchers employed a series of experiments to explore the timing and mechanisms of these effects. Inducing maternal immune activation (MIA) in pregnant mice through a substance miming viral infection, they observed both autism-like behavioral symptoms and GI inflammation in the offspring. Interestingly, the neurodevelopmental alterations occurred in utero, while the altered immune responses developed after birth. Cross-fostering experiments further revealed that the maternal microbiome plays a pivotal role in immune priming. Pups born to MIA mothers but reared by control mothers exhibited autism-like symptoms but not intestinal inflammation. In contrast, pups born to control mothers but reared by MIA mothers developed gut inflammation but not autism-like behaviors.

To delve deeper into the role of the maternal microbiome, researchers raised mice in germ-free environments and transplanted stool from MIA or control mice into these germ-free subjects. Pups born to mice receiving MIA stool exhibited intestinal inflammation, confirming that changes in the maternal microbiome mediate immune priming. The researchers identified increased IL-17a production by T cells in these offspring, linking maternal infection-induced microbiome changes to postnatal immune dysregulation.

Blocking IL-17a during pregnancy provided further evidence of its role. Pregnant mice treated with IL-17a-blocking antibodies before immune activation gave birth to offspring that did not exhibit gut inflammation. Its successful blocking suggests that IL-17a’s influence on the maternal microbiome is critical in shaping offspring’s immune system. These findings have far-reaching implications, particularly in light of recent pandemics, as maternal infections could have long-term health consequences for children.

The co-morbidity of ASD and GI issues, however, is not limited to inflammatory mechanisms. Broader research on autistic individuals highlights the complexity of their physical health challenges. Studies, such as those led by Dr. Elizabeth Weir at the Autism Research Centre in Cambridge, have documented high rates of multimorbidity in autistic populations, spanning conditions like coeliac disease, migraines, and connective tissue disorders such as Ehlers-Danlos Syndrome. Sensory sensitivities and trauma often compound these issues, amplifying emotional dysregulation and physical stress that may exacerbate underlying health conditions.

These findings underscore the urgent need for tailored, multidisciplinary healthcare approaches. Early identification and continuous monitoring of chronic conditions in autistic individuals are essential. Collaborative care models integrating neurology, gastroenterology, and immunology could provide more comprehensive management of co-occurring conditions. Additionally, addressing sensory sensitivities through environmental modifications and incorporating therapies such as Dialectical Behavior Therapy (DBT) for emotional resilience could enhance overall well-being.

The link between maternal inflammation, neurodevelopment, and immune priming offers a compelling framework for understanding the shared pathways underlying ASD and GI issues. By recognizing the interplay of neurodevelopmental and physical health challenges, healthcare systems can move toward more inclusive, patient-centered models of care. These efforts not only address the immediate needs of autistic individuals but also advance a broader commitment to fostering environments where all individuals, regardless of neurological or physical differences, can thrive.