Intestinal-brain connections in autistic patients

Many people with autism spectrum disorders also experience unusual gastrointestinal inflammation, but so far, scientists have not determined whether these conditions are related, and how they are connected

Now, researchers at Harvard Medical School and the Massachusetts Institute of Technology (MIT) have discovered the missing link by studying mouse models: infections during pregnancy cause the inflammatory signaling molecule interleukin-17a (IL-17a) Increased levels will not only affect the brain development of the fetus, but also change the maternal microbiota, thereby preparing the newborn’s immune system for future inflammatory attacks

In four studies starting in 2016, the second author of the research article Gloria Choi of MIT and Xiaojun of Harvard Medical School tracked how elevated IL-17a acts on neuroreceptors in a specific area of ​​the fetal brain during pregnancy.

New research findings published last month in the journal Immunity show that IL-17a can also change the trajectory of the immune system of offspring

"We have shown that IL-17a acting on the fetal brain can induce autism-like behavioral phenotypes, such as social deficits," said Choi, who is a member of the Picower Institute of Learning and Memory and the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology.

The researchers warn that although the findings have not been confirmed in humans, they do provide a hint that the central nervous and immune system problems of patients with autism spectrum disorder have a common environmental driver: mothers during pregnancy Infection

Professor Xu, associate professor of immunology at the Blavatnik Institute of Harvard Medical School, said: “There is currently no mechanistic understanding of why the immune system of patients with neurodevelopmental disorders is dysregulated

Tracking time

First, the research team began to prove that maternal immune activation (MIA) increases the susceptibility of offspring to intestinal inflammation

The neurodevelopmental abnormalities the research team tracked occurred while the fetus was still in the womb, but it is not clear when the altered immune response occurred

Microbiome-mediated molecular mechanism

But there is still a problem that cannot be ignored: How do mice with MIA affect their pups after birth? Other studies have found that the maternal microbiota can affect the development of the immune system of the offspring

Then, in order to determine whether these differences are causal, the researchers cultivated a new group of female mice in a "sterile" environment, which means that these mice do not carry any microorganisms in or on their bodies

One of the significant differences in the intestinal inflammatory response measured by the research team is the increase in IL-17a production by T cells, a major immune cell

This discovery prompted researchers to observe potential differences in how different groups of CD4 T cells alter gene transcription

"Therefore, the increase in IL-17a of the mother during pregnancy will cause the offspring to produce more IL-17a during the immune challenge," Choi said

After determining that the offspring’s immune system will become dysregulated by exposure to the mother’s altered microbiota due to an infection during pregnancy, the remaining question is how the microbiota changed in the first place

Suspecting IL-17a, the research team tested the effects of antibodies that block cytokines
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When they blocked IL-17a in pregnant mice before immune activation, their offspring would not have intestinal inflammation later in life
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This was also true when the researchers repeated the experiment of transplanting MIA feces into sterile mice, this time including the feces of pregnant MIA mice with IL-17a blockers
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Third, blocking IL-17a in the mother's infection will produce a microorganism that will not improperly activate the offspring's immune system
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Long-term problem

Xu Wenshuo said that the research results emphasized that environmental exposure during pregnancy, such as infection, may have long-term health consequences for offspring.
This concern has always existed, but it may be exacerbated by the COVID-19 pandemic
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He said that further research is needed to determine the long-term effects on children born to mothers infected with SARS-Cov-2
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Choi added that the link between inflammation and neurodegenerative diseases (such as Alzheimer's disease) may also require further research, because the team found that maternal infections lead to increased inflammation in offspring
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