Maternal inflammation could link autism and bowel problems, suggests mouse study

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Although many individuals with autism spectrum issues even have uncommon gastrointestinal infections, scientists have failed to find out how these issues may very well be associated. Now researchers at Harvard Medical School and MIT, who work with mouse fashions, could have discovered the connection: If a mom suffers an an infection throughout being pregnant and her immune system produces elevated ranges of the molecule interleukin-17a (IL-17a), it can not to alter solely the mind improvement of your fetus, but additionally to alter its microbiome in such a manner that the immune system of the new child may be ready for future inflammatory assaults after delivery.

In 4 research beginning in 2016, examine co-senior writers Gloria Choi of MIT and June Huh from Harvard have adopted how elevated IL-17a throughout being pregnant acts on neural receptors in a particular area of the fetal mind to change circuit improvement resulting in autism-like behavioral signs in mouse fashions. The new examine, which was launched on December seventh in. has been revealed immunity reveals how IL-17a also can alter immune system improvement.

"We have shown that IL-17a, acting on the fetal brain, can induce autism-like behavioral phenotypes, such as social deficits," stated Choi, Mark Hyman Jr. Associate Professor of Career Development on the Picower Institute for Learning and Memory and the Department of Brain and Cognitive Science at MIT. "Now we are showing that the same IL-17a causes comorbid symptoms such as a prepared immune system in mothers through changes in the microbiome community."

The researchers warn that the examine leads to people have but to be confirmed, however that they do present proof that central nervous system and immune system issues in folks with autism spectrum issues share an environmental issue: maternal an infection throughout being pregnant.

"There has been no mechanistic understanding of why patients with neurodevelopmental disorder have dysregulated immune systems," stated Huh, affiliate professor of immunology at Harvard Medical School. “We have linked these fragmented connections collectively. The cause could also be that they had been uncovered to this enhance in irritation throughout being pregnant. "

Eunha Kim and Donggi Paik from Huh's laboratory are the co-lead authors on the study.

Tracking timing

The research team first confirmed that maternal immune activation (MIA) made offspring more susceptible to intestinal inflammation by injecting pregnant mice with poly (I: C), a substance that mimics a viral infection. As expected, their offspring, but not the offspring of mothers in an unaffected control group, showed symptoms similar to autism and also bowel inflammation when exposed to other inflammatory stimuli.

While the neurodevelopmental disorders tracked by the team occur while the fetus is still in the womb, it was not clear when the altered immune responses developed. To find out, the team swapped the mouse pups at birth so that those born to MIA mothers were raised by control mothers and those born to control mothers were raised by MIA mothers. The team found that puppies from MIA mothers raised by control mothers had the symptoms of autism but no bowel inflammation. Puppies born to control mothers but raised by MIA mothers did not show symptoms of autism but did show bowel inflammation. The results showed that while neurological development is altered before birth, the immune response is altered postnatally.

Microbiome-mediated molecular mechanism

The question then arose how MIA mothers have this postnatal effect on puppies. Other studies have found that the maternal microbiome can influence the development of the offspring's immune system. To test whether this was the case in the MIA model, the researchers examined the stool of MIA and control mice and found that the diversity of the microbial communities was significantly different.

To find out whether these differences play a causal role, they bred a new group of female mice in a "sterile" environment, which means that they do not carry any microbes in or on their bodies. Then the scientists transplanted stool from MIA or control mothers into these aseptic mothers and bred them with males. In contrast to controls, puppies born to mothers with MIA stool transmission showed bowel inflammation. These results showed that the altered microbiome of MIA mothers leads to the immune activation of the offspring.

Among the notable differences the team measured in the intestinal inflammatory response was an increase in IL-17a production by immune system T cells. IL-17a is the same cytokine that levels are upregulated in MIA mothers. When the scientists compared T cells from MIA microbiome-exposed offspring to control offspring, they found that CD4 T cells in MIA offspring were more likely to differentiate into Th17 cells, which release IL-17a.

This prompted them to investigate possible differences in the way the CD4 T cells of the different groups transcribe their genes. CD4 T cells exposed to MIA microbiome showed higher expression of genes for T cell activation, suggesting that they were more prepared for T cell-dependent immune responses in response to infection.

"Therefore, a rise in maternal IL-17a throughout being pregnant causes the offspring to supply extra IL-17a when challenged by the immune system," Choi said.

After discovering that the immune system of offspring can be misdirected by exposure to the altered microbiome of a mother infected during pregnancy, the question remained, how is this microbiome altered in the first place. When IL-17a was suspected, the team tested the effects of antibodies that block the cytokine. When they blocked IL-17a in mothers before immune activation, their offspring did not show bowel inflammation later in life. This was also true when the researchers repeated the experiment of transplanting MIA stool to aseptic mothers, this time including stool from MIA mothers with IL-17a blockers. Again, the blockade of IL-17a during a maternal infection resulted in a microbiome that the offspring's immune system did not improperly prepare.

Long term questions

Huh said the results highlight that environmental stresses during pregnancy, such as: More studies are needed, he said, to determine the long-term effects on children of mothers infected with SARS-Cov-2.

Choi added that emerging links between inflammation and neurodegenerative diseases like Alzheimer's disease could warrant further study, given the team's findings on how infections in the mother can lead to increased inflammation in the offspring.

Reference: Kim E., Paik D., Ramirez RN, et al. Maternal gut bacteria promote intestinal inflammation in offspring with neurodevelopmental disorders by changing the chromatin landscape of CD4 + T cells. immunity. 2021; 0 (0). do: 10.1016 / j.immun.2021.11.005

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