Mum’s bacteria may harm offspring’s immune systems

Though many individuals with ASD also have severe gastrointestinal inflammation, experts have yet to determine how the two conditions are related.

Now, a new study from Harvard Medical School and MIT researchers suggests that when a mother has an infection during pregnancy, her immune system makes more of the molecule Interleukin-17a (IL-17a), which can change her fetus’s brain development and her microbiome so that after birth, the newborn’s immune system can be ready for more inflammatory attacks.

After Gloria Choi and Jun Huh started their research in 2016, they focused on four studies that looked at how high levels of IL-17a during pregnancy affect neural receptors in a region of the brain, causing the development of circuits that make mice act like they have autism-like behavior.

The new research, which was published today in Immunity, shows how IL-17a can also change the way the immune system grows.

“We’ve shown that IL-17a acting on the fetal brain can induce autism-like behavioral phenotypes such as social deficits,” says Choi, an associate professor at MIT.

“Now we are showing that the same IL-17a in mothers, through changes in the microbiome community, produces comorbid symptoms such as a primed immune system.”

There is still a lot of work to be done to confirm the study results in humans, but they do show that people with autism-spectrum disorders have problems with their central nervous and immune systems because their mothers were sick while they were pregnant.

 “There has been no mechanistic understanding of why patients with a neurodevelopmental disorder have a dysregulated immune system,” says Huh, an Associate Professor of Immunology at Harvard Medical School.

“We’ve tied these fragmented links together. It may be that the reason is that they were exposed to this increase in inflammation during pregnancy.”

First, the team injected pregnant mice with poly(I:C), a substance that looks like a virus, to show that maternal immune activation (MIA) makes offspring more likely to have intestinal inflammation. It was expected that their offspring would have autism-like symptoms, but not the offspring of mothers in a group that wasn’t affected. When they were exposed to other inflammatory stimuli, their intestines also became inflamed.

During the time the fetus is still in the womb, the neurodevelopmental aberrations happen, but it’s not clear when the immune responses changed. Mouse pups were switched at birth so that those born to MIA mothers were raised by the control mothers, and those born to control mothers were raised by the MIA mothers. This way, the team could figure out what happened. People who did the study found that pups born to MIA moms but raised by control moms had autism symptoms but not intestinal inflammation. Pups born to control moms but raised by MIA moms didn’t show signs of autism, but they did have a lot of inflammation in their intestines. While the brain changes before birth, the immune system changes after birth.

It then became a question about how MIA moms have this effect on pups after they’ve been born. Other studies have found that the mother’s microbiome can have an effect on the immune system development of her children. To see if that was true in the MIA model, the researchers looked at the stool from MIA and control mice. They found that the diversity of the microbial communities was very different between the two groups.

To see if these changes were causal, scientists raised a second batch of female mice in a “germ-free” environment, which means they don’t have any bacteria in or on their bodies. The scientists then implanted faeces from MIA or control mothers into these germ-free mothers and bred them with males. Unlike the controls, pups delivered to MIA-transferred mothers had intestinal inflammation. These findings suggested that the altered microbiota of MIA mothers causes immunological priming in their infants.

Among the major changes in the intestinal inflammation response observed by the team was an increase in IL-17a production by immune system T cells. IL-17a is the same cytokine that is elevated in MIA mothers. When the authors compared T cells from MIA-microbiome-exposed offspring to control offspring, they discovered that CD4 T cells from MIA-offspring were more likely to develop into Th17 cells, which release IL-17a.

This motivated them to investigate potential changes in how various populations’ CD4 T cells transcribe their genes. MIA-microbiome-exposed CD4 T cells expressed more T cell activation genes, indicating that they were better prepared for T cell-dependent immunological responses in response to infections.

“Thus, increase in IL-17a in moms during pregnancy leads to susceptibility to produce more IL-17a in offspring upon an immune challenge,” Choi adds.

After establishing that offspring’s immune systems can be mis-primed as a result of exposure to an altered microbiome of a mother who was infected during pregnancy, the next question was how that microbiome got altered in the first place. The team suspected IL-17a and examined the effects of antibodies that block the cytokine. When scientists suppressed IL-17a in mothers before immunological activation, their children did not have intestinal inflammation later in life. This was also true when the researchers performed the transplantation of MIA stool to germ-free women, this time incorporating stool from MIA-moms treated with IL-17a blockers. Again, inhibiting IL-17a during maternal infection resulted in a microbiome that did not mis-prime offspring’s immune systems.

Pregnant women who are exposed to things like infections can have long-term health effects on their offspring, which is a concern that has always been there but may be made worse by the Covid-19 pandemic. According to the authors, more research is needed to figure out how children born to mothers who had SARS-Cov-2 will fare in the long run.

Choi said that new research into the link between inflammation and neurodegenerative diseases like Alzheimer’s may be justified after the team found that maternal infection can make offspring more prone to inflammation.

Source: 10.1016/j.immuni.2021.11.005

Image Credit: Getty

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