Harvard and MIT researchers identify possible mechanism linking autism and intestinal inflammation

Many people with autism spectrum disorders also experience unusual gastrointestinal inflammation, but thus far scientists have not established whether and how those conditions might be linked.

Now, Harvard Stem Cell Institute (HSCI) researchers at Harvard Medical School, along with MIT researchers, may have found the missing link: infections during pregnancy can lead to high levels of the inflammatory signaling molecule interleukin-17a (IL-17a). The molecule can not only affect brain development in the fetus, but also alter the maternal microbiome in a way that primes the newborn’s immune system for future inflammatory attacks.

In four studies beginning in 2016, study co-senior authors Gloria Choi of MIT and Jun Huh of Harvard Medical School have traced how elevated IL-17a during pregnancy acts on neural receptors in a specific region of the fetal brain to alter circuit development, leading to autism-like behavioral symptoms in mouse models.

The new research findings, which were described in the journal Immunity last month, show how IL-17a can also act to alter the trajectory of offspring’s immune system development.

“We’ve shown that IL-17a acting on the fetal brain can induce autism-like behavioral phenotypes such as social deficits,” said Choi, the Mark Hyman Jr. Career Development Associate Professor in the Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences at MIT. “Now we are showing that the same IL-17a in mothers, through changes in the microbiome community, produces comorbid symptoms in the offspring, specifically a primed immune system.”

The researchers caution that while the study findings are yet to be confirmed in humans, they do offer a hint that central nervous and immune system problems in individuals with autism-spectrum disorders share an environmental driver: maternal infection during pregnancy.

“There has been no mechanistic understanding of why patients with a neurodevelopmental disorder have dysregulated immune system,” said Huh, an HSCI affiliate faculty member and associate professor of immunology at the Blavatnik Institute at Harvard Medical School. “With the new findings, 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.”

Tracking timing

First, the research team set out to confirm that maternal immune activation (MIA) leads to enhanced susceptibility to intestinal inflammation in their offspring. To do so, they injected pregnant mice with a substance that mimics viral infection. As expected, their offspring exhibited autism-like behavioral symptoms as well as gut inflammation when exposed to other inflammatory stimuli. These symptoms and inflammation were absent in the offspring of pregnant mice in an unaffected control group.

The neurodevelopmental aberrations the team tracked occurred while the fetus was still in the womb, yet it was not clear when the altered immune responses developed. To find out, the researchers switched mouse pups at birth so that those born to mice with immune activation were reared by mice from the inflammation-free control group, while pups born to mice from the control group were reared by mice with MIA.

The team found that pups born to mice with MIA but reared by mice from the control group exhibited the autism-like symptoms but not the intestinal inflammation. Pups born to mice from the control group but reared by mice with MIA did not show autism-like symptoms but did experience intestinal inflammation. The results indicate that while neurodevelopmental pathways are altered before birth, the immune response is altered after it.

Microbiome-mediated molecular mechanism

Still one question loomed large: How did mice with MIA exercise this immune-altering effect on pups after birth? Other studies have found that the maternal microbiome can influence the immune system development of offspring. To test whether that was the case in the MIA model, the researchers examined stool from MIA and control mice and found that the diversity of the microbial communities was significantly different.

Then, to determine whether these differences played a causal role, the researchers raised a new set of female mice in a “germ-free” environment, meaning that the mice do not carry any microbes in or on their body. Then the scientists transplanted stool from MIA or control mice into these germ-free mice that subsequently got pregnant. Unlike with the controls, pups born to mice that received stool (and thus microbes) from mice with MIA exhibited intestinal inflammation. These results indicate that the altered microbiome of mice with MIA leads to the postnatal immune priming of offspring during rearing.

The intestinal inflammation response included an increase in IL-17a production by T cells, a major class of immune cells. IL-17a is the same cytokine that gets upregulated in mice with MIA. When the scientists compared the T cells of offspring from mice with MIA with those from control offspring, they found that in MIA-offspring, CD4 T cells were more likely to lead to the release of IL-17a.

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

Long-term questions

Huh said the results highlight how environmental exposures during pregnancy, such as infection, could have long-term health consequences for the offspring, a concern that has always been present but that may be exacerbated by the COVID-19 pandemic. Further study is needed, he said, to determine long-term effects on children born to mothers infected with SARS-Cov-2.

Choi added that emerging connections between inflammation and neurodegenerative diseases such as Alzheimer’s may also warrant further study given the team’s findings of how maternal infection can lead to enhanced inflammation in offspring.

Read more

Eunha Kim and Donggi Paik of Huh’s lab are the study’s co-lead authors. Other investigators included Ricardo Ramirez, Delaney Biggs, Youngjun Park, and Ho-Keun Kwon.

The work was supported by the National Research Foundation of Korea, the Jeongho Kim Neurodevelopmental Research Fund, The Simons Foundation Autism Research Initiative, the National Institutes of Health, the N of One Autism Research Foundation, and the Burroughs Wellcome Fund.

This story was adapted from the MIT news website.

Kim, E., Paik, D., et al. (2021). Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4+ T cells. Immunity. DOI: 10.1016/j.immuni.2021.11.005