Children diagnosed with autism spectrum disorders (ASD) often also suffer from inflammation of the gut resulting in gastrointestinal (GI) issues. A new study based on mouse models of autism, led by scientists at Harvard Medical School and the Massachusetts Institute of Technology, uncovers underlying mechanisms that trigger ASD-linked gut inflammation and GI symptoms.

The researchers show exposure to maternal inflammation in the womb increases susceptibility to bacteria-induced gut inflammation in the offspring later in life. The study zeroes in on interleukin-17A—a cytokine that is heightened in the mother following an infection during pregnancy.

The authors show IL-17A not only alters brain development in the fetus, but it also changes the mother’s gut microbiome that in turn affects the offspring’s immune system by altering the chromatin landscape in a subset of immune cells called CD4 positive T cells. This change in immune development primes the offspring for inflammatory attacks of the gut after birth.

The new findings are reported in an article titled, “Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4+ T cells,” published in the journal Immunity on December 7.

Gloria Choi, PhD, associate professor at the department of brain and cognitive sciences at the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, is co-senior author of the paper.

Earlier studies by co-senior authors of the paper Gloria Choi, PhD, associate professor at the department of brain and cognitive sciences at the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology, and Jun Huh, PhD, associate professor of immunology, Harvard Medical School, have focused on how increased levels of IL-17a during pregnancy acts on neural receptors in a specific region of the fetal brain to affect the development of neural circuits, leading to ASD-like behaviors in mouse models. The current paper focuses on how increased IL-17a can affect immune development as well.

Choi said: “One of the striking findings we made is that offspring’s immune cells remember what happened in the maternal womb, and this information gets transferred by the mother’s gut bacteria.”

The study suggests maternal immune activation (MIA) due to infection during pregnancy is a common environmental driver for neurodevelopmental and immunological symptoms in individuals with ASD.

“There has been no mechanistic understanding of why patients with a neurodevelopmental disorder have a dysregulated immune system,” said Huh. “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.”

Commenting on the study design Choi said, “We used a multi-pronged approach encompassing immunology, germ-free work, neuroscience, and behavioral biology.”

To confirm that MIA increases susceptibility to intestinal inflammation in the offspring, the researchers injected pregnant mice with polyinosinic:polycytidylic acid (poly I:C)—an immunostimulant that mimics viral infection—and observed that their offspring showed autism-like symptoms and gut inflammation when exposed to inflammatory stimuli.

Although neurodevelopmental abnormalities in the offspring in response to maternal MIA clearly develop prenatally, the time point when immune dysfunction starts in the offspring exposed to maternal MIA in the womb is not clear.

To identify the time window when the immune system in the offspring is affected, the researchers switched mouse pups at birth so that pups born to moms with MIA were reared by normal moms and pups born to normal moms were reared by MIA moms.

This experiment showed that pups born to MIA moms but reared by control moms exhibited ASD symptoms but not inflammation of the gut, whereas pups born to control moms but reared by MIA moms did not show neurobehavioral abnormalities but did show intestinal inflammation.

From these cross-fostering experiments, the authors inferred that while neurodevelopment is altered before birth, immune dysfunction in the offspring is altered postnatally.

The authors then probed how mouse moms with MIA affect the immune development of their pups postnatally. Earlier studies have shown that the maternal microbiome in the gut can influence the offspring’s immune development. To test whether the gut microbiome of mothers with MIA affects the immune development of their offspring, the researchers first examined stool samples from MIA and control mice and found that the microbiota was significantly different.

They then raised a new set of female mice in a germ-free environment such that they did not carry any microbes in or on their body. Upon transplanting stool samples from MIA or control moms into these germ-free moms and breeding them with germ-free males, they found pups born to MIA-stool-transferred moms experienced intestinal inflammation, but the controls did not.

Jun Huh, PhD, associate professor of immunology at Harvard Medical School, is co-senior author of the paper.

Based on these microbiota-transfer experiments, the authors concluded that the altered microbiomes of MIA moms result in immune priming of offspring for gut inflammation.

The pups exposed to the gut microbiota of moms with MIA also show higher levels of IL-17a, which the authors show is due to the increased differentiation of CD4 positive T cells into IL-17a-producing Th17 cells. Looking deeper into gene expression in CD4 T cells, the researchers noted that MIA-microbiome-exposed CD4 T cells exhibited higher expression of genes for T cell activation, indicating they were highly primed for T cell-dependent immune responses to infections.

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

Although the study suggests maternal infection can have long-term consequences for the offspring, further study is needed Huh said, to determine long-term effects on children born to mothers infected with SARS-Cov-2.

Choi added, “We hope to identify detailed mechanisms by which maternal gut bacteria can affect offspring’s immune cell function by changing the way their DNA structure is organized.” Emerging connections between inflammation and neurodegenerative diseases such as Alzheimer’s may also warrant further study in the light of the current findings that indicate maternal infection increases inflammation in offspring postnatally, Choi said.