Infection in Pregnant Mice Increases Risk of Gut Problems in Puppies | Spectrum

Immune boost: Alterations in the gut microbiome of a mother mouse can instill an overactive immune response in her offspring.

IKELOS GmbH/Dr. Christopher B. Jackson/Scientific Source

Pregnant mice that develop an immune reaction have offspring with autism-like traits and a increased susceptibility to intestinal inflammation, according to a new study.

Findings May Help Explain Why Many Autistic People Have Gastrointestinal Problems, Study Investigator Says Eunha Kim, postdoctoral researcher in june eh‘s lab at Harvard University.

Previous work has shown that prenatal exposure to the maternal immune response – brought about by viral mimicry – induces autism-like traits in mice. And a serious infection or an overactive immune system during pregnancy increases the likelihood of having an autistic child, other studies show.

But a different mechanism underlies gut problems, Kim and her colleagues found. They come from alterations in the mother’s gut microbiome – the mix of microbes that inhabit the stomach and intestines – to which puppies are exposed after birth. The mother’s atypical gut microbiome, in turn, causes the puppies’ immune system to overreact to infections later on.

Studying this newly identified mechanism may help researchers better understand how maternal immune activation and autism are linked to other conditions, such as allergies, says John Lukens, associate professor of neuroscience at the University of Virginia in Charlottesville. Lukens was not involved in the study but wrote about the results in a article preview.

“It could be some kind of evolutionary advantage that went haywire,” he says.

Kim and his colleagues injected pregnant mice with either a fake virus or a saline solution. As adults, male offspring exposed to the fake virus exhibited atypical social behaviors, similar to those seen in people with autism.

The team then infected the adult offspring with the bacteria Citrobacteria rodentium, which can cause an inflammatory bowel condition resembling colitis. Ten days after infection, animals of both sexes exposed to the dummy virus had shortened colons – a sign of colitis – and increased levels of the inflammatory immune molecule IL-17A.

When mice born to mock-virus-treated mothers were reared by saline-injected mothers, they still exhibited autism-like behaviors, but they no longer produced a rapid inflammatory response to a pathogen. The offspring of saline-treated mice that were reared by mock virus-treated mothers, on the other hand, did – suggesting that the enhanced immune response is acquired after birth. The findings were published in Immunity December 7.

One way a mother influences her offspring’s immune system during typical development is through the gut microbiota. Mice, in particular, eat the feces of their cagemates, which changes the contents of their gut. In this way, changes to a mother mouse’s microbiome can disrupt the establishment of her pup’s immune system.

Mice treated with a fake virus, Kim and his colleagues found, have an atypical and less diverse gut microbiome than their saline-injected counterparts. And the germ-free mice that received a fecal transplant from mice treated with a fake virus went on to have their own offspring with an enhanced immune response, further involving the microbiome of the mothers.

Puppies raised by mothers with this atypical and less diverse microbiome have altered helper T cells, which release IL-17A and other immune molecules to sound the alarm for other immune cells after exposure to a pathogen. The study shows that the T cells in these puppies have differences in the accessibility of their chromatin – the tightly coiled form of DNA – which causes them to produce an unusually high level of IL-17A, and therefore inflammation, in response to an immune system. system challenge.

Injecting pregnant mice with a compound that blocks IL-17A before treating them with the fake virus prevented the pups they raised from having a heightened immune response to further infection, the researcher found. team, confirming the involvement of the immune molecule.

JAlthough the study doesn’t explain how autism arises in people, “it does give you insight into the role of early microbes in immune reactivity,” says Jane Foster, professor of psychiatry and behavioral neuroscience at McMaster University in Hamilton, Canada, who was not involved in the study.

IL-17A often appears in studies of atypical immune responses and autism, and previous work by Kim’s colleagues found that blocking IL-17A in pregnant mice that undergo maternal immune activation prevents their puppies to develop autism-like traits.

Likewise, “blocking IL-17A activity may be a potential therapeutic target” for preventing gastrointestinal problems in some children, Kim says. But because the molecule has many other functions, “this needs to be studied in more detail,” she says.

A safer option, says Lukens, may be to try to normalize a mother’s gut microbiome with a specific diet or probiotics.

But it’s unclear how the microbiome would need to change to achieve this goal. “The thing that’s missing here is that they haven’t mapped these microbes” to identify which ones are important, Foster says.

Kim and her colleagues plan to look into that next. They also plan to explore whether these findings hold in children exposed to a maternal immune response, Kim says.

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