Mom's Microbiome, Inflammation Linked to Autism?

Batya Swift Yasgur, MA, LSW

July 27, 2018

The risk of developing autism spectrum disorders (ASD) may be influenced by the mother's microbiome and the effects her intestinal microbes have on gestational inflammatory responses, new research suggests.

Investigators combined fecal material from two sets of mice with different microbiomes: one group with a microbiome known to promote robust interleukin-17a (IL-17a)–mediated immune responses, and the other harboring a microbiome that is less effective at promoting IL-17a responses.

They induced inflammation in both sets of mice and injected half of them with an agent that neutralizes the impact of IL-17a, an inflammatory cytokine.

Mice that were susceptible to inflammation had offspring that exhibited autisticlike social and communicative behaviors; but offspring of mice that received IL-17a blocker did not exhibit these behaviors ― even in those whose mothers had a more susceptible microbiome.

"Our data indicate that the microbiome is a major contributor to susceptibility to autisticlike disorders and that IL-17a in mothers during pregnancy could potentially be a biomarker for autism and also a potentially efficacious target," John R. Lukens, PhD, assistant professor, Department of Neuroscience and Center for Brain Immunology and Glia at the University of Virginia School of Medicine, Charlottesville, told Medscape Medical News.

"While the translational implications of this finding are exciting, we have not yet explored any treatments that are yet approved for treatment in pregnant women. But they do further underscore the importance of prenatal health in ensuring optimal developmental conditions," Lukens said.

The study was published online July 2 in the Journal of Immunology.

Altered Neurodevelopment

"The cause of ASD currently remains poorly understood; however, emerging clinical and experimental evidence suggests central roles for immune dysregulation during pregnancy in autism pathogenesis," the investigators write.

Some reports have linked maternal immune activation (MIA) during pregnancy to ASD. For example, autoimmune disorders, obesity-associated inflammation, and infectious diseases may increase the risk of having a child with autism.

ASD-like phenotypes can be modeled in mice by using a viral mimetic polyinosinic-polycytidylic acid (Polyl:C) at key time points during embryonic neurodevelopment, the researchers explain.

Offspring of pregnant mice treated with Polyl:C display many defining features of ASD, including defects in social preference, communicative impairments, and repetitive/stereotypes behaviors.

In addition, ASD in human beings has been associated with higher-than-average rates of dysbiosis and gastrointestinal inflammation, suggesting a potential role for the microbiome in ASD.

"There has been growing speculation that the microbiome plays an important role in shaping neurodevelopmental disorders," Lukens said.

He noted that the number of children being diagnosed with ASD is increasing, the researchers were interested in investigating what environmental changes might be behind this increase.

"As people increase consumption of antibiotics and other microbiome-altering foods, we turned our attention to how the microbiome and its connection to inflammation could contribute to altered neurodevelopment and neurodevelopmental disorders," he said.

The microbiome in pregnant mothers may play several roles in the potential neurodevelopmental problems in their offspring.

"Microbes can make metabolites that can disrupt neurodevelopment. Bacteria can make analogues for serotonin and other developmental pathways," he said.

Lukens reported that his laboratory has shown that "if you manipulate maternal immune activation and induce inflammation during pregnancy in a mouse model, you can recapitulate many of the symptoms that are used to diagnose autism."

Unprotected Strains

To investigate these questions, the researchers used two sets of mice from different vendors. Each set had slightly different microbiomes.

Those originating from the Taconic Biosciences (Tac) harbor microflora that promote potent IL-17a-mediated inflammatory responses, whereas mice on the same genetic background from the Jackson Laboratory (Jax) develop blunted IL-17a-mediated immune responses.

Previous studies by other laboratories have found that the commensal microbe segmented filamentous bacteria (SFB), which is uniquely present in the Tac microbiota, is largely responsible for skewing immune responses toward IL-17a in mice.

By contrast, the same genetic background of mice from Jax are devoid of SFB and, as a result, exhibit attenuated IL-17-mediated inflammatory responses.

Cohousing the two sets of mice enabled microbiota transplantation, so that the Jax mice became inhabited by the IL-17a-inducing microbe SFB.

"We put Jax mice, which have the protective microbiome, together with Tac mice, which is the equivalent to a fecal transplant, since mice eat each other's feces. And we discovered that microbes typically only present in the Tac microbiome transferred over," Lukens explained.

He noted that the microbiome associated with autism susceptibility in Tac mice is dominant, so "the protected strain became unprotected following fecal transplantation."

Two additional groups in the Jax and Tac mice were not cohoused.

After the mice were mated and impregnated, the pregnant mice were treated either with Polyl:C or saline, which induced MIA. However, monoclonal antimouse IL-17A neutralizing Ab, an antibody to IL-17a, was administered prior to the injection.

A group of control mice received saline injections.

The offspring were separated from their mothers 3 to 4 weeks later (after the offspring could eat and survive on their own) and were subjected to behavioral testing.

"Middleman"

Only the offspring of the PolyI:C-treated Tac and cohoused Jax mice displayed autisticlike behaviors on the ultrasonic vocalizations test, the 3-chamber social preference test, and the marble burying test. The tests were designed to assess communication, social behavior, and repetitive/stereotyped behavior, respectively.

However, "the IL-17a blockade rescued the behaviors in both the Tac and the cohoused Jax-treated offspring mice," Lukens reported.

"We mimicked a viral infection, and during that infection, we blocked IL-17a and showed that if you block IL-17a-mediated inflammation in the pregnant mother, that is sufficient to negate the effects of the less protected microbiome on autistic behavior," he said.

He explained that the microbiome "calibrates, educates, and sets the immune response because when [the immune response] becomes active, the microbiome shifts it down different inflammatory pathways and primes it for its response later on."

The findings have important implications, he added.

"The basic key is that IL-17a can be targeted with the neutralizing antibody or the microbiome can be shaped so that it no longer supports inflammation, since the microbiome is the 'middleman' to IL-17a," said Lukens.

He noted that the US Food and Drug Administration has approved a similar neutralizing antibody for psoriasis and other indications, and there are "other therapeutics that can technically be used, but that is still a long ways off in human beings."

In addition, blocking IL-17a can cause a mother to be subject to potential fungal infection, which can adversely affect fetal development. So, "further research has to be done if IL-17a is targeted in human pregnant women," he said.

Opens Up Possibilities

Commenting for Medscape Medical News, Brittany G. Travers, PhD, assistant professor, Occupational Therapy Program, Department of Kinesiology, and Waisman Center Investigator, University of Wisconsin-Madison, called the study "exciting."

The findings suggest that "the microbiome may be able to prevent the effects that maternal immune activation may have on a fetus," said Travers, who was not involved with the research.

"This work is further strengthened by identifying the mechanisms by which the microbiome alters the maternal immune activation — IL-17a."

She suggested that, in terms of clinical applications in humans, there is still much more to learn about the microbiome's role in health and disease.

However, "these results open the door to the possibility that a healthy microbiome may be able to prevent the negative impact that a mother's hyperactive immune system, and corresponding inflammation, have on a child's neural development," she said.

"The information may help us better understand the mechanisms of autism and other neurodevelopmental disorders," added Travers.

Lukens agreed, noting that "since the microbiome is greatly influenced by diet and stress, we would recommend eating a well-balanced diet and limiting stress and perhaps considering probiotics."

The work was supported by the Hartwell Foundation, the Owens Family Foundation, and the Simons Foundation Autism Research Initiative. Members of the research team received support from the National Institutes of Health/National Institute of General Medical Sciences, the University of Virginia's Medical Scientist Training Program, and Hutcheson and Stull undergraduate research fellowships. Dr Lukens, the article's coauthors, and Dr Travers have disclosed no relevant financial relationships.

J Immunol. Published online July 2, 2018. Abstract

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