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Developmental biology - Pregnant Microbiome

Autism risk determined by state of mom's gut

Could preventing autism be as simple as changing an expectant mothers' diet?...

A collection of microorganisms naturally live inside all of us - our microbiome. During pregnancy, new research from the University of Virginia (UVA) School of Medicine suggests the risk of developing autism-spectrum disorders may be determined by a mother’s microbiome. UVA's work raises the possibility that preventing forms of autism could be as simple as an expectant mom modifying her diet or taking custom probiotics. Their work is published in The Journal of Immunology.

UVA scientists were able to prevent autism-like neurodevelopmental disorders in lab mice by blocking a particular inflammatory molecule, interleukin-17a, produced by our immune system. Researchers believe their work offers a potential avenue for preventing autism, but advise caution as the approach is made more complex by a risk for side effects.

"We determined that the microbiome is a key contributor in determining susceptibility to autism-like disorders, so it suggests that you could target either the maternal microbiome or inflammatory molecule IL-17a. You could also use IL-17a as a biomarker for early diagnosis."

John Lukens PhD, Department of Neuroscience, UVA.

Microbiome and Autism

The groundbreaking work from Lukens and his colleagues sheds light on the complex relationship between the health of the mother's microbiome and the healthy development of her children. "The microbiome can shape the developing brain in multiple ways," explains Lukens of the Center for Brain Immunology and Glia (BIG), and The Carter Immunology Center at UVA. "The microbiome is really important to the calibration of how the offspring's immune system is going to respond to an infection, injury or stress."

An unhealthy microbiome in a mom can create problems. It can make her unborn child susceptible to neurodevelopmental disorders as research found that the IL-17a molecule is a key contributor to development of autism-like symptoms in lab mice.

The good news: The microbiome can be modified easily, either through diet, probiotic supplements or fecal transplant. All of these approaches seek to restore a healthy equilibrium among the different microorganisms that live in the gut.

"In terms of translating our work to humans, I think the next big step would be to identify features of the microbiome in pregnant mothers that correlate with autism risk. I think the really important thing is to figure out what kind of things can be used to modify the microbiome in the mother as effectively and safely as we can," Lukens adds.

Another Option for Preventing Autism

Blocking IL-17a also might offer a way to prevent autism, but Lukens says that path carries much more risk. "If you think about pregnancy, the body is basically accepting foreign tissue, which is the baby," he explains. "As a result, maintenance of embryonic health demands a complex balance of immune regulation. So, people shy away from manipulating the immune system during pregnancy."

IL-17a previously has been implicated in conditions such as rheumatoid arthritis, multiple sclerosis and psoriasis. Although there are already drugs available that target IL-17a, Lukens points out that the molecule has an important purpose in stopping infections, especially fungal infections. Blocking it "could make you susceptible to all kinds of infections," and doing so during pregnancy could have complex ripple effects on a child's development that science and medicine should sort out first.

This new research from the UVA School of Medicine shows:

• A mother's microbiome determines the risk for autism and other neurodevelopmental disorders in her offspring.

• The microbiome can be manipulated by consuming beneficial bacteria, probiotics, or transplantation of fecal material from one person to another.

• In mice, blocking IL-17a prevents autism-like disorders - also implicated in multiple sclerosis and rheumatoid arthritis.

• The discovery may help detect autism early in pregnancy.

For their next steps, Lukens and his team plan to explore the potential role of other immune molecules in the development of autism and other such conditions. IL-17a may be just one piece in a much larger puzzle.

While Lukens' work links the immune system with neurodevelopmental disorders, he emphasizes this in no way vaccines contribute to the development of autism. Lukens: "There's a definite link between the immune response and the developing brain. It just doesn't have anything to do with vaccines, as it's much, much earlier."

Abstract
Recent studies suggest that autism is often associated with dysregulated immune responses and altered microbiota composition. This has led to growing speculation about potential roles for hyperactive immune responses and the microbiome in autism. Yet how microbiome–immune cross-talk contributes to neurodevelopmental disorders currently remains poorly understood. In this study, we report critical roles for prenatal microbiota composition in the development of behavioral abnormalities in a murine maternal immune activation (MIA) model of autism that is driven by the viral mimetic polyinosinic-polycytidylic acid. We show that preconception microbiota transplantation can transfer susceptibility to MIA-associated neurodevelopmental disease and that this is associated with modulation of the maternal immune response. Furthermore, we find that ablation of IL-17a signaling provides protection against the development of neurodevelopmental abnormalities in MIA offspring. Our findings suggest that microbiota landscape can influence MIA-induced neurodevelopmental disease pathogenesis and that this occurs as a result of microflora-associated calibration of gestational IL-17a responses.

Authors: Catherine R. Lammert, Elizabeth L. Frost, Ashley C. Bolte, Matt J. Paysour, Mariah E. Shaw, Calli E. Bellinger, Thaddeus K. Weigel, Eli R. Zunder and John R. Lukens.

Acknowledgements
This work was supported by The Hartwell Foundation (Individual Biomedical Research Award to J.R.L.), the Owens Family Foundation (to J.R.L.), and The Simons Foundation Autism Research Initiative (Pilot Award 515305 to J.R.L. and E.R.Z.). C.R.L. was supported by a National Institutes of Health/National Institute of General Medical Sciences predoctoral training grant (3T32GM008328), A.C.B. was supported by the Medical Scientist Training Program at the University of Virginia (Grant 5T32GM007267-38), and C.E.B. was supported by Hutcheson and Stull Undergraduate Research Fellowships.

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Jul 25, 2018 Fetal Timeline Maternal Timeline News News Archive

The microbiome is the collection of microorganisms, such as bacteria, that naturally live inside us. Science is increasingly revealing its vital importance to good health. Researchers at the University of Virginia School of Medicine have determined that the health of an expectant mother's microbiome determines the risk to her infant of autism and neurodevelopmental disorders.
Image: Illustration by Alexandra Angelich, University Communications.