Exposure to 'good bacteria' during pregnancy buffers risk of autism-like syndrome

Study in rats suggests prenatal microbial exposures influence neurodevelopment

May 27, 2020

Science Daily/University of Colorado at Boulder

Giving beneficial bacteria to stressed mothers during the equivalent of the third trimester of pregnancy prevents an autism-like disorder in their offspring, according to a new animal study by University of Colorado Boulder researchers.

The study, published in the journal Brain, Behavior, and Immunity, marks the latest in a series of studies in animals and humans suggesting that exposure to certain immune-modulating microbes can dampen inflammation, positively impacting the brain and central nervous system.

It's among the first studies to suggest that such exposures during pregnancy influence neurodevelopment of a fetus and, while far more research is necessary, could open the door to new prenatal interventions.

"It suggests that you could develop microbial interventions that lower the risk of neurodevelopmental syndromes like autism," said co-author Christopher Lowry, an associate professor in the Department of Integrative Physiology.

In humans, research has long shown that maternal stress during pregnancy prompts systemic inflammation in both the mother and fetus and is a risk factor for autism, said senior author Daniel Barth, a professor of psychology and neuroscience.

In a previous study, Barth found that when rats were stressed and given a drug called terbutaline, which is often administered to women to delay preterm labor, their offspring demonstrated an autism-like syndrome -- including the two hallmark features of social deficits and repetitive behavior. They also developed an epilepsy-like seizure disorder.

"Our fundamental question with this new study was whether we could use an immunoregulatory microbe to prevent the long-term consequences of environmental stressors during pregnancy," said first author Zachariah Smith, a post-doctoral researcher in Barth's lab.

For the study, the researchers exposed rats to mild stressors and gave them terbutaline during what would be the equivalent of the third trimester of pregnancy in humans.

Half were also given a series of injections of a heat-killed preparation of a friendly bacterium known as Mycobacterium vaccae (M. vaccae), shown in previous studies to have lasting anti-inflammatory effects on the brain. A third control group of rats got no treatments.

At two and four months, the pups were given a series of tests assessing, among other things, their degree of social interaction and whether they exhibited repetitive behaviors.

As in the previous study, those whose mothers had been stressed and given terbutaline showed autism-like behaviors. But those who had been immunized with M. vaccae did not.

"Immunization with M. vaccae appears to provide some protection against the negative effects of environmental stressors during development, specifically against Autism Spectrum Disorder (ASD)-like behavior," said Smith.

The inoculation did not appear to protect against development of seizure disorders. But because epilepsy tends to develop later in life, the researchers intend to repeat the experiment with a larger sample size and longer treatment period.

Autism and epilepsy often manifest together in humans, with about 30% of autistic individuals exhibiting epileptic symptoms, such as seizures. Stress-induced inflammation likely plays a role in both, the researchers suspect.

"It could be that if we continue the treatment for longer we could also prevent the development of some cases of epilepsy, but much more research is necessary," said Lowry.

The researchers caution that they are not developing an "autism vaccine" and they are not suggesting that microbial interventions could reverse the disorder in children who already have it. But their study does reinforce the idea that exposure to beneficial microorganisms, sometimes referred to as "old friends," can play a critical role in brain development in utero.

Ultimately, Lowry envisions a day when stressed moms deemed particularly high risk of having a child with a neurodevelopmental disorder could be given a specially formulated probiotic or inoculation to support healthy brain development of their child.

"This is the first maternal intervention that I know of that has been able to prevent an autism-like syndrome, including the behavioral and social aspects," Lowry said. "If this could be replicated in humans, that would be pretty profound."

Meantime, they say, mothers should be cognizant of the potential risks of emotional and environmental stressors, including the drug terbutaline, during pregnancy.

And they should try to expose themselves to beneficial bacteria, through fermented foods like yogurt and sauerkraut and even time spent in nature.

https://www.sciencedaily.com/releases/2020/05/200526173818.htm

Can't sleep? Prebiotics could help

Dietary compounds found to influence gut metabolites, buffering stress

March 3, 2020

Science Daily/University of Colorado at Boulder

New research shows that animals on a prebiotic diet sleep better and are buffered from the physiological impacts of stress. The undigestible dietary compounds, found in fibrous foods and some dairy products, serve as nourishment for beneficial bacteria and influence metabolites that, in turn, impact the brain.

Specific fibers known as prebiotics can improve sleep and boost stress resilience by influencing gut bacteria and the potent biologically active molecules, or metabolites, they produce, new University of Colorado Boulder research shows.

The research could ultimately lead to new approaches to treating sleep problems, which affect 70 million Americans.

"The biggest takeaway here is that this type of fiber is not just there to bulk up the stool and pass through the digestive system," said Robert Thompson, a postdoctoral researcher in the Department of Integrative Physiology and lead author of the study, published today in the journal Scientific Reports. "It is feeding the bugs that live in our gut and creating a symbiotic relationship with us that has powerful effects on our brain and behavior."

Food for our bugs

Most people are familiar with probiotics, friendly bacteria present in fermented foods like yogurt and sauerkraut. More recently, scientists have taken an interest in prebiotics -- dietary compounds that humans cannot digest but serve as nourishment for our microbiome, or the trillions of bacteria residing within us. While not all fibers are prebiotics, many fibrous foods like leeks, artichokes, onions and certain whole grains are rich in them.

For the study, the researchers started adolescent male rats on either standard chow or chow infused with prebiotics and tracked an array of physiological measures before and after the rats were stressed.

As reported in the researchers' previous study, those on the prebiotic diet spent more time in restorative non-rapid-eye-movement (NREM) sleep. After stress, they also spent more time in rapid-eye-movement (REM) sleep, which is believed to be critical for recovery from stress.

While rats eating standard chow saw an unhealthy flattening of the body's natural temperature fluctuations and a drop in healthy diversity of their gut microbiome after stress, those fed prebiotics were buffered from these effects.

The new study sheds light on how prebiotics can help bust stress.

"We know that this combination of dietary fibers helps promote stress robustness and good sleep and protects the gut microbiome from disruption. With this new study, we wanted to try to identify the signal," said senior author and Integrative Physiology Professor Monika Fleshner, director of the Stress Physiology Laboratory.

Using a technology called mass spectrometry to analyze the rats' fecal samples, the researchers measured metabolites, or bioactive small molecules produced by bacteria as food is broken down.

They found rats on the prebiotic diet had a substantially different "metabolome," or make-up of metabolites. Theirs was higher in dozens of them, including fatty acids, sugars and steroids which may, via gut-brain signaling pathways, influence behavior. The rats' metabolome also looked different after stress.

For instance, the rats on the standard chow diet saw dramatic spikes in allopregnanolone precursor and Ketone Steroid, potentially sleep-disrupting metabolites, while those on the prebiotic diet saw no such spike.

"Our results reveal novel signals that come from gut microbes that may modulate stress physiology and sleep," said Fleshner.

In search of a better sleeping pill

While prebiotic dietary fiber is certainly healthy, it's uncertain whether just loading up on foods rich in it can promote sleep. The rats were fed very high doses of four specific prebiotics, including: galactooligosaccharides, which are present in lentils and cabbage; polydextrose (PDX) an FDA-approved food additive often used as a sweetener; lactoferrin, found in breast milk; and milk fat globular protein, abundant in dairy products.

"You'd probably have to eat a whole lot of lentils and cabbage to see any effect," said Thompson.

Prebiotic supplements already abound on natural food store shelves. But Fleshner said it's too soon to say whether a supplement or drug containing such compounds would be safe and effective for everyone. Depending on what their microbial make-up is, different people might respond differently.

"These are powerful molecules with real neuroactive effects and people need to exercise some caution," she said.

Human studies are already in the works at CU Boulder.

Ultimately, Fleshner believes what they are learning in her lab could lead to a new class of options for people who can't sleep but don't like taking narcotics.

"Armed with this information, we might be able to develop a targeted therapeutic that boosts the molecules that buffer against stress and tamps down the ones that seem to disrupt sleep," she said. "It's exciting to think about."

https://www.sciencedaily.com/releases/2020/03/200303155658.htm