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'Friendly' bacteria treat autism-like symptoms in mice

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Jessica Wright
5 December 2013

Good germs: Certain kinds of bacteria that live in the gut protect people from harmful strains such as Escherichia coli.

A strain of bacteria that lives in some people’s guts alleviates obsessive behaviors, anxiety and other symptoms in mice that model autism, researchers report today in Cell1. The finding supports the intriguing link between the gut, brain and behavior.

This strain, Bacteroides fragilis, is one of many bacterial strains that populate the digestive tract and are collectively referred to as the gut microbiome. Most of the strains are helpful, or probiotic, and protect people from harmful strains. B. fragilis in particular has been shown to protect mice from gut inflammation caused by bacteria such as Helicobacter hepaticus2.

The new study suggests that probiotics may improve behavior in people with autism, says Paul Patterson, professor of biology at the California Institute of Technology. “What we show in the mouse model is that if you block the gastrointestinal problem, you can treat the behavioral symptoms,” he says. “There’s a causal relationship.”

Patterson and his colleagues first injected pregnant mice with a mock virus. The resulting spike in immune activity is known to lead to autism-like behaviors in the pups. The pups obsessively groom themselves, for example, and are anxious and disinterested in other mice — all behaviors reminiscent of those seen in people with the disorder. They also make fewer and shorter vocalizations than controls do, suggesting deficits in communication.

A study published earlier this year found a similar trend in monkeys born to infected mothers. These studies are aimed at recapitulating the increased autism risk seen in children born to women who have a severe infection, such as the flu, while pregnant.

The new study is the first to show that maternal infection alters the microbiome in the offspring. The finding is significant for autism, as many children with the disorder are plagued by gastrointestinal problems, including diarrhea, vomiting and stomach discomfort.

“The possibility that there is a critical stage during gestation when inflammation in the mother can influence development of the fetal intestine is very intriguing,” says Dan Littman, professor of immunology at New York University, who was not involved in the study.  

Emily Elert

Stomach troubles:

The mouse pups go on to develop a ‘leaky gut,’ a condition in which molecules produced by the gut bacteria seep into the bloodstream, and possibly reach the brain.

Leaky gut is also reported in children with autism and is associated with several other disorders, such as inflammatory bowel disease and Crohn’s disease, and perhaps with Alzheimer’s and Parkinson’s diseases, says Sarkis Mazmanian, professor of biology at the California Institute of Technology.

To diagnose leaky gut in the mouse pups, the researchers fed them a carbohydrate molecule attached to a fluorescent molecule. The molecule later turned up in their blood, showing it had escaped through the gut wall. The mice also showed elevated gut levels of an immune molecule called interleukin-6 (IL-6) — a prime suspect in mediating the effects of maternal infection.

These mice also have different types of gut bacteria than those found in control mice, which in turn affects the blood levels of various compounds. Strikingly, these mice have 46-fold higher levels of a certain metabolite produced by gut bacteria than controls do.

“We are looking at an initial report in one mouse model. At best, they represent a subset of the autism population.”

This molecule, called 4-ethylphenyl sulfate (4EPS), has not been found in people with autism. However, two studies found elevated levels of a chemically similar molecule called p-cresol in the urine of people with autism3, 4.

When injected directly into mice, 4EPS makes mice more anxious, the study found, showing that the metabolite directly affects behavior. 

“The beauty of the paper is that they actually pinpoint a potential metabolite,” says Sven Pettersson, professor of microbiology at Karolinska Institute in Sweden, who was not involved in the study. “The fact that a metabolite can change behavior is an intriguing observation.”

The researchers then treated the mice with B. fragilis. This strain of bacteria isn’t commercially available, but exists naturally in about 20 percent of the human population.

Mice treated with B. fragilis at 3 weeks of age don’t have a leaky gut five weeks later, their levels of blood 4EPS and gut IL-6 plummet, and the assortment of bacterial species in the gut reverts to something closer to that of control mice. And the mice do better behaviorally: They stop obsessively burying marbles in their cages, become as vocal as controls and are less anxious.

The mice don’t shake their social difficulties, however — they remain relatively uninterested when a new mouse is put in their cage.

“This is a real limitation in the conclusions from this study, as, in many ways, social interaction deficits are at the core of the phenotype of autism,” says Ted Abel, professor of biology at the University of Pennsylvania, who was not involved in the research. He suggests that other mechanisms may underlie the social behavior in these mice.

The researchers emphasize that the results are in mice and that they may model only one type of autism. “We need to be very cautious here. We are looking at an initial report in one mouse model,” says Mazmanian. “At best, they represent a subset of the autism population.”

Researchers also shouldn’t underestimate the challenges of trying to change the microbiome in people, says Littman. Finding a gut molecule that is elevated in people with autism and pinning down bacteria that reverse its production would be “a tremendous advance,” he says. “It’s very difficult to target the microbiome without knowing what’s going on.”

The researchers do, however, have promising preliminary results with mice that carry mutations seen in people with autism. They are now treating mice with commercially available probiotics and are planning a clinical trial with B. fragilis in people with autism. These are only the early first steps, notes Patterson. “I don’t want people rushing out trying to buy B. fragilis,” he says.

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

References:

1: Hsiao E.Y. et al. Cell 155, 1-13 (2013) Abstract

2. Mazmanian S.K et al. Nature 453, 620-625 (2008) PubMed

3: Altieri L. et al. Biomarkers 16, 252-260 (2011) PubMed

4: Persico A.M. and V. Napolioni Neurotoxicol. Teratol. 36, 82-90 (2013) PubMed

Comments

Name: Katie Wright
6 December 2013 - 12:30AM

Fantastic work!

Name: Alain Couvier
6 December 2013 - 4:49AM

It is important to understand the wider implications that this paper holds not only for the Autism community but the wider 'mental health" health community.

" Importantly, particular behavioral and neuropathological symptoms seen in the MIA model (and in human autism) are not exclusive to ASD. MIA offspring exhibit additional endophenotypes that resemble schizophrenia, such as enlarged ventricles, deficient latent inhibition and deficient parvalbumin-positive interneurons (Li et al., 2009,Smith et al., 2007), and the behavioral abnormalities characteristic to human ASD can be individually seen in other neurological diseases such as schizophrenia, obsessive compulsive disorder, Angelman syndrome, and Prader-Willi syndrome. Moreover, other nondiagnostic behaviors relevant to ASD, including anxiety and impaired PPI, are commonly reported in several neurological disorders. The phenotypic overlaps across different disease diagnoses suggest that our findings on the gut-microbiome-brain connection and microbe-based treatments for behavior might be broadly applicable to various disorders. We propose the transformative concept that autism, and likely other behavioral conditions, are potentially diseases involving the gut that ultimately impact the immune, metabolic, and nervous systems, and that microbiome-mediated therapies may be a safe and effective treatment for these neurodevelopmental disorders."

There have been many, many vociferous critics of the gut/brain axis in Autism. Families have had to endure unfounded criticism surrounding the care of their children, it is hoped that will give some pause to reflect on how they have acted and will act in the future.

Name: Paul Whiteley
6 December 2013 - 2:58PM

Very glad to see that this work has seen the peer-reviewed light of day. That being said, there is already a growing body of peer-reviewed research to suggest that gut hyperpermeability (leaky gut) is present in real people with autism (not just mice) alongside some potential 'therapeutic' indications...

http://www.ncbi.nlm.nih.gov/pubmed/20683204

Alterations of the intestinal barrier in patients with autism spectrum disorders and in their first-degree relatives.
de Magistris L, Familiari V, Pascotto A, Sapone A, Frolli A, Iardino P, Carteni M, De Rosa M, Francavilla R, Riegler G, Militerni R, Bravaccio C.
J Pediatr Gastroenterol Nutr. 2010 Oct;51(4):418-24.

Name: JSS
6 December 2013 - 8:42PM

Hey, folks, re: caption. Normal E. coli isn't a bad guy; it's normal in all of us. It's the toxin-producing mutant strains of E. coli that are dangerous - most of them coming from livestock heavily dosed with antibiotics. Thanks.

Name: Sarah
8 December 2013 - 12:27AM

I hope the testing of this probiotic in children with autism can be expedited so we can use it as for treatment for our kids. autism parents have been waiting a long time for something like this. Good work!

Name: Payman
10 December 2013 - 8:56PM

Being a father of nonverbal autism of 11 yr old boy and living with him daily, I can say the genetic basis of autism has no ground as well as the brain connections which would mean they are static as his behaviors regression and progression are so dynamic that the most probable factor ifluencing his behavior would be gut or metabolites affecting the brain or his thinking, sensory processes. Please research this avenue more in depth.

Name: Steve White
10 December 2013 - 10:41PM

Dr. Patterson wrote a very interesting and accessible book "Infectious Behavior" about connections between the immune system and brain. It's really worth reading. This is very interesting research. And it might lead to both treatment and prevention eventually. Thanks to all the researchers for this work.

Name: Portia Iversen
12 December 2013 - 6:23AM

I really admire Paul Patterson for hanging in there to get this and his other important research through the grant review grinding machine, where innovation is usually considered highly suspicious at best. This particular work harkens back eerily to some very early findings that could not be followed through on, such as those of Paul Shattock (urinary metabolites), Rosemary Waring (sulphation abnormalities) and Karl Reichelt (leaky gut). Now I'm just waiting for the research proposal from the psychologists: "Can Friendly Bacteria Convert Asocial Bacteria in Autism Model?".

Name: Julie Chou-Lachapelle
12 December 2013 - 10:50AM

3 weeks before delivering my son(who is autistic), I got a terrible flu and was hospitalized because we couldn't get the fever down. So this maternal infection theory could be true in my case. Have their been studies reviewing public health records to see the statistics of maternal infection leading to ASD ? I'd love to see those numbers. And just to throw this out there for you brilliant scientists, wouldn't vaccinations ( I.e. flu vaccine, etc.) on pregnant woman elicit an immunological response that might put the child at risk? Anyone studying that? FYI I'm not on any side in the vaccine debate for children, just curious given this latest theory on maternal infection.

Name: Elaine Hsiao
13 December 2013 - 9:41PM

Thank you for sharing your story with us. There is epidemiological evidence that maternal infection increases the risk for ASD in the offspring (see 1.usa.gov/1frjvsm and 1.usa.gov/1cslLeW). Importantly, this is not to say that maternal infection causes ASD, but rather, perhaps it can exacerbate or potentiate ASD outcomes in individuals with genetic susceptibility and/or additional exposure to environmental risk factors. There is no evidence that vaccinations, in particular, during pregnancy increase the risk for ASD in the offspring. We recommend, per CDC guidelines (1.usa.gov/1bCu5aS), that pregnant women receive the flu vaccine. The risk of infection from not being vaccinated during pregnancy may lead to outcomes far worse than receiving the actual vaccine itself.

Name: JacksonBrown
25 August 2014 - 10:51PM

I don't think infection versus inflammation is the same thing. I have inflammation but never had an infection

Name: Amanda
18 December 2013 - 7:51PM

No there is certainly not ample evidence that the flu vaccine is safe for pregnant women. "The Lancet" recently questioned the value of the flu vaccine period, stating that independent research has found it is only 17% effective! The "New England Journal of Medicine" has also recently found that effectiveness of the flu shot is grossly oversold and that adverse reactions are more prevalent than believed.

No one wants to get the flu but the flu shot does an poor job of prevention. The best we can do is thoroughly wash our hands with soap and water- not anti-bacterial soap. If any

Name: Laura
11 February 2014 - 8:34PM

Could somebody, just jump and cure our childrens. It is amazing that we can explore the space, do heart transplants, and still do not have the answer of what to do?

Name: FK
4 March 2014 - 9:51AM

Can we commercially buy the Bacteroides Fragilis Probiotic? If not, how we can get it?

Name: Seth Bittker
16 March 2014 - 8:15PM

Very interesting. Does anybody know where one can buy b. Fragilis probiotics? Patterson seems to think there may be risk with this, but I don't see why.

Name: Katherine
27 July 2014 - 9:36PM

My granddaughter is 16 and severely autistic. When she was 7 we put her on a glutten and ciatin free diet, we also started giving her probiotics. After about a year she started making eye contact with us and started saying single words but not sentences, and her aggression level went way down. This is where she is still at in her behavior. Even though she hasn't had more progress I don't think she would have never made any progress if we had not tried the diet or probiotics.

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