The human microbiome is a hot topic in biology these days. It is becoming clear that the microbes living in and on our body can have major consequences for our health and happiness. In fact, abnormalities in the gut microbiome may underlie one of the great medical mysteries of our time: autism. That some bacteria in our intestines could affect our behaviors and brain development is mind blowing.
Hsiao et al. recently published a study in the journal Cell that investigated the connection between the gut microbiome and autism using a mouse model of autism. They were drawn to this subject based on the fact that individuals with autism spectrum disorder (ASD) often have gastrointestinal abnormalities, like irritable bowel syndrome and increased intestine permeability.
Apparently you can produce mice that exhibit the “core communicative, social and stereotyped impairments” associated with ASD, by injecting their pregnant mothers with a molecule that stimulates an immune response. In humans, maternal infection is linked to increased risk of autism in their children. The production of these mice was the most questionable part of the paper in my opinion. They never call these mice autistic, and the mice do show impairments associated with neurological diseases. So perhaps we should think of it as a model of a generic neurological disorder. For the sake of simplicity, though, I will refer to them as “autistic mice”, but remember that it is not a perfect model system.
They find that the autistic mice have various defects in their gastrointestinal (GI) tract. For instance, their intestinal walls are leaky, so molecules that are not supposed to be absorbed can cross from the gut into the blood stream. This problem seems to be caused by the fact that these mice express less of the proteins that make the tight junctions between cells. Think of these as fences between cells, so molecules can’t sneak through there into the body. In an ideal situation, all molecules that are absorbed from the gut must go through the cells, a process which is highly regulated.
|Tight junctions prevent molecules from passing from the gut into the blood. Image adapted from dbriers.com|
They find a number of metabolites that are produced in the intestine from bacteria, which end up in the blood of autistic mice, but not in the normal mice. In other words, these are potentially toxic molecules that they need to get rid of, but the toxins are leaking into the blood of the autistic mice. That’s not good. In fact, if you inject one of these molecules into a normal mouse, it will become more anxious, similar to the autistic mice. They couldn’t reproduce all of the behaviors of the autistic mice just with this one molecule, but it’s a good proof of principle. Presumably it’s the build up of all of these metabolites in the blood that cause impairments of the nervous system.
Dysbiosis of the intestinal flora
I love that word “dysbiosis”. It means that the intestinal microbiome is out of whack. The wrong types of bacteria are in there messing stuff up. Hsiao et al. found a number of species present in the autistic mice that were not in normal mice and vice versa. Presumably this imbalance in the microbiome is what is making the gut leaky.
To prove this, the authors fed the autistic mice a probiotic (a “good” type of bacteria) called Bacteroides fragilis (B. frag). Interestingly, B. frag never actually colonized the guts of the mice, but just having it pass through helped to restore the normal microbiome. Some of the species that were only present in autistic mice disappeared after they consumed B. frag. The leakiness of the gut was almost completely reversed, including expression of tight junction proteins. It wasn’t a perfect reversal, but a number of those metabolites in the blood decreased back to normal.
Behavior affected by microbiome
To review: when a pregnant mouse has an infection, her offspring show signs of autism (a mouse-version). Somehow this infection causes the wrong bacteria to colonize the guts of the offspring. The dysbiosis leads to changes in gene expression and a leaky gut that allows toxic molecules into the blood stream, thus affecting the development of the nervous system. Consumption of a probiotic at weaning age fixes a lot of the gut issues. Does it also reverse some of the behavior impairments associated with autism?
The short answer is yes! Autistic mice fed B. frag were less anxious, less obsessive, more communicative and interacted more with other mice. The test for obsessive behavior was kind of cute. The mice were put in a cage filled with sand with marbles sitting on top. The autistic-like mice bury a greater percentage of the marbles, demonstrating a stereotyped behavior.
Yogurt from everyone!
If I had an autistic child and read this paper, I would start them on probiotics right away. I mean probiotics are good for everyone, right, so it definitely seems worth trying. In fact, the authors say that B. fragilis is depleted in human ASD children compared to matched controls. Furthermore, probiotics have already been shown to be beneficial in treating chronic fatigue syndrome.
The authors end their paper with this bold statement: “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.”
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