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N of One: Autism Research Foundation is a 501c3 non-profit organization

© 2018 N of One

Why the Microbiome Matters in Autism

September 4, 2018

 

You are not alone.

 

You might think that the sum total of your genetics and biology make up the entirety of your physical being, but you’re wrong. Your body also plays host to a variety of biological beings that are picked up from your earliest days - some of them staying with you throughout your life. You shouldn’t be disturbed by this. Indeed, as science is starting to understand, some of our various biological passengers are vital to our health.

 

A large portion of our companions are bacteria. They reside in and on various parts of our body. They’re small, they’re numerous and they live in highly complex ‘societies’. They seemingly communicate with one and another and, as a result of such complex ‘chemical communication’, we derive benefit or detriment from them.

 

The largest number of bacteria reside in our gastrointestinal tract (gut): the gut microbiome. From the mouth all the way down to the erm, other end, bacteria flourish and serve important biological purposes. Originally, it was thought that their primary purpose was to help us digest our food, but science is starting reveal that they also play a role in many other important aspects of our health including our immune system, and even our moods and behavior.

 

Bacteria affecting behavior?

 

I know how that sounds: ‘bacteria affecting psychology and behavior’. It implies that we might not have as much control over our thoughts, feelings, mood and behavior as we perhaps thought. It implies that our brain might not always be the ‘master control center’ that it’s been made out to be. It implies that our bacterial passengers might, on some occasions, not just be along for the ride…

 

The evidence for a ‘behavioral role’ for bacteria is accumulating. An important example of this is the 2016 Buffington study which shows how a mouse maternal diet during pregnancy seemingly shifts the pattern of gut bacteria in offspring, resulting in stereotypical behavior effects for little children mice [1]. The authors expanded on that theory, also potentially revealing a therapeutic target, with the idea that ‘microbial reconstruction’ via the artificial addition of more ‘preferred’ bacteria i.e., probiotics, seemingly affect both the balance of bacteria present in offspring guts as well as some of their mouse behaviors.

 

In light of the rising research in this area it’s perhaps not unexpected that discussions in the peer-reviewed science domain have turned to whether some developmental diagnoses might also show some gut microbiome involvement. One of the first diagnosis examined is autism or the autism spectrum disorders (ASDs).

 

Perhaps one of the most profound studies demonstrating the role of gut bacteria looked at the Maternal Immune Activation (MIA) autism mouse model.  In this well-studied model, pregnant mice are given a simulated infection, which triggers an immune response. The male offspring of those pregnant immune-activated mice develop autism-like symptoms [2]. When  researchers from Caltech examined the gut bacteria compositions of the offspring they were found to be different compared to controls.  Stop and think about this for a moment: from birth these mice were grown under identical lab conditions and received identical food, yet they had very different microbiomes -- the ONLY difference was an immune system challenge of their mother during pregnancy. Now here is where it gets really interesting. When the researchers fed the mice a specialized probiotic, currently only available to researchers, the autism-like symptoms disappeared and their microbiomes normalized to that of the controls.

 

The gut microbiome and autism.

 

 It’s no surprise that autism is a focal point when it comes to a gut bacteria-behavior connection. One of the earliest examples beginning to make the connection is a clinical trial that published results in the Journal of Child Neurology over 18 years ago where researchers at Chicago Rush Children’s Hospital gave the antibiotic vancomycin to a small group of severely autistic children [3]. Eight out of ten of these children experienced a marked improvement in their autism symptoms. The authors speculated that the improvements were likely triggered by changes in the gut microbiome resulting from the antibiotic.

 

Conversely, but perhaps also validating the role of gut bacteria in autism, is research suggesting that early antibiotic use might be an over-represented feature in kids with autism [4]. Antibiotics are a wonder of modern medicine that have saved millions of lives, but in the current age of antibiotic resistance, where bacteria evolve strategies to ‘fight back’, we start to understand what a double-edged sword they can be. One thing we do know is that antibiotics are far from selective in terms of the bacteria they target, and when it comes to their use early in life, they can have profound effects on the developing gut microbiome with some possibly life-altering downstream effects.

 

The consistent and potentially meaningful differences in the gut bacterial composition in children with autism vs. those without autism also provide important clues as to the role of the microbiome in autism. For instance, researchers have found that ASD children have less species diversity in their gut microbiome, some researchers have found species in children with autism that they did not find in controls, and a recent meta-analysis of all autism and gut microbiome studies concluded that there were consistent differences in the gut bacteria of groups of ASD patients compared to healthy controls - although the exact compositional differences were inconsistent [5]. This is not surprising given the great variation in our diets (a powerful driver of gut microbiome composition), or the restrictive food interests and specialized diets of many ASD children. The lack of standardized approaches, including what type of sample is used (stool vs. biopsy), collection techniques, and how the samples are analyzed, could contribute to inter-study variances. However, the point remains that regardless of experimental conditions, children with autism have consistently been found to have differential gut bacterial compositions compared to controls.

 

The research observations suggesting that some dietary interventions might also affect the presentation of autism for some also provides a potential clue to the gut bacteria involvement. Diet, as previously mentioned, is a nutrition source for bacteria as well as the body, and it is likely that a change in diet impacts the balance of bacteria in the gut as well. For example, a 2012 study published in the journal Frontiers in Human Neuroscience came to the conclusion that “experimental studies on the use of a ‘specialized’ diet…have suggested an amelioration of symptoms and improved developmental outcome for at least a proportion of people on the autistic spectrum.” [6].

 

Adding even more weight to the possible involvement of the gut microbiome is the over-representation of bowel issues in kids with autism. Alongside functional bowel issues such as constipation and diarrhea being consistently detailed in relation to autism, other research has also talked about bowel disease being more likely to occur alongside a diagnosis of autism [7,8]. It’s not a huge leap to infer that bowel symptoms experienced by some on the autism spectrum could be associated with the gut microbiome.

 

When we begin to discuss therapeutic interventions related to the gut microbiome in autism, the clinical trial conducted by James Adams and colleagues at Arizona State University [9] is not to be overlooked. In this trial, fecal microbiota transfer  (an ancient therapeutic tool that is reserved now mostly for C. difficile infections [10]) was performed on 18 children with autism diagnoses. The researchers concluded that both GI and ASD core features showed significant improvements following this treatment. This is an important study because, like the vancomycin study previously mentioned, it is an example of a treatment leading to improved symptoms of autism in humans (not mice).

 

Where next?

 

It would be premature to assume that the gut microbiome plays a pivotal role in relation to all autism. It would also be premature to assume that is doesn’t.

 

What does seem clear, at least to us, is that the microbiome should be a major focus area for autism research. Almost unbelievably, however, despite the compelling body of evidence of microbiome involvement, there is still limited funding for this type of research. At N of One, we are working to change that by highlighting the role of the microbiome and supporting important studies, like our antibiotic response study being done at Baylor College of Medicine. We need your help so that greater resources can be allocated to such research.

 

We can do this together, all the while accepting that, biologically-speaking, we are not alone...

 

 

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About the author: 

 

Paul Whiteley is a well known autism researcher and blogger in the UK whose research interests include examining the effectiveness of a gluten and casein free diet for people with autism and the application of data mining technologies to various health conditions. Paul holds a B.Sc (Hons), M.Phil. and a PhD in health informatics for pervasive developmental disorders.

 

 

 

References

 

[1] Buffington SA. et al. Microbial Reconstitution Reverses Maternal Diet Induced Social and Synaptic Deficits in Offspring. Cell.2016; 165: 1762-1775.

 

[2] Hsiao EY, McBride SW, Hsien S, Sharon G, Hyde ER, McCue T, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155:1451–63.

 

[3] Sandler RH. et al. Short-term benefit from oral vancomycin treatment of regressive-onset autism. J Child Neurol. 2000 Jul;15(7):429-35.

 

[4] Niehus R. & Lord C. Early medical history of children with autism spectrum disorders. J Dev Behav Pediatr. 2006 Apr;27(2 Suppl):S120-7.

 

[5] Voreades N, Kozil A, Weir TL. Diet and the development of the human intestinal microbiome. Front Microbiol. 2014;5:494.

 

[6] Whiteley P. et al. Gluten- and casein-free dietary intervention for autism spectrum conditions. Front Hum Neurosci. 2013; 6: 344

 

[7] Holingue C. et al. Gastrointestinal symptoms in autism spectrum disorder: A review of the literature on ascertainment and prevalence. Autism Res. 2018 Jan;11(1):24-36.

 

[8] Lee M. et al. Association of Autism Spectrum Disorders and Inflammatory Bowel Disease. J Autism Dev Disorders. 2018; 48: 1523-1529.

 

[9] Kang D-W. et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017; 5: 10.

 

[10] From Wikipedia, The concept of treating fecal diseases with fecal matter originated in China millennia ago. Fourth century Chinese medical literature mentions it to treat food poisoning and severe diarrhea. 1200 years later Li Shizhen used "yellow soup" (aka "golden syrup") which contained fresh, dry or fermented stool to treat abdominal diseases. "Yellow soup" was made of fecal matter and water, which was drunk by the person.

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