The Scoop on Poop: Possible Links Between Gut Microbes and Autism Spectrum Disorder

Background:

Autism spectrum disorder (ASD) is a developmental disorder that affects communication and behavior (NIMH, 2019).  The CDC reports that about 1 in every 59 kids is identified with ASD (CDC, 2019).  It is very common for children with ASD to have some degree of gastrointestinal (GI) issues, such as constipation, diarrhea, and abdominal pain (Hsiao, 2014).  It is estimated that between 30-50% of children with ASD also have GI problems (Buie et al., 2010, McElhanon et al., 2014), but it is unknown why this is and what is causing it.  Scientists have looked into an imbalance of the gut microbiome (all the living organisms, such as bacteria, within the gut) as a potential factor in causing ASD symptoms and have found differences between the gut microbes of ASD children and neurotypical, or ‘normal’, children (children with no mental disabilities) (Finegold et al., 2002, Adams et al., 2011).  The researchers think that reductions in beneficial microbes and increases in harmful microbes could be causing ASD symptoms and associated problems.  However, we lack evidence to determine if the differences in microbes are actually the cause of the ASD symptoms, or if the ASD is causing the differences in microbes.

An unhappy gut with bad microbes
From “9 signs you have an unhealthy gut (and how to repair it)” by Haisam Buzeyan (2016)

Instead of just looking at what microbes are present, researchers have started to look at substances the microbes are producing, such as metabolites, to see if they could be causing the symptoms associated with ASD.  The National Cancer Institute from the National Institute of Health defines a metabolite as “A substance made or used when the body breaks down food, drugs or chemicals, or its own tissue,” (National Cancer Institute, 2019).  In other words, metabolites are the substances both produced and consumed by your body when it is functioning.  Common metabolites are lactic acid, hormones, sugars, etc.  Microbes within the body can produce these metabolites, which can then be used by the rest of the body for various functions.

Central Question:

The relationship between ASD and GI problems has left us wondering…  Are there differences in fecal microbes and metabolites between children with autism spectrum disorder and normal children, and can these differences be contributing to GI issues and ASD behavioral symptoms?

Evidence:

A recent study by Kang et al. (2018) attempts to address this question.  These researchers looked at fecal samples of ASD and normal children to determine if there were differences in metabolites produced by the gut microbiome and if these differences could be correlated with specific changes in the microbes.

Before I talk about what the researchers found, keep in mind that fecal samples are not a complete representation of ALL of the microbes in the gut.  They are used because it is the easiest way to get a snapshot of many microbes that are present without using more invasive methods.

Kang et al. (2018) measured the metabolites present in the fecal samples with a machine that can detect substances made of different combinations of chemicals.  Each substance detected represented a specific metabolite.  They then compared the amount of each metabolite found in each sample to determine if there were differences between ASD children and normal children.

Person with upset stomach and intestines with magnifying glass showing microbes
From “Problems you can face due to an Unhealthy Gut” (2018)

Overall, they found 59 different metabolites throughout all the samples, but isopropanol was the only one found in significantly different amounts between ASD and normal children.  Kang et al. (2018) found that isopropanol is 82% higher in ASD children than normal children.  Isopropanol is rapidly absorbed in the GI tract and can cause abdominal pain (Abramson & Singh, 2000).  Kang et al. (2018) think that the presence of isopropanol may be due to bacteria converting acetone to isopropanol, but of the bacteria that are known to have this ability, none were detected in the fecal samples of either ASD or normal children.  It is still possible that there are other unknown bacteria in the gut that can convert acetone to isopropanol.  Another explanation could be that the particular bacteria were just not captured in these fecal samples.  Either way, the higher amount of isopropanol in ASD children could be contributing to the more severe GI issues found to be associated with ASD.

There was another metabolite, p-cresol, that could be contributing to GI issues that was generally found in higher amounts in ASD children.  P-cresol is known to cause damage to the cells lining the colon when too much is present.  This can cause diarrhea because the damaged cells have trouble absorbing water properly.  It is unclear if p-cresol is being produced by microbes in the intestine or if it is being introduced through the skin, but having more of it could be causing some GI problems for children with ASD.

Two metabolites, called GABA and glutamate, which are really important for brain function, were found in the samples.  The ratio of these metabolites was found to be slightly different between ASD and normal children.  This altered ratio could be one way in which the microbiome is contributing to ASD behavioral symptoms because the balance of necessary metabolites for proper brain function is off.  The right ingredients for the brain to function are present but in the wrong amounts, so the brain can function, just not normally.

This study found that, overall, children with ASD have significantly lower bacterial diversity and a different microbial composition than normal children.  This means they have fewer types of bacteria present and the quantities of microbes differ between ASD and normal children.  The children with ASD had a lower amount of Faecalibacterium and Haemophilus bacteria, which are just fancy names for two different kinds of microbes.  Faecalibacterium has been considered a beneficial microbe in the gut and is related to anti-inflammatory effects.  Having less of this kind of microbe makes you more likely to have irritable bowel syndrome (Rajilić–Stojanović et al., 2011), so the lower amount of these microbes in ASD children could be related to their GI problems.  Kang et al. (2018) were surprised to see a lower abundance of Haemophilus because it is usually considered a harmful microbe since it is an opportunistic pathogen.  This means it is not always bad, but if the environment is right, it can cause infections.  Typically higher amounts of this microbe are associated with ‘unhealthy’ guts (Mitchell & Hill, 2000).  They expected to see more of this microbe in children with ASD instead of less.

It is worth noting that other studies have had conflicting results regarding whether or not children with ASD had more or less bacterial diversity (Gondalia et al., 2012).  Kang et al. (2018) also did not find any relationship between specific metabolites and specific changes in microbes between ASD and normal children, suggesting that they’re not closely related to one another.  Since there have been conflicting results between the diversity and types of microbes found in ASD children compared to normal children, and the types of microbes are not necessarily related to the metabolites found in the gut, we can conclude that the metabolites the gut microbes produce might have more of an affect on ASD symptoms and GI issues than what specific microbes are present in the gut.  With that being said, the results from Kang et al.’s (2018) study only show a correlation between specific metabolites produced by gut microbes and ASD children. They cannot prove causation between the metabolites, ASD symptoms, and GI issues.

Future Experiments:

While Kang et al. (2018) found some metabolites that could be potential causes of GI issues and ASD symptoms, more studies would have to be done to confirm whether or not the metabolites they found are definitely causing GI issues or ASD behavioral symptoms.  In order to prove causation between the metabolites, ASD symptoms, and GI issues, the researchers would need to do experiments in which they manipulate the amount each metabolite and monitor whether or not ASD symptoms and GI issues occur.

First, the researchers would need to make sure the results Kang et al. (2018) found are also found in other populations and were not just random.  With more people in the studies, they should look for the specific metabolites they found in the original study, such as isopropanol and p-cresol, directly and see how they differ between ASD and normal children.  If the same trends are found in larger groups, they will know for sure the specific metabolites are associated with ASD and are worth studying.

They should then do experiments, possibly with mice, in which they directly change the amount of each metabolite and see if the subjects develop ASD symptoms or reduce the severity of the symptoms.  The same experiments could be done to test the effects of the metabolite levels on GI problems.  To test the effects on GI problems, it would be good just to see how the changes affect normal subjects alone, and then test them in subjects who also have ASD to see how the GI issues change, if at all.  This is important because they can see if the metabolite levels have different effects on GI issues in ASD children compared to normal children.

Further Reading:

For more information on autism spectrum disorder, you can visit the National Institute of Mental Health website, as well as the CDC website.

If you want to read more about possible links between ASD and the human microbiome, check out the scientific journal articles below:

This review paper looks at all the current information about the gut microbiome’s association with ASD and the effectiveness of current treatments, so it’s a great source for a general overview of this topic.

 

These researchers compiled information from multiple studies and looked more specifically at the kinds of microbes that differ between normal people and people with ASD.

 

This paper addresses common abnormalities associated with the microbiome of people with autism and potential causes of these abnormalities.  It also talks about possible treatments to fix the problems.

 

This paper discusses how specific metabolites made by the gut microbiome might be affecting ASD symptoms.

 

This study looks at the immune response of the gut in people with ASD by looking at levels of a specific metabolite in fecal samples.

References:

  1. Abramson, S. & Singh, A. K. (2000). Treatment of the alcohol intoxications: Ethylene glycol, methanol and isopropanol. Current Opinion in Nephrology and Hypertension, 9(6): 695-701. DOI: 10.1097/00041552-200011000-00017 
  2. Adams, J. B., Johansen, L. J., Powell, L. D., Quig, D., & Rubin, R. A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism- Comparisons to typical children and correlation with autism severity. BMC Gastroenterology, 11: 22. DOI: 10.1186/1471-230X-11-22
  3. Buie, T., Campbell, D. B., Fuchs, G. J., Furuta, G. T., Levy, J., VandeWater, J., … Winter, H. (2010). Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: A consensus report. Pediatrics, 125: S1-S18. DOI: 10.1542/peds.2009-1878C 
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  8. Hsiao, E. Y. (2014). Gastrointestinal issues in autism spectrum disorder. Harvard Review of Psychiatry, 22(2): 104-111. DOI: 10.1097/HRP.0000000000000029
  9. Kang, D., Ilhan, Z. E., Isern, N. G., Hoyt, D. W., Howsmon, D. P., Shaffer, M., … Krajmalnik-Brown, R. (2018). Differences in fecal microbial metabolites and microbiota of children with autism spectrum disorders. Anaerobe, 49: 121-131. DOI: 10.1016/j.anaerobe.2017.12.007
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  11. Mitchell, J. L. & Hill. S. L. (2000). Immune response to Haemophilus parainfluenzae in patients with chronic obstructive lung disease. Clinical and Diagnostic Laboratory Immunology, 7(1): 25-30. 
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  13. Rajilić–Stojanović, M., Biagi, E., Heilig, H. G. H. J., Kajander, K., Kekkonen, R. A., Tims, S., & de Vos, W. M. (2011). Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology, 141(5): 1792-1801. DOI: 10.1053/j.gastro.2011.07.043