By Gita Gupta

When my son was first diagnosed with autism, he also had problems like chronic diarrhea. The diarrhea caused him a lot of distress, and he was not gaining weight or growing. We saw many specialists. When I asked them about what causes the diarrhea, I was often told “that’s just autism.” I heard this a lot, back in those days. Now helping out other families, I realize my story is not uncommon.

Today, our understanding of the processes in the body that are abnormal in autism has come a long way from saying “it’s just autism. The term for these abnormal processes is autism pathophysiology. Recent research has given us great insights on one specific aspect of autism pathophysiology – the role played by the microbes in the gut. The collection of microbes in the gut are called “gut microbiota“. This term includes different types of microbes like bacteria, fungi like yeast and molds, viruses etc.

We’ll start with some key insights, and then we’ll look at the big picture of how gut microbiota cause abnormalities in autism. You probably know all of this already, one way or another, but if you see any medical practitioners who are new to autism, this is hopefully a good resource to share with them – because we can cite specific peer-reviewed research references (about 160 papers worth!) for everything said here.

Key insights    

• Gut dysbiosis is common in autism– “Gut dysbiosis” is a term that means an imbalance or disruption of gut microbiota. Peer-reviewed studies confirm that children with autism have disruptions in gut microbiota compared to neurotypical children (1) Gut bacteria in children with autism has less variety compared to neurotypical children. There are also higher levels of certain kinds of bacteria (e.g. Clostridia.)Not just gut bacteria – there are also disruptions in other microbes like fungi (e.g. Candida.)  One study that looked at duodenal juice reported that 43% of children with autism had a positive fungal culture for yeast in their duodenal juice, vs. 23% of controls of the same age (2) We need more studies in larger samples, for sure – but early studies show that when there is imbalance in gut bacteria, fungi like candida can grow, which makes dysbiosis worse.
• Gut Issues like Constipation, diarrhea, reflux etc. are linked to gut bacteria – physicians and researchers debated for a long time whether there is a true increase in the rate of gastrointestinal (GI) symptoms like constipation and diarrhea in ASD kids. The debate: are constipation and other GI issues due to behaviors (like the child withholding stool) or are they caused by actual problems in the gut?  I think it’s time to settle the debate – several studies, including a large study of over 3900 ASD kids (3), confirm that ASD kids are more likely to have GI issues like constipation, diarrhea, bloating and reflux. What’s more, research shows that gut microbiota can cause GI issues, in part by influencing the immune system and metabolism.
• the Gut is “leaky” in autism. So is the “blood-brain barrier” (BBB)–  A recent study from researchers at Harvard looked at intestinal tissue and gene expression in autism (4.) The study showed that the intestinal wall in autism is “leaky” or has increased permeability. It’s “leaky” in the sense that particles that aren’t supposed to get through the gut wall, such as toxins and other products from bacteria, are able to pass through. For example, parts of the cell walls of gram-negative bacteria (e.g. Klebsiella) can pass through the intestinal wall and enter the blood stream. The same study also looked at brain tissue in autism, and found that the “blood brain barrier” (BBB, for short) – a barrier which keeps unwanted particles from entering the brain – is also leaky in autism. What this means is that the toxins that get out of the gut through the leaky gut wall can then enter the brain through the leaky blood-brain-barrier!
• Toxins from gut bacteria enter the brain and cause autism behaviors – Substances produced by gut bacteria which escape through the leaky gut and enter the brain through the leaky BBB can change behavior. Common behaviors in autism like hyperactivity, repetitive behavior, anxiety, self-injury and aggression are linked to substances produced by gut bacteria. Here’s an example of how it works – propionic acid, which is produced by a few types of bacteria, such as Clostridia & Desulfovibrio, is a substance that is toxic to the brain. In animal studies, we’ve found that this toxin can cross the BBB and enter the brain (5). Once it enters the brain, it alters neurotransmitters like serotonin and dopamine and causes hyperactivity, repetitive behaviors and abnormal motor movements.
• Gut bacteria affect the immune system & trigger inflammation -the gut communicates with the brain through immune pathways. Gut bacteria can produce toxins, which make leaky gut worse. The leaky gut lets bacteria cross the intestinal wall even more easily – bacteria moving around like that is called “translocation”. Bacteria translocate, enter lymph tissue and activate the immune system. The activated immune system releases inflammatory substances called cytokines, which signal the brain and alters brain functioning and behaviors.
• Gut bacteria affect the brain through neurotransmitters – The pathway through which gut bacteria communicate with the brain also involves neurotransmitters. Gut bacteria produce neurotransmitters like Dopamine, serotonin, GABA and histamine, which can activate or inhibit brain function through the vagus nerve. As a result, gut bacteria can have long-term effects on brain development. This can have negative consequences for what happens when the child grows into an adult.

The Big Picture: How Gut Bacteria Affect the Brain

Here’s how it all fits together –

• Compounds made by gut bacteria (e.g. serotonin) can activate neurons in the gut. These neurons impact brain function through the vagus nerve, and can cause abnormal behaviors.
• Compounds made by gut bacteria can affect the endocrine system through the HPA axis and can cause increases in cortisol, which is involved in the fight-or-flight response.
• Toxins from bacteria activate immune cells, which release inflammatory substances called cytokines into circulation.
• Compounds and toxins produced by gut bacteria can leave the gut through the leaky gut, enter the brain through the leaky BBB and affect brain function.

Therapies based on modulating gut bacteria

The good news is that what we’re learning about gut bacteria in autism might also provide therapies for treating some of these issues.

Diets, Probiotics and Prebiotics – Anecdotally, we know diets can help. Obviously, not all diets used in autism have been formally studied, but studies do show that specialized diets e.g. gluten-free casein-free diet (1) improve behaviors, physiological symptoms and social behaviors in autism.  Diets also alter gut bacteria profiles. For example, one animal model study found that the ketogenic diet (5) results in reduction of total gut bacteria counts, normalizes levels of certain disease-causing bacteria (e.g. Akkermansia muciniphila) and improves sociability and deceases repetitive behavior. Antibiotics like Vancomycin have been shown to produce improvements in behaviors but we need more studies on this, since antibiotics can also hurt gut balance. Probiotics and prebiotics can help normalize the gut bacteria, reduce dysbiosis, improve the gut barrier and improve ASD behaviors … but the topic of probiotics is a big one, and a blog post in itself!

Fecal Transplant & Micriobiota Transfer Therapy (MTT) – you’ve probably heard of a therapy called “fecal microbiota transplantation (FMT, for short.) In FMT, stool from a healthy individual is delivered to a patient with gut dysbiosis. MTT is a modified version of FMT, where antibiotics are given first, followed by bowel cleansing, and then the patient is given a high dose of a standardized form of human gut microbiota for 7-8 weeks. MTT showed improvement in ASD behaviors as well as positive changes in the gut environment including more diversity of gut microbes.

What’s Next?

We need more research to increase our understanding, but gut microbiota clearly plays a big role in causing autism behaviors and symptoms. Therapies focused on correcting abnormalities in gut microbiota are very promising. We need a lot more research and investment in this important area! We also need the professionals seeing our kids to understand the gut can play a big role in behaviors, learning, sleep – it can touch pretty much everything, even if the child does not have obvious gut symptoms. We need to test and treat for the concerns outlined in this blog to help each individual with autism have a better quality of life.

 References

1. Q.Li et al (2017) “The Gut Microbiota and Autism Spectrum Disorders, “Frontiers in Cellular Neuroscience.
2. Horvath K et al (2002) “Autism and gastrointestinal symptoms. Curr Gastroenterol Rep.
3. Alexeef, SE et al (2017) “Medical Conditions in the First Years of Life Associated with Future Diagnosis of ASD in Children”, J Autism Dev Disord.
4. Fiorentino, M et al (2016) “Blood-brain barrier and intestinal epithelial barrier alterations in autism spectrum disorders”, Mol. Autism.
5. Newell, C (2016) “Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder”, Mol. Autism

For more information about Gita Gupta please visit  https://www.tacanow.org/about-taca/ambassadors/

This topic is so important to TACA and our families we serve.  We will be covering this topic at our National TACA Autism Conference with Dr. Sarkis Mazmanian. We hope you join us:  https://www.tacanow.org/national-taca-autism-conference/