Altering Gut Microbiota: A Potential Therapy for Autism Spectrum Disorders (ASD)

Autism spectrum disorder (ASD) is a group of developmental disorders, which usually begins early in childhood. People with ASD could have a wide range of symptoms and levels of disability, hence the name “spectrum” disorder. These patients have stereotyped and repetitive behavior, limited interests and could have difficulty communicating and interacting with others. It is believed that gastrointestinal symptoms such as abdominal pain, flatulence, diarrhea, constipation are a common comorbidity in ASD patients and some studies have demonstrated an alteration in fecal flora and metabolic products of the gut microbiome in these patients.

The gut microbiota is known to be associated with brain development and behaviors by regulating the nervous system development, hence it is sometimes referred to as ‘brain peacekeeper’. The primary method of communication between the brain and the gut microbiota is thought to be the ‘microbiota-gut-brain axis’.

Gut Microbiota

• Gut microbiota is basically the microbe population residing in our intestine and each one of us is known to have a unique microbiota. It is estimated that about 1kg of bacteria live in the human gut.
• Many factors such a maternal diet, delivery method and postnatal factors which include breast-feeding, antibiotics exposure could determine the structure of neonatal microbiome.
• Studies have shown that babies delivered vaginally are known to resemble their mother’s vaginal microbiota (mainly Lactobacillus, Prevotella, or Sneathia species), whereas those delivered by cesarean section resemble their mother’s skin microbiota (mainly Staphylococcus, Corynebacterium and Propionibacterium species)

Are Gut Microbiota and ASD Related?

• Even though ASD is primarily a disorder of the brain, new research suggests that gut bacteria might have a role to play in autism, either directly or indirectly by influencing the immune system and metabolism.
• Research suggests that about 23 to 70% of children with ASD may have GI symptoms which include diarrhea (19%), constipation (20%) and others such as abdominal pain and flatulence.
• It has been demonstrated that ASD patients experiencing the GI symptoms may exhibit behavioral issues including anxiety, self-injury and aggression.
• Abnormal intestinal permeability was observed in 36.7% of patients with ASD as compared to 4.8% in control children. This results in a higher antigenic load from the GI tract.
• The gut microbiota of children with ASD is typically less diverse with lower levels of Bifidobacterium and Firmicutes and higher levels of Lactobacillus, Clostridium, Bacteroidetes, Desulfovibrio, Caloramator and Sarcina as compared to children without ASD.
• Autistic children with GI symptoms reportedly have lower abundances of the genera Prevotella, Coprococcus, and unclassified Veillonellaceae as compared to neurotypical children without GI symptoms.
• Fecal samples of children with ASD have shown to contain greater levels of the Clostridium histolyticum group compared with samples from healthy children.
• Studies have shown that babies who were born via Cesarean section are at higher risk of developing ASD (odds ratio of 1.23) as compared to babies born through vaginal delivery method.
• Children with ASD typically use more antibiotics than their normal counterparts and this could be one of the factors that alters the microbial flora in the gut.
• There are very few studies which have evaluated the relationships between gut fungi (mainly Candida albicans) and ASD. These studies have shown that Candida was two times more abundant in autistic individuals than in normal individuals. Candida releases ammonia and toxins which reportedly induces autistic behavior and worsens the dysbiosis.

Pathways of Communication between Gut and Brain

• The gut-brain axis: This is a bi-directional communication system between the gut and the brain. The gut microbiota influences brain function through the neuroendocrine, neuroimmune and autonomic nervous systems, as well as, via microbiotic toxin production. The mucosa of the GI tract contains millions of neurons which regulate GI functions, hence the gut is also known as a “second brain”
• Leaky gut: Reports have shown that there is increased permeability of the intestinal tract in ASD individuals, referred to as a “leaky gut”, allowing entry of toxins and bacterial products into the bloodstream, which influences the brain function.
• Vagal pathway: Metabolites of gut microbiota, such as short-chain fatty acids (SCFAs), phenol compounds and free amino acids (FAA) influence ASD-like behaviors through the vagal pathways.
• Immunological pathways: The gut can also communicate with the brain through immunological pathways. Results of many studies have shown increased levels of pro-inflammatory cytokines in the plasma of ASD patients, which regulate the CNS activity. Examples of such cytokines include such as IL-1β, IL-6, IL-8, and IL-12p40.
• Neurotransmitter-induced pathway: The gut microbiota produces neurotransmitters (dopamine, 5-HT, γ-aminobutyric acid, histamine) which are known to activate or inhibit the central neurons via the vagus nerve.

Modulation of Gut Microbiota – An Effective Therapy for Children with ASD?

• Probiotics and Prebiotics: Probiotics (Lactobacilli, Bifidobacteria and Saccharomycetes) are known to introduce good bacteria into the gut whereas prebiotics are non-digestible oligosaccharides that act as a fodder for the good bacteria that’s already present.
• Probiotics/prebiotics have been shown to normalize the gut microbiota, enhance gut barrier and relieve the ASD-like behaviors in animal models as well as ASD patients.
• Even though both are known to be beneficial to the host, their positive role in treatment of ASD patients is controversial due to lack of sufficient studies.
• Fecal Microbiota Transplantation (FMT): This is the process of transplantation of fecal bacteria from healthy individual to a patient with dysbiotic gut bacteria. Safety and side effects profile (diarrhea, abdominal cramps, bloating) should be considered when using FMT to treat children with ASD.
• Microbiota Transfer Therapy (MTT): Studies have shown that microbiota transfer therapy (MTT), which is a modified FMT improves gastrointestinal and autism symptoms. The treatment consists of 14 days of antibiotic therapy followed by bowel cleansing and the administration of a high initial dose of standardized human gut microbiota (SHGM) for 7 to 8 weeks. An open-label trial has shown that MTT improved GI symptoms (constipation, diarrhoea, indigestion and abdominal pain) as well as ASD-related symptoms.
• Diet Therapy: Food is known to delay the composition of gut microbiota. It has been seen that children with ASD have more feeding problems and eat fewer fruits, vegetables, and proteins as well as have a significantly lower daily intake of potassium, copper, folate and calcium as compared to children without ASD.
  
  In a study conducted by Ruskin et al, it was shown that a ketogenic diet (diet high in fat and low in carbohydrate) lowered the total gut microbial count, improved social skills and communication as well as decreased repetitive behaviors in an ASD animal model.

Conclusion

Even though only a few studies have demonstrated that treatments which regulate the gut microbiota improve ASD symptoms, more well designed research studies with greater number of participants are needed to provide conclusive evidence.

References:

1. Frontiers in Cellular Neuroscience - (http://journal.frontiersin.org/article/10.3389/fncel.2017.00120/full)
2. Autism Spectrum Disorder - (https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd/index.shtml)
3. The Gut Microbiota and Autism Spectrum Disorders - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408485/)

Source-Medindia