Gut Microbiome and Autism Spectrum Disorder

Introduction

Autism Spectrum Disorder (ASD) comprises a complex neurodevelopmental disorder. It is characterized by cognitive dysfunction, repetitive behaviors, and a lack of social interaction and communication, severely impairing the affected individual’s life. While the question of its etiology remains to be answered, environmental and genetic factors have been named contributing factors. ASD is a neuropsychiatric disorder with a high rate of occurrence of comorbid conditions like gastrointestinal issues, psychiatric illness, and seizures. A gut disorder resembling Crohn’s disease, called autistic enterocolitis, may occur in autistic kids. Recent studies have hypothesized and examined the nature of the relationship between diet, the gut microbiome, and brain development and function. Results of microbiome studies in animals suggest that a change or problem in one affects the others, and they are required to work together in a delicate balance for an individual's mental and physical well-being.

What Is Gut Microbiome?

The gut microbiome refers to the different species of bacteria present in the intestine. Microbiota, in general, refers to commensal, pathogenic, and symbiotic microbes found in multicellular organisms, including not only bacteria but also protista, fungi, and viruses. It evolves and develops uniquely in each individual and has an immense impact on physical and mental health. The human gut contains 500–1000 different bacterial species, and a healthy gut flora plays a significant role in preserving an individual's general state of health. Some of the important functions of this microbiome are immunologic, metabolic, regulation of inflammation, and homeostasis (physiological processes involved in the maintenance of a health state).

• It is involved in the synthesis of vitamins and nutrients, and amino acid chains.

• Synthesis of short-chain fatty acids from indigestible dietary fibers.

• Production and regulation of neurotransmitters like serotonin and GABA (Gamma amino butyric acid).

• Affords protection to the intestinal lining by maintaining the epithelial barrier.

• Inhibitory effect on pathogenic microbes through nutrient competition and through anti-microbial metabolites.

• Decreases inflammation in the body, detoxification of harmful substances.

• Regulates immune response and induces IgA antibodies.

• Helps in the absorption of nutrients from food and also controls gastric emptying and motility.

The relationship between the human host and these bacteria can result in symbiosis or dysbiosis. While symbiosis is related to good health, dysbiosis due to a disturbance in the microbiome with respect to changes in populations of certain species can cause diseases such as coeliac disease, inflammatory bowel syndrome (IBS), allergy, asthma, cardiovascular disorders, metabolic syndrome, and ASD.

What Is the Microbiota-Gut-Brain Axis and How Does It Function?

The gut is lined by a complex network of nerve cells that forms the enteric nervous system (ENS), considered to be our second brain. The vagus nerve connects the brain to the gut. This signaling pathway between the brain and the gut constitutes the microbiota-gut-brain axis (MGBA). A bidirectional relationship where each can influence the other is maintained through this axis. Changes are effected through neurotransmitters, immune responses, and hormones.

1. Microbiota exerts its effects on the brain by the synthesis, turnover, and expression of neurotransmitters such as serotonin, GABA, and neurotrophic factor; immune regulation; protecting the intestinal epithelial barrier, etc. Hence it affects mood, emotions, sleep, and cognition.

2. Conversely, the brain is anticipated to exert its action through mechanisms like altered intestinal motility, increased intestinal permeability, altered mucous secretion, and biofilm formation. Microbes in the gut are sensitive to changes in the intestinal environment like pH, mucus secretion, etc.

Animal studies on germ-free mice (mice raised without any exposure to microbes and have no gut microbiome) have been performed to understand the functioning of the MGBA.

• Fecal samples of children with and without autism were inoculated into the stomachs of germ-free (GF) mice and mated pairs of mice were colonized by similar microbiomes to expose offspring to the human microbiome during the developmental stages. Mice colonized with germs from children with autism were less sociable and displayed more repetitive behavior than mice colonized with bacteria from children without autism. Animals with the autism-derived microbiome also had decreased amounts of numerous bacterial species thought to be beneficial.

• The effect of chronic antibiotic treatment was studied in mice. The group treated with antibiotics like Metronidazole, Vancomycin, etc., and antifungal drugs like Amphotericin B, leading to a disrupted microbiome, showed increased anxiety and altered cognition. This is thought to be due to dysregulation of the MGBA due to the loss of beneficial bacteria in the gut owing to antibiotic treatment.

How Is the Gut Microbiome Related to ASD?

Autistic children exhibit dysbiotic gut microbiota in addition to increased intestinal permeability (leaky gut). This leads to the production and spread of proinflammatory substances like endotoxins and Lipopolysaccharides (LPS). A cascade effect results in increased activity in brain areas like the amygdala, which controls emotions and behavior, and the production of inflammatory cytokines from immune cells that alter the brain physiology and synthesis of neuropeptides.

The microbiomes in autistic children revealed an increase in bacterial species such as Clostridium (produces endotoxins), Bacteroides, Proteobacteria (produces LPS), Faecalibacterium prausnitzii and a decrease in species like Prevotella, Veillonella, Bifidobacterium, Blautia, Dialister, etc.

When the immune function of the gut microbiome is disrupted due to altered populations of different microbes, the immune system is activated, releasing chemokines and cytokines such as interleukin-1β (IL-1β), interleukin-6(IL-6), interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α) which crosses the BBB (Blood Brain Barrier). It can ultimately contribute to brain inflammation which is relevant in ASD.

Is Maternal Microbiota Related to ASD?

The time between conception and gestation is critical for fetal neurodevelopment. Many variables, including an improper diet, microbial infection, and metabolic stress, can cause maternal microbiome dysbiosis, which can cause the offspring's aberrant brain development, leading to lasting behavioral abnormalities. Several studies have found that newborns born by vaginal delivery have a higher proportion of beneficial germs than kids born via cesarean surgery. Treatment with antibiotics up to the age of three also impacts the microbiota and, consequently, brain development.

What Is the Significance of Microbial Therapeutics in Autism?

With an increasing incidence of autism and the side effects of conventional medication, and the mounting evidence of the role of microbiome dysbiosis in ASD, adjuvant therapy to manage comorbid conditions and control symptoms is gaining importance. The gut microbiome may be targeted in the following ways:

• MMT (Microbiome transfer therapy), where standardized human gut microbiota is transferred to an autistic individual to alter the gut microbial composition. It was shown to improve gastrointestinal symptoms in ASD. Thorough studies are required for its large-scale application.

• Probiotics, a non-pharmacological option to promote digestion and gut health

• Modulatory therapy involving diet intervention - gluten-free, casein-free diet is advised to prevent gut inflammation. Traditional Chinese medicinal food can lead to improvement of gut microbial profile.

• Use of targeted antibiotics that spare gut-friendly bacteria can prevent microbiome disruption.

Conclusion

The gut microbiome consisting of several species of bacteria, plays numerous pivotal roles in maintaining health. The gut is connected to the brain through the MGBA (microbiota-gut-brain axis), a bidirectional signaling pathway. Hence a disruption in the gut microbiome leads to concomitant changes in the central nervous system. An alteration in the microbiome in the initial years of life can affect brain development. Studies show the role of a disrupted microbiome in the pathogenesis of ASD. With knowledge of the link between the gut microbiome and ASD, adjuvant therapies for ASD targeting the microbiome can prove beneficial.