THE MICROBIOME-GUT-BRAIN-AXIS IN AUTISM SPECTRUM DISORDER
Axial Therapeutics is focused on understanding the interaction between microbes in the gastrointestinal system (GUT) and the human brain. The end goal is to develop new ways to treat and possibly prevent some of the brain disorders that have been resistant to treatment. Axial’s objective is to think outside the brain, to get a more holistic picture of what drives behavior and mental health.
Concerning brain disorders, particularly Autism, research has shown that the microbes (bacteria) in the gut can contribute to the autism behavioral spectrum. Axial Therapeutics is currently developing a therapy that could help generate some improvements without the side effects that accompany some of the drugs administered by a Psychiatrist.
THE GUT-BRAIN AXIS: The three major “highways” of communication between the gut and brain are:
Enteric Nervous System (Neuronal Signaling):
Sometimes called the “Second Brain”. The Enteric Nervous System, is a major component of the autonomic nervous system that controls Gastrointestinal (GI) Enzyme Secretions, Gastrointestinal motility (the movement of food from the mouth through the pharynx (throat) esophagus, stomach, small and large intestines and out of the body. The GI system is responsible for digestion.), movements of cells to absorb nutrients and communicates with the brain primarily through a direct link via the vagus nerve.
Circulatory System (Metabolites/Hormones):
Is the communication through the blood. In the Circulatory System, we have hormonal access, otherwise known as the Hypothalamic-pituitary-adrenal axis (HPA), and Neurotransmitters/Small Molecule Metabolites.
The Hypothalamic-pituitary-adrenal axis is the major neuroendocrine system. It regulates stress reactions, digestion, emotions (fight or flight syndrome which is an instinctive reaction/response that is driven by hormones in the HPA), etc., through the release of hormones (e.g., vasopressin, cortisol, adrenocorticotropic hormone (ACTH), etc.)
Neurotransmitters/Small Molecule Metabolites generate from the gut and move to the brain, and vice versa. Several critical neurotransmitters are predominantly produced in the gastrointestinal system (GABA, Serotonin, dopamine, acetylcholine, norepinephrine). Norepinephrine or Adrenaline production in the gut leads to increased levels of dopamine in the brain.
Immune System (Immunomodulatory Processes):
80% of the human body’s immune system is contained in the gut tissue. The gut “educates” and helps maintain our immune system. There are two organs that interface between us and the outside world (The Mouth & The Anus), that’s where our immune system is developed and maintained. Microbes and their fragments can cross the gut barrier, and get into the body, which is often compromised in certain disorders, resulting in a disseminated infection that can lead to neuroinflammation (Peripheral activation of the immune system).
THE GUT MICROBIOME: THE “ELEPHANT IN THE ROOM”
The gut microbiome is a significant contributor to the gut-brain axis. The gut microbiome is a major source of neurotransmitter synthesis (Bacteria, dopamine, and serotonin, etc.) it is estimated at up to 50% of circulating metabolites.
The intestinal permeability (“leaky gut”): leads to enhanced translocation of microbial products, further driving inflammation, stress levels, and allows oxygen into GI lumen (normally anaerobic) which alters microbial populations and functions.
OVERVIEW OF THE HUMAN MICROBIOME
We are more microbe than human;
- Total bacteria outnumber human cells by approximately 1:25:1
- Total bacterial genes outnumber human genes > 100:1
- These numbers do not consider fungi (e.g., yeasts), viruses, and bacteriophage.
AUTISM SPECTRUM DISORDER (ASD) OVERVIEW
There are three symptoms and diagnostic criteria/areas that are considered “core” for ASD:
- Socialization deficits
- Language/communication difficulties/delays
- Repetitive, stereotyped behaviors and interests
Children in the autistic spectrum, battle with common co-occurring conditions that impact the quality of life, such as Anxiety, Irritability, Seizures, OCD, Mood Disorders, ADHD, Sleep disorders, and Cognitive deficits, etc.
EPIDEMIOLOGY: CORRELATIVE RELATIONSHIP BETWEEN ASD AND THE GUT MICROBIOME
Many ASD children have Gastrointestinal Dysfunction, which correlates with ASD severity. The microbiome of children with ASD is compositionally different compared to neurotypical controls. Several other ASD risk factors implicate microbiome involvement:
- Maternal infection during 2nd Trimester
- C-section delivery
- Reduced breastfeeding
- Use of repeated antibiotics early in life
Formally, the Diagnostic and statistical manual of mental disorders (5th edition) (DSM-V) describes two main criteria for ASD diagnosis:
- Social communication
- Restricted, repetitive behaviors or interests
DSM-V does not require the use of standard assessment tools; however, there are two standard tools that are broadly implemented and generally accepted:
- Autism Diagnostic Observation Schedule (ADOS)
- Autism Diagnostic Interview-Revised (ADI-R)
1. GI symptoms are prevalent and likely contributing to ASD, both at the core level and as an exacerbator of core and non-core symptoms.
2. Network-related dysfunctions and pathologies, including altered myelination and network connectives, are associated with ASD.
3. GUT microbiome may be a key contributor to these problems:
- Release of small molecule metabolites, some of which are neuroactive or immunologically active
- Production of neurotransmitters (GABA, serotonin, dopamine)
- Amino acid metabolites (e.g., 4-EPS, IS)
- Production of SCFA’s (microglial activation, metabolically active)
4. Potential to intervene at the functional level to effect changes, and perhaps blunt some of the core and non-core ASD symptoms to improve quality of life.
5. These concepts are likely generalizable to several neurodevelopmental and neuropsychiatric disorders.