The Gut-Brain Axis

The gastrointestinal tract (GIT) of mammals, with a length of 5 meters and a surface area the size of a tennis court, is the largest sensory organ of the brain. As one might expect from its sheer size, it is endowed with over 100 million “enteric” neurons, which communicate exquisitely detailed information relating to luminal nutrients, toxins, and microbiome to relevant parts of the brain. They also serve as the first line of defense against continuous insults from pathogenic organisms. Much of the information received by enteric nerves is conveyed to the brainstem via afferent fibers of the vagus and spinal nerves. Second and third order neurons inform the hypothalamus, hippocampus, and limbic system, eliciting learning, and relevant affective, metabolic, and immune responses. Appropriate responses are transmitted via efferent branches of sympathetic and parasympathetic nerves to the GIT.

The “gut brain axis” refers to these bidirectional networks and circuits enabling the continuous flow of information between the enteric nervous system (ENS) and the brain. Some of those signals entrain the circadian rhythms controlled by the brain and GIT, regulate sleep-wake cycles, adjust body temperature, gastric emptying, digestion, and peristalsis.

The Gut & Neurodegeneration

Over the past few years, groundbreaking research has shown that a protein called alpha synuclein (αS) accumulates within enteric nerves of people who eventually develop Parkinson’s Disease (PD). We have shown that this protein is a normal component of the ENS, a defensive protein involved in innate immunity. We have also shown that αS production is induced in response to viral infections in the GIT in children. If the infection persists, αS production becomes unremitting. Toxic αS aggregates form and deposit on the inner nerve membrane, impairing neural function and reducing messaging via the vagus and other nerves from gut to brain. Over decades, αS accumulates in the brain, damaging neurons and leading to non-motor and eventually motor symptoms of PD.

Neurons, unlike other cells, do not divide during the lifetime of an individual. Toxic proteins such as aggregates of αS must be eliminated if the neuron is to survive. As the neuron ages, it naturally loses the ability to eliminate such toxic proteins. Ultimately, these cells lose function and die. We believe that Parkinson’s Disease manifests itself as an age-related disease because ageing neurons fail to clear the cell sufficiently to remain healthy. By preventing αS aggregate formation, ENT-01 reduces the burden on the digestive system of the cell.

As the disease progresses from the nerves of the GIT to the brain, the brainstem and hypothalamus are affected. As a result, the earliest symptoms of αS in the brain involve disruption of the circadian rhythm (e.g., sleep dysfunction and REM-behavior disorder). Interestingly, circadian dysfunction is present in all neurodegenerative disorders including Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, schizophrenia, and autism. By the time motor symptoms develop, the substantia nigra is almost completely destroyed. Circadian dysfunction eventually leads to the development and progression of dementia and psychosis.