Meet the second brain
An enigmatic brain-microbiota relationship
The microbiota is defined as the collection of the trillions of microorganisms inside (e.g., gut or mouth) or on (e.g., skin) the body. A microbial imbalance (i.e., dysbiosis) may play a role in the pathogenesis of neurological diseases.
- Microorganisms, specifically certain bacteria, synthesize a multitude of molecules that act on nerve cells.
- The gut and the brain are directly connected by the vagus nerve and exchange information through neurotransmitters (chemical messengers) produced in the gut.
Bypassing the complexity in CNS (Central Nervous System) R&D
The incidence of neurological illnesses is rising sharply, but no effective treatment has yet been developed. The pathogenesis is still unclear, making targets challenging to identify and confirm. Bidirectional communication between the CNS and microbiota provides new therapeutic targets to explore.
- Delivering the drug through the gut microbiome avoids the current hurdle of passing the blood-brain barrier (BBB), which protects the brain.
Differentiated treatments for neurodegenerative diseases
Two main microbiota are currently studied: those of the gut and the mouth. Most players are still at a preclinical stage (animal testing), and just a few are in clinical trials (human testing).
- Cortexyme is looking to leverage the presence of the oral bacterium P. gingivalis in the brain of more than 90% of Alzheimer's patients.
- Axial Biotherapeutics and Kallyope are harnessing the relationship between the gut and the brain and have candidates in autism and Parkinson's disease, among others.
Three Connected Routes
The vagal pathway (vagus nerve)
The gut has its nervous system, called the Enteric nervous system, composed by 500mn of neurons. It produces 50% and 95% of dopamine and serotonin, respectively. Through the vagus nerve, neurotransmitters are sent to the brain and influence our mental health.
- 40 neurotransmitters have been identified in the gut.
- Dopamine correlates with Parkinson's disease (low levels), and schizophrenia (high levels).
- Major depressive disorders, as well as autism or Parkinson’s, are associated with serotonin.
The immune pathway
Oral and intestinal dysbiosis (i.e., microbial imbalance) may promote a neuroinflammation response, associated with Alzheimer’s and Parkinson’s diseases. This inflammation is part of an immune response triggered by an abnormal presence of gut or oral bacteria.
- Cytokines, immune-system signaling mediators, could indicate an intestinal-led inflammation of the brain.
- Chronic inflammation in the brain could lead to damage and death of neurons.
The metabolic pathway
Metabolites (i.e., SCFA, Short-Chain Fatty Acids), produced by bacteria in the gut, can influence our brain. Metabolites can modulate neurotransmission, the process of communication between neurons.
- Neurotransmitters are released by the neuron and then bind to receptors in another neuron, thus sending a signal through the neural network.
- Enzymes can modulate the production of neurotransmitters. Some metabolites can control the expression of enzymes.
Succeeding Where It Previously Failed
A poor success rate in CNS (central nervous system) R&D
Neurological diseases are the world’s leading cause of disability-adjusted life years (i.e., healthy years lost due to disability or death), but there is little or no cure available on the market today.
- The success rate in terms of FDA approval for a CNS drug is 8.4% vs. 14.8% for drugs in all other non-neurological indications.
- At more than $1.3bn to develop a new drug, neurology is one of the most expensive therapeutic areas for R&D.
The blood-brain barrier (BBB) permeability issue
The blood-brain barrier (BBB) permeability and safety are two reasons why many neurological drugs have failed. Most drug delivery methods are not able to cross the barrier, and even if the drug crosses the BBB, much of it ends up in other parts of the body, causing side effects.
- It is easier to deliver a drug into the gut than directly into the brain.
Early detection and action
The main problem with existing CNS drugs is to target patients as early as possible. Abnormalities in the enteric nervous system can occur before those in the brain. Ultimately, scientists hope to spot (and cure) damage to the enteric nervous system before they see it in the central nervous system.
- 90% of all signals passing through the vagus nerve come from the gut.
- The microbiota and the presence of abnormal bacteria could be used as a biomarker to identify patients at risk.
How Do We Target The Microbiota-Brain Axis?
Targeting the gut microbiota
The trillions of microorganisms in the intestinal microbiota could be involved in many brain diseases. Some misfolded proteins have been observed as traveling from the gut to the brain and are currently being studied for therapeutic purposes.
- Axial Biotherapeutics is testing the role of bacteria in αSyn protein aggregation, which is associated with Parkinson’s disease.
- Kallyope develops a platform to explore all gut-brain circuits and find targets in several disorders (depression, Parkinson’s, autism).
Don’t forget the oral microbiota
The mouth is the second-largest microbiota after the intestine with 700 different bacteria. The presence of neuroinflammation and immune response related to this microbiota has been observed in the brain of Alzheimer’s disease patients.
- Cortexyme’s lead product, COR388, targets P. gingivalis, an oral bacterium that produces toxins causing neuroinflammation, with promising preliminary data (Phase II/III trial) already been published.
- COR388 showed a significant decreased in the growth of P. gingivalis, antiinflammatory effects and lowered the burden of amyloid plaques, which play a role in Alzheimer’s disease.
Beyond neurological diseases
Several studies showed the role of the microbiota in many other diseases, from cancer to liver disorders. A specific mix of bacteria was found in several tumors, such as bone or pancreatic.
- Second Genome has three pre-clinical and research programs targeting several indications: inflammatory bowel diseases, immuno-oncology, and metabolic diseases.
- Seres Therapeutics has a discovery platform to understand which microbes/ bacteria (absence or overexpression) can cause dysbiosis. The company designs drugs in inflammatory, metabolic, and infectious diseases.
- Cortexyme’s drug results. Interim data are expected at the end of 2020 and top-line data in Q4 2021. Any proof of concept in the field would drive the whole sector upwards and may trigger M&A.
- Microbiome sequencing. New methods, such as the single-cell sequencing technique, will allow each bacterial genome to be obtained separately. We will be able to understand the individual role of each bacterium.
- Biogen’s potential approval of Aducanumab in 2020. The potential approval of its drug on Alzheimer’s disease could restore investors’ enthusiasm for neurological treatments.
- Failure in Alzheimer’s disease. Renewed failures in Alzheimer’s disease after recent ones (Lilly, Pfizer) may lead to a binary reaction from investors.
- The chicken or egg dilemma. The cause and effect relationship between the microbiota and the brain is not well known. Does the microbiota lead to neurological disease, or does neurological disease lead to changes in the microbiota?
- A complex community. Microbiomes are studied in an artificial environment. The wild diversity of bacteria is not well represented in the patient’s selection in clinical trials and could lead to misleading interpretation.
Global Burden of Disease Study, Lancet Neurology, Mullard, A. Parsing clinical success rates. Nat Rev Drug Discov 15, 447 (2016)
Companies mentioned in this article:
Axial Biotherapeutics (Not listed), Cortexyme (CRTX US), Kallyope (Not listed), Second Genome (Not listed), Seres Therapeutics (MCRB US)
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