New Preclinical Research Published in Nature Highlights an Active Role by Microbiome-Derived Metabolites in Brain Function and Anxiety-like Behavior

WOBURN, Mass.--(BUSINESS WIRE)-- Axial Therapeutics, a clinical-stage biopharmaceutical company dedicated to improving the lives of people with neurological disorders and conditions, today announced the publication of preclinical research demonstrating that microbial metabolites produced by gut bacteria commonly found in the gastrointestinal (GI) tract can impact brain activity and influence complex behaviors in mice. The research was published in the journal Nature, and was led by Sarkis Mazmanian, Ph.D., Luis B. and Nelly Soux Professor of Microbiology and Heritage Medical Research Institute Investigator at the California Institute of Technology (Caltech). The studies in mice showed that gut-derived metabolites can enter the brain and disrupt the maturation of oligodendrocytes, which leads to alteration of myelination and region-specific changes in brain activity and functional connectivity.

The paper, “A gut-derived metabolite alters brain activity and anxiety behavior in mice,” offers new mechanistic insight into how the gut microbiome can influence complex behaviors via the gut-brain axis. The research demonstrates that chronic exposure to a specific small molecule metabolite originating from microbes in the gut can lead to changes in brain function and behavior. Specifically, the metabolite can alter oligodendrocyte activity, leading to decreased myelination in specific regions of the brain associated with complex behaviors such as anxiety.

In the studies, the team of researchers developed an innovative mouse model system to evaluate the effects of the gut microbiome-derived metabolite 4-ethylphenol sulfate (4EPS) on complex behaviors and brain function. In the murine model, the researchers used engineered gut bacteria that either constitutively produce or do not produce 4EPS. The authors demonstrated that 4EPS can enter brain tissue, and that chronic exposure to 4EPS leads to arrest of oligodendrocyte maturation and corresponding region-specific changes in myelination. Specifically, 4EPS reduces myelination of neuronal axons, which has been linked to behavioral outcomes, and promotes robust anxiety-like behaviors. Further, pharmacological treatments that enhance oligodendrocyte differentiation prevented the behavioral effects of 4EPS in the murine model.

“The study identifies a potential mechanism for molecular communication between the gut microbiome and the central nervous system,” said Sarkis Mazmanian, Ph.D., senior corresponding author of the paper and scientific co-founder of Axial Therapeutics. “Continued research that validates the link between microbial metabolites and brain function has the potential to guide discovery of novel therapeutic approaches based on understanding the gut-brain axis.”

The preclinical study adds to a growing body of research that suggests the gut-brain axis may be influenced by an assortment of microbial molecules that are produced by bacteria commonly found in the GI tract. Earlier studies in animal models were the basis for the foundational concept that metabolites produced by intestinal bacteria can circulate in the bloodstream and affect the pathology, progression, and symptoms of neurodegenerative diseases and neurodevelopmental disorders.

Axial Therapeutics was founded based on this research as well as additional preclinical studies to discover and develop new treatments for neurological conditions, including those associated with Autism Spectrum Disorder, Parkinson’s disease, and others.

“This groundbreaking research validates a new concept in the biology of the gut-brain axis, and informs potential new interventional strategies for neurological conditions,” said A. Stewart Campbell, Ph.D., chief executive officer of Axial Therapeutics. “By starting to identify how bacterial metabolites in the gut can impact behavior, it offers a tremendous opportunity to discover and validate new drug targets in the gut microbiome that may lead to novel medical interventions for the treatment of neurological conditions that adversely affect quality of life.”

About Axial Therapeutics

Axial Therapeutics is a clinical-stage biopharmaceutical company dedicated to improving the lives of people with neurological disorders and conditions. The company is a scientific leader in the biological role of the microbiome-gut-brain axis and its influence on the central nervous system. Harnessing its unique expertise in the microbiome, Axial is developing small molecule drugs with defined mechanisms of action that act on new targets to mitigate the impact of metabolites and bacteria in the gut linked to neurological disorders and disease pathology, progression, and symptoms. The company is advancing a pipeline of “microbial-inspired therapeutics™” for conditions with significant unmet patient need, including autism and Parkinson’s disease, and is also pursuing pre-clinical discovery of gut-targeted therapies in oncology. Axial’s lead product candidate is AB-2004, a molecular therapeutic in Phase 2b clinical trials for the treatment of irritability in children with autism. For more information, visit https://axialtx.com.

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