Decoding The Gut-Brain Axis

In Biologics, Drug Development, Drug Targets, The WEEKLY by Emily Burke

Microbiome & Disease

The biotech world is abuzz with talk of the latest microbiome startup launch Axial Biotherapeutics (Boston, MA). What caught our eye here at the WEEKLY is the company’s focus on the gut microbiome — the entire collection of microbes living in the gut — and its interplay with the brain.

The connection between the gut microbiome and inflammatory bowel disease is much more intuitive since they occur in the intestine. In the past few years, however, new research has made it clear the gut microbiome also impacts neurological health, leading to the phrase “the gut-brain axis.” Let’s explore this connection and examine the early efforts to translate these discoveries in the clinic.

Gut Microbiome Primer

The human microbiome is the complex collection of microbes (mostly bacteria, but also includes small numbers of fungi and viruses) that reside on and inside the human body, including our skin, mouth, nose, respiratory tract, and digestive tract (gut). The microbiome is huge — microbial cells outnumber human cells by a ten to one ratio! Human cells are much larger than bacteria cells, however, so don’t worry — you’re still mostly human. For every 100 pounds that you weigh, it is estimated that about two pounds of that weight come from bacteria.

Most of us think of bacteria as harmful and certainly some types are; however, those that have evolved with humans to become part of the human microbiome are either neutral — causing no harm — or beneficial. Scientists are busy trying to better understand and characterize these beneficial bacteria and the role that they play in human health.

The gut contains the largest number of bacteria, as well as the greatest diversity of bacteria, when compared to other parts of the body. Thus much of the attention directed towards the human microbiome has been focused on the gut microbiome in particular, which continues to surprise us with its influence on diseases such as obesity, diabetes, and, increasingly, brain disorders.

Trail Blazers: Axial Biotherapeutics & The Mazmanian Lab

Axial is focusing much of its initial attention on work originally done at microbiologist Sarkis Mazmanian’s lab in the California Institute of Technology (Pasadena, CA) — mostly relating to the gut-brain axis’ role in Parkinson’s disease (PD) and autism.

Parkinson’s Disease

Parkinson’s disease (PD) is a chronic and progressive movement disorder, according to the Parkinson’s Disease Foundation. Symptoms include tremor of the hands, arms, legs, jaw, and face; slowness of movement; rigidity of the limbs and trunk; and impaired balance and coordination. These symptoms are caused by the malfunction and death of neurons that produce the neurotransmitter dopamine. PD affects nearly one million people in the U.S., and the cause is unknown. About 75% of PD cases are accompanied by gastrointestinal disorders such as constipation, which provided an initial impetus to examine a possible connection between gut health and the disease.

A key molecular characteristic of PD is the aggregation of a protein called alpha-synuclein (αSyn) within cells of the brain and gut. Researchers in the Mazmanian lab used a strain of mice that over produce αSyn to study the disease. One group of mice were bred in a completely sterile environment to create “germ-free” (GF) αSyn mice. The other αSyn mice had the normal collection of gut bacteria. On a series of tests designed to assess motor skills, the GF αSyn mice performed significantly better — suggesting that even in mice that overproduced the αSyn protein, the presence of certain microbes are required for the disease to progress. Further work suggested that a molecule called butyrate, produced by certain gut bacteria, can enter the brain and activate an immune response, leading neurons to malfunction or die.

There is reason to believe that this connection is also at work in humans with PD. In collaboration with Rush University (Chicago, IL) gastroenterologists, Mazmanian lab researchers transferred fecal samples from PD patients into the GF αSyn mice. Fecal transplants are an established way to “reset” the gut microbiome of the recipient to make it match that of the donor. After transplantation, the mice began exhibiting symptoms of PD. Transfer of fecal matter from healthy people did not trigger these symptoms. These experiments suggest that the gut microbiome is a major contributor to the disease process in PD patients.

Of course, these promising early stage findings still need to be translated into human therapeutics. This may be easier than traditional neurological approaches because it is much easier to deliver drugs to the gut than to get them to cross the blood-brain barrier. Following up with a targeted approach to modulate the production of butyrate and other inflammatory compounds produced in the gut may bring the first truly effective PD therapy into the clinics.

Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a developmental brain disorder characterized by impaired social interaction, communication, and restrictive and repetitive behavior. These symptoms impact a child’s educational, social, emotional, and physical development. More than 3.5 million Americans live with an autism spectrum disorder according to the Autism Society. The cause is unknown, although genetics is thought to play a role.

Similar to PD, a significant portion of ASD patients exhibit gastrointestinal problems. The Mazmanian lab demonstrated that feeding ASD mice a specific strain of bacteria called B. fragilis — a part of the human microbiome — altered the mouse microbiome and reduced some of the ASD-like behaviors such as anxiety and repetitive behavior, and increased levels of communication with other mice. These experiments suggest a possible probiotic therapy for autism.

Carb Loading With Symbiotix

Another early-stage company making headlines in the gut-brain axis space is Symbiotix (Boston, MA). Focusing on multiple sclerosis (MS), their lead candidate is a carbohydrate molecule produced by B. fragilis.  This therapy increases the production of regulatory T-cells, which are a class of T-cells that “turn down” an overactive immune response by releasing anti-inflammatory signaling molecules. Symbiotix is preparing to enter clinical trials with an orally-administered product for the treatment of MS and inflammatory bowel disease.

Kallyope On The Lookout

Launched just one year ago, Kallyope (New York City, NY) also hopes to translate our growing knowledge of the gut-brain axis into new therapeutics. The company is developing a discovery platform using tools such as genome sequencing and brain imaging to precisely identify gut-microbiome-derived molecules of potential therapeutic interest.

The emerging work described here gives credence to the old expression “think with your gut.” In addition to the diseases discussed above, scientists are discovering links between the gut microbiome and other brain disorders such as anxiety and depression. As the story continues to unfold, we are likely to see new therapeutics based on restoring the balance that millions of years of human-microbe co-evolution has fine-tuned.