In an extensive lab in Cambridge, Massachusetts Phil Strandwitz, CEO at Holobiome, and his colleagues are working to isolate gut bacteria that they hope will produce new treatments for depression and other disorders of the brain and nervous system.
New drug development for neuropsychiatric disorders has slackened for decades, and many existing drugs cause unpleasant side effects. Researchers at Holobiome see a promising alternative in microbe-based treatments, or “psychobiotics.” In this article, we uncover the amino acid behind their new therapies targeted for treating both mental health and intestinal disorders.
Why the Gut?
As droughts go, the one tormenting the antidepressant drug development scene for the past few decades has been noteworthy, according to The Scientist. The prevailing move has been to look at brain chemistry, or brain circuitry, as the cause of depression and other mental health disorders. Clinical trials in new therapeutics are taking place; however, getting these drugs to market has been challenging. Today, scientists are looking to the gut-brain axis and psychobiotic therapies as potential targets for antidepressant drugs. This territory is very young – but impressive.
Why the gut? According to the American Psychological Association, trillions of microbes in the gastrointestinal tract, known as the microbiome, influence health in many ways. Inside the gut, microbes program the developing immune system, helping to defend against infection, make nutrients, and create neurochemicals necessary for brain function. Science Magazine also states that with as many as 20 million genes among them, microbes pack a punch that our 20,000 genes can not match. Gut bacteria can make nutrients and other molecules in ways the human body can not produce. However, the “second brain” that prevails in this area of the body, is also vital to researchers.
The Second Brain
Within our digestive system, there is a “second brain” helping researchers, like the ones at Holobiome, called the enteric nervous system (ENS). The ENS is two layers of over 100 million nerve cells lining the gastrointestinal tract from the esophagus to the rectum. It contains around 500 million neurons and controls essential reflexes, such as the contraction of muscles in the gut, allowing digestion. The ENS is also a vital part of the gut-brain axis, and the vagus nerve is particularly crucial for conveying information about the intestines to the brain.
In a new study published in eNeuro, researchers have identified a novel way that neurons in the gut wall can activate neurons that connect to those in the spinal cord. They found coordinated activity in the gut wall neurons, which they suggest is a powerful mechanism to transmit information about what is going on in the gut to the brain. According to Nick Spencer, senior author of the study, “Understanding how the gut communicates and controls other organs in the body can lead to important breakthroughs for disease treatment.” Holobiome’s lab has led multiple studies on how microbes influence the brain and are now researching potential therapies for mental health and intestinal disorders.
Finding the Perfect Psychobiotic
Holobiome has created one of the world’s largest collections of human gut microbes. With access to these collections, researchers culture and test these gut microbes to find the perfect psychobiotic. Animal studies conducted by the team support the idea that gut microbes can influence the brain, and the presence or absence of specific microbes in young mice affects how the mice respond to stress as adults. Researchers at the lab think the amino acid tryptophan, which some gut bacteria produce, could be a causal link.
Microbes can convert tryptophan into serotonin, a neurotransmitter involved in depression and other mental health disorders. Cells also turn tryptophan into a substance called kynurenine, forming outputs that can be toxic to neurons. Changes in the microbiome might tilt the production of those various substances in a way that threatens mental health. Holobiome has several papers that have helped support the case for microbial effects on several psychological and neurological disorders. However, finding effective psychobiotics out of those links will be tricky. One researcher admits, “It’s one thing to know that a particular aspect of host physiology is influenced by our gut microbes and quite another to bend this influence to our will.”
GABA Producers – The Holy Grail?
Strandwitz identified one growth factor that turned out to be the key to launching his company. He and colleagues isolated a bacterium that couldn’t survive on typical culture platforms and required the amino acid gamma-aminobutyric acid (GABA) to grow. Misregulation of the neurotransmitter GABA has been linked to mental health problems.
Researchers concluded that if this gut microbe had to have GABA, some other microbe must be producing it. The researchers added gut microbes one at a time to petri dishes containing the GABA eater. If the GABA eater flourished, the team would know they’d found a GABA producer. They discovered such producers among three groups of bacteria, including Bactereroides. They found that people with fewer Bacteroides had a more robust pattern of hyperactivity in the prefrontal cortex – an area in the brain associated with severe depression. Holobiome discovered that the bacteria produce GABA in the rat digestive tract, which may increase GABA levels in the brain.
Currently, the research team has identified 30 promising GABA-producing bacteria. The next phase will be to figure out which GABA-producing bacteria are best suited to test in people. Strandwitz states that they hope to “target ailments, including depression and insomnia, constipation, and visceral pain like irritable bowel syndrome (IBS) and conditions that may have neurological and intestinal components.” The team hopes to start human trials by early 2021.