Louise McCullough, MD, PhD, didn’t originally plan to study the microbiome — the collection of trillions of bacteria, viruses, fungi, and other microorganisms that live in the gastrointestinal (GI) tract.
A neurologist who is now the founding director of the BRAINS Research Laboratory at the University of Texas McGovern Medical School in Houston, McCullough set out over a decade ago to understand why aging increases mortality in stroke victims.
She and her team induced strokes in young and old mice and found that 90% of the young mice recovered, while almost none of the older mice survived. At first, the team thought that the high mortality in the older mice was caused by larger strokes, but, in fact, their strokes were smaller than those in the young mice and yet the mortality remained extremely high. Then the researchers looked at blood samples from both groups and found that the older mice had much higher levels of inflammation than the younger mice had.
In subsequent studies, the team discovered that bacteria had infiltrated the older mice’s organs and were leading to infections and sepsis, which are common causes of morbidity and mortality in elderly stroke patients. The researchers sequenced the bacteria and found that many had migrated from the GI tract, which is home to a large colony of microorganisms that digest food and produce various metabolites, also known as the gut microbiome. In a healthy gut, the mucosal barrier and immune cells in its lining prevent bacteria from escaping into the bloodstream. The researchers examined the aged mice’s guts and found that the stroke had compromised the integrity of the mucous barrier. They also found that the bacteria that were in the guts of aged mice were different and more pathogenic than the bacteria residing in the guts of young mice.
This discovery prompted the researchers to transplant the bacteria from young, healthy mice into the guts of older mice after an induced stroke. Remarkably, the older mice with the younger gut bacteria recovered better, and survival rates skyrocketed.
These and other related discoveries formed the foundation for McCullough’s ongoing research into how the microbiome plays an integral role in neurological conditions. Other researchers have found connections between the gut and a wide variety of ailments — from depression to inflammatory bowel disease. This emerging field of research is fueling a movement in medicine toward novel therapies and prevention strategies that take this integrated network — known as the gut-brain axis — into consideration.
“The field has completely exploded,” McCullough says. “It’s a targetable intervention. It’s easier to change gut health than it is to target the brain directly.”
Researchers and innovators studying the gut-brain axis say that, while there’s still much to learn in this area, it holds promise for an evidence-based, holistic approach to healing and disease prevention that recognizes the interplay between the gut, the mind, the body, and the brain.
“I think we’re ready, more than ever, to incorporate this mode of thinking,” says Benjamin Sahn, MD, a pediatric gastroenterologist, an instructor at the Feinstein Institutes for Medical Research, and an assistant professor of pediatrics at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. “Modern medicine has left behind the idea that the brain and the body are separate entities.”
The ‘second brain’
Scientists have identified more than 100 million neurons, the cells responsible for transmitting electric signals across the nervous system, in the human gut. Together, they make up the enteric nervous system, which communicates with the brain and controls bodily functions, such as digestion and metabolism, and signals feelings of hunger or satiety, Sahn explains.
The gut also produces 90% of the body’s serotonin, the neurotransmitter that is associated with feelings of happiness and influences sleep, memory, sex drive, and other behaviors. It’s sometimes referred to as the second brain.
The enteric nervous system connects to the brain via the vagus nerve. The pathway for signals to and from the brain, this nerve controls functions such as digestion, heart rate, and the immune system.
The bacteria and other organisms that inhabit the microbiome are also essential to healthy bodily processes, including aiding in digestion and regulating the immune system. But an imbalance in gut bacteria can trigger or exacerbate chronic conditions, particularly those related to inflammation. This imbalance, known as dysbiosis, can be caused by diet, antibiotics, or stress. It could also result from inflammation-related diseases that dysbiosis could, in turn, exacerbate.
“What happens in the gut is information that is relayed to the brain, and the brain, in turn, responds based on those signals that further influence the gut,” Sahn says. “It is truly bidirectional.”
Sahn specializes in treating inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis, which are associated with life-altering symptoms including abdominal pain, irregular bowel movements, fatigue, malnutrition, and anxiety.
He led a clinical trial that tested the use of bioelectric medicine, in this case using electrical stimulation to augment vagus nerve activity, in children with IBD. The goal was to regulate the autoimmune response behind the inflammation and thus relieve the symptoms. Among 22 pediatric participants, half of those with Crohn’s disease and a third of those with ulcerative colitis were in remission at the conclusion of the trial. Sahn is now leading another similar trial for children and adults with ulcerative colitis.
“Influencing the gut-brain connection — one can do that with medication, with diet, with complementary and alternative medicine practices, such as meditation and yoga and deep relaxation techniques; all of these can influence the gut-brain connection,” Sahn says. “In my case, we’re using electricity to stimulate nerve endings and using the neurocircuitry of the body to modify disease.”
Far-reaching applications
After decades of study in animal models, researchers have begun to translate their understanding of the gut-brain connection into clinical trials to test therapies for a range of conditions.
A trial led by Kevin Tracey, MD, president and CEO of the Feinstein Institutes for Medical Research and a professor of molecular medicine and neurosurgery at the Zucker School of Medicine, tested vagus nerve stimulation as a treatment for rheumatoid arthritis.
Trials are ongoing for testing gut-brain connection therapies for depression, fibromyalgia, migraines, Parkinson’s disease, and Alzheimer’s disease.
As Sahn explained, one of the reasons researchers and clinicians find the microbiome a compelling avenue for treating disease is because it can be influenced by using various kinds of interventions.
Researchers at the Indiana University School of Medicine studied mice and reported that niacin, a B vitamin that’s usually ingested through the diet, played a role in preventing the buildup of amyloid plaques in the brain. These plaques are associated with cognitive decline in Alzheimer’s patients. The researchers are now testing the use of a U.S. Food and Drug Administration-approved drug that delivers niacin to Alzheimer’s patients to slow disease progression.
In another study by researchers in Switzerland, people with major depressive disorder were treated with a short-term, high-dose probiotic supplement and had some success with symptom relief.
Various studies are evaluating how diet alterations impact gut health and, by extension, overall health. Stanford School of Medicine scientists found that fermented foods, including yogurt, kefir, and kombucha tea, had a positive impact on microbiome diversity and reduced inflammation among healthy trial participants.
Several studies have also shown that the use of mindfulness or meditation exercises to reduce stress can improve symptoms for IBD patients.
A more invasive intervention, fecal transplantation — when stool from a healthy donor is introduced into the patient’s gut, usually via colonoscopy — is approved to treat Clostridioides difficile (C. diff) bacterial infections and is being tested for a range of conditions, including IBD, autism spectrum disorders, diabetes, anxiety, and depression. This treatment is complex, however, since microbiomes vary considerably in each individual and there are risks associated with introducing bacteria (or other components that can be found in the biome, such as viruses or fungi) into a person who is immunocompromised, McCullough explains.
And while she finds the range of treatment options for improving gut health exciting, she acknowledges that the scientific knowledge is currently lacking on how to optimize the treatments for individuals and specific diseases.
“The biome is extremely complex,” McCullough says. “We need to look at it holistically.”
For many with chronic disease, simply taking an oral probiotic may not be enough, she says. Scientists are still studying which bacteria should be introduced for which diseases, what doses are needed, and what the most effective form of delivery might be.
As the research in this area develops, treatments for microbiome health could be a pioneering field for personalized medicine. Researchers at the University of Virginia School of Medicine envision a future when individuals’ microbiomes are analyzed and they’re given medications or supplements customized to their specific needs, even to treat or prevent cancer.
McCullough goes so far as to say that, someday, researchers may find a way to use the microbiome to slow or even reverse the effects of aging.
“This is going to be a huge area. The silver tsunami is coming as the older population is outpacing the youth population,” McCullough says. “Keeping people healthy and cognitively intact as long as possible is going to be a goal of the millennium.”
So long as the types of basic research that led to her discoveries about the gut-brain axis continue, McCullough is hopeful human health will improve.
“A hundred and fifty years ago, our life expectancy was 37 [years]; it’s now 80. We’ve done a great deal to enhance human health and longevity,” she says. “The question is how to age more healthily. That’s why it’s so important to get young people engaged and keep our [biomedical research] pipeline strong if we really want to move the needle on chronic diseases.”
