The gut microbiome — the ecosystem of tiny organisms inside us all — has emerged as fertile new territory for studying a range of psychiatric conditions and neurological diseases.
Research has demonstrated the brain and gut are in constant communication and that changes in the microbiome are linked to mood and mental health. Now a study published this month in Nature Mental Health finds distinct biological signatures in the microbiomes of people who are highly resilient in the face of stressful events.
“The accuracy with which these patterns emerged was really amazing,” says Arpana Church, a neuroscientist at UCLA’s Goodman-Luskin Microbiome Center who led the new study.
The research is a jumping off point for future human studies that some researchers believe could ultimately lead to treatments. It may also point the way to biomarkers in the microbiome that can help tailor decisions on how to use existing therapies in mental health.
Resilience linked to anti-inflammatory microbes
For their analysis, Church and her team separated 116 adults without a mental health diagnosis into two groups based on how they scored on a scale of psychological resilience.
Next, they sifted through a huge amount of data gathered from brain imaging, stool samples and psychological questionnaires and fed that into a machine-learning model to find patterns.
This analysis of gene activity, metabolites and other information came up with several key associations in the high resilience group. In the brain, there were increased features related to improved emotion regulation and cognition.
“Think about the cognitive part, or the frontal part, of your brain being like the brakes,” says Church. “The highly resilient individuals had really efficient brakes, and less of this hyper-stressed response.”
Then they delved into the microbiome, looking not only at the abundance of different microorganisms, but also at their genetic activity to see what they were actually doing.
Two major patterns emerged in people who were more resilient to stress: The activity in their microbiome was linked to reduced inflammation and to improved gut barrier integrity.
This tracks with previous research that has shown patients with a variety of psychiatric conditions have a balance of gut bacteria that includes more of certain pro-inflammatory bacteria and less of those with anti-inflammatory effects.
Church notes the gut barrier absorbs nutrients and keeps toxins and pathogens from entering the bloodstream. When that becomes more permeable, or “leaky,” the resulting inflammation acts as a stress signal to the brain that all is not well.
Microbes that ‘talk’ to our nervous system
The new study fits into a quickly-expanding body of work on the brain-gut connection.
“I was really excited to see this being done in quite a big human cohort,” says Thomaz Bastiaanssen, a bioinformatician who studies the gut microbiome and mental health at Amsterdam University Medical Center.
In recent years, he says scientists have established that there’s a strong “bi-directional relationship” between the gut and the brain. Much of that is based on preclinical lab studies using animal models, as well as some human observational studies and in vitro work.
“All of this points towards roughly four ways that the microbiome communicates with the host,” says Bastiaanssen.
Along with the immune system, there’s the vagus nerve that functions like a superhighway, running from the brain to the gut and directly interfacing with the microbiome.
These gut microbiota also talk with the central nervous system by secreting neurotransmitters, like serotonin and dopamine (about 90% of serotonin is produced in the gut and about 50% of dopamine).
In addition, the microbiome can produce short-chain fatty acids that help maintain the gut barrier and exert an anti-inflammatory effect on the brain, among other things.
Just last year, Jane Foster, a neuroscientist at UT Southwestern Medical Center, found that a community of bacteria related to the production of these short-chain fatty acids was reduced in people with depression who had elevated anxiety.
In recent years, other observational studies have strengthened the evidence linking gut microbiome and mental health in humans, although there are still many unanswered questions because this research is finding correlations.
For example, large studies from scientists in the Netherlands and elsewhere have found microbiomes with less diversity of bacteria can be predictive of depression, and that having more or less of certain bacteria linked to the synthesis of neurotransmitters and short chain fatty acids may be key.
Foster praised the UCLA study as “novel” because it took a full-body view of the brain-gut-microbiome and its potential role in resilience.
She notes the analysis turned up a link between anxiety and the microbiome, which is already a well-established area of research. More than a decade ago, Foster and others showed this link in lab experiments with “germ-free” mice and anxiety.
In the context of stress, scientists have found even short term exposure to stress can lead to alterations in the microbiome, and that changing the composition of the microbiome could make some mice more resilient to stress.
Probiotic treatments for stress? Not yet
There are growing efforts to move this research into actionable treatments, using diets, prebiotic and probiotic supplements. But Bastiaanssen says the complexity of the microbiome calls for a different approach than what’s typically used in pharmaceutical development, which tends to focus on finding a single molecule or drug.
He says that would be like trying to grow a forest in a desert by planting a few seeds.
“Obviously it’s not going to work,” he says, “because there is no supporting ecosystem.”
He says the microbiome field is still coming out of its infancy stage.
“We've established a link in the microbiome, gut-brain axis. We’ve got really robust evidence,” he says. “The next question we need to understand is, how exactly it works?”
He notes there is some promising evidence from small human studies that have shown targeting the microbiome with certain diets (one rich in fermented foods) can reduce inflammation.
Another trial, this one from Bastiaanssen and a team at the University College Cork, found that a diet focused on vegetables and foods known to influence the microbiota, could reduce perceived stress.
While these efforts are completely “valid,” Foster argues the power of these studies is they can lead to the discovery of biomarkers that can help steer decisions about how to use existing treatments and who will be the best candidate.
“Can I measure something in your microbiome, maybe in your blood and maybe in your brain to determine if you're depressed, should I give you an antidepressant? ... or neurostimulation? Shall I do cognitive behavior therapy or tell you to exercise?”
That could be the value of a holistic marker that can be measured in your microbiome, she says. And she thinks it could become an effective tool for clinical care within the next decade.
For her part, Church envisions, hypothetically, one day leveraging this field of research to “engineer a probiotic blend that could help mitigate stress” and prevent the onset of some diseases.
“The biggest problem is that we need more studies that are actually going to test these in human trials,” she says. She acknowledges there are all sorts of unsubstantiated claims out there when it comes to improving the microbiome. For now she tells people the data isn’t strong enough yet to know which treatment to try.
“There isn't really one out there that's been really tested,” she says, “I say come back to me in a year or more and I'll let you know.”
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