Only recently, the idea that your gut could be shaping your mental health was considered far-fetched, more science fiction than actual science.
Now, UCalgary researchers are at the vanguard of worldwide research into what’s known as the gut-brain axis and how it may affect the way you think and feel, hoping their work will hold clues to causes of illness and perhaps novel new treatments.
As we gain a better understanding of how microbes in the gut play a role in our health, researchers are examining whether this information could also yield new therapies for psychiatric illness.
So, can our microbiome, which is the genetic material of the trillions of microbes (bacteria, fungi and viruses) that live in and on our body, influence our mental health?
“I’d say that really is the million-dollar question,” says Dr. Valerie Taylor, MD, PhD, a professor and head of the Department of Psychiatry in UCalgary’s Cumming School of Medicine, and a member of the school’s Mathison Centre for Mental Health Research & Education and the Hotchkiss Brain Institute.
"We’re doing research but the jury is still out on whether we can actually leverage what seems to be a gut-brain connection into the next generation of therapies. There is reason to be excited and to pursue this work and that's what fuels us — the possibility.”
Microbial therapies hold the promise of leveraging the gut-brain axis in ways that could shape cognition, behaviour and emotion.
It’s exciting, though key aspects of why and how it may work have yet to be determined. The mechanisms by which the microbiome may shape brain function are unclear, and we have not conclusively determined how they might influence conditions such as anxiety.
The gut-brain axis is a two-way, biochemical signaling system between the gastrointestinal tract and the central nervous system. The gut is considered by some researchers to act as a “second brain,” given that the enteric nervous system in the gut can operate independently of the brain and spinal cord.
Researchers are exploring if it is possible to manipulate this system to boost health and treat disease.
UCalgary's International Microbiome Centre is coordinating efforts in Canada to understand how the microbiome works and if it can be harnessed to improve human health. This centre represents the biggest academic germ-free facility in the world.
Evidence in studies around the world seem to indicate that not only is the gut linked to mental health, but the microbiome of healthy people appears to differ from those who have a mental illness.
Still, despite the promise, Taylor cautions against unproven treatments that have not been rigorously tested and explained, as the field of research exploring the microbiome and its potential links to mental health is still new.
So far, the study of the gut-brain axis in humans has been limited, though more clinical studies are being undertaken than ever before, with Taylor leading three of them.
“At this point, we do not have a magic microbiome associated with wellness and we don’t want people thinking that this will be a panacea cure-all that will allow them to stop taking other therapies,” she says.
Further confounding the issue is the growing understanding that what works for one person may not work for another, or may even be problematic, although this area of research may offer unique opportunities for the application of precision medicine.
The role of the fecal transplant
Fecal microbiota transplantation (FMT) is a technique where stool from a healthy donor is transferred to a patient who is ill, the goal being to introduce or restore certain gut bacteria with the aim of modifying disease and health.
With an FMT, the assumption is that the introduction of microflora from a healthy person will help recolonize the system with a microbial pattern more in keeping with wellness, says Taylor. This would happen either by establishing a new, healthy microbiota or by allowing the host to reset their own microflora to a pre-illness state.
Taylor is using a fecal transplant pill developed at UCalgary in a current study.
“Right now, the most robust findings are from the pre-clinical work (animal models),” she says. “There is research looking at the microbiome in animal models and whether manipulation can help treat illnesses such as anxiety and depression.”
Germ-free mice are used in studies as researchers try to determine the cause-and-effect relationship between the microbiome and disease, as well as the basis through which microbes influence the host.
One of Taylor’s studies, in the clinical trial stage, is testing if transplanting fecal matter from a healthy person to a person with bipolar depression can have positive results. Another looks at depression in the context of irritable bowel syndrome (IBS).
She wants to see if symptoms improve in the person who receives the transplant, and examine participants' microbiomes to try and understand how any changes prompted by the procedure actually work.
Depression under the microscope
The GI system (gastrointestinal tract) plays a role in terms of modulating inflammation, which has been linked to mental illness. Taylor says this is an ongoing area of research.
A 2015 study into fecal microbiota composition in patients with major depressive disorder found that particular bacteria (Bacteroidetes, Proteobacteria and Actinobacteria) are increased and the bacteria Firmicutes is decreased in depression.
Most of the body’s serotonin, a neurotransmitter that sends messages among cells and which can influence emotions, is produced in the gut. A study in mice led by UCLA (University of California, Los Angeles) biologists and published in the journal Nature Microbiology suggests that serotonin and drugs such as anti-depressants that target serotonin affect microbiota in the gut.
There are more serotonin receptors in the gut than the brain.
If brain activity can be modulated by changes in the gut microbiome, we need to determine which specific brain mechanisms are affected.
“Antidepressants can change the level of neurotransmitters such as serotonin and we know there are more serotonin receptors in the gut than the brain,” says Taylor. “Certain bacteria also produce or impact the levels of many neurotransmitters, so, some of the bacteria could directly impact, or be related, to mental illness.”
This isn't as far-fetched as you might think.
“There has been research that shows if you take bacteria from depressed mice and put it into non-depressed mice, they become depressed,” says Taylor. “Microbiota are not benign, and we want to ensure people are aware of that.”
The brain-gut connection is a growing industry
There is much to learn about the mechanisms of the gut-brain axis, including whether microbiota in the gut can prompt disease or if it's the other way around. Regardless, research is ramping up as probiotics and other health supplements increasingly find their way onto market shelves.
“Patients are desperate for new treatments,” says Taylor. “Sometimes the current treatments don’t work for everyone or have side effects that are not tolerable. So, people are looking for anything that will help them.”
As the financial potential for therapies rises, so do claims about what probiotics, containing certain kinds of live bacteria, may be able to do for consumers.
Patients are desperate for new treatments.
The growing global wellness industry had a $4.2-trillion market in 2017, according to a Global Wellness Industry report; even so, there have been class-action lawsuits for claims that probiotic-enriched foods can boost the body’s defences and enhance the immune system, says Taylor.
Questions continue to arise about how various gut-related therapies may work and the potential consequences of using them. Something that might aid gut health in the short-term doesn't necessarily benefit a person’s overall health.
New methods being used to manipulate the gut microflora are not without risk, says Taylor. Earlier this year, two people in the United States who had undergone fecal transplants developed drug-resistant infections from bacteria in the stool that they were provided. One patient died.
“If someone says they're going to cure your mental illness by changing your gut microbiome, at this stage of the science, beware,” says Taylor. “I don’t want my patients taken advantage of, and that’s why I'm really invested in doing this work. By doing the right research in the right way, we can inform people so they can make the right choices.”
So, when it comes to the potential links between the microbiome and mental health, asks Taylor, are we looking at hope or hype?
Exploring the potential of the gut-brain axis
Using FMT to improve health operates on the assumption that dysbiosis in the gut microbiome predisposes a person to disease. Dysbiosis, also known as intestinal or gastrointestinal dysbiosis, is a condition in which there is an imbalance of micro-organisms within our intestines.
The exact mechanisms through which dysbiosis occurs have not yet been established, but even so, several potential direct and indirect pathways exist through which the gut microbiota can modulate the gut-brain axis, says Taylor.
These pathways include endocrine (cortisol), immune (cytokines) and neural (vagus and enteric nervous system) pathways.
If we consider that changes can be made to improve health using FMT, then it follows that introducing the wrong microbiota from a particular donor could result in adverse health, says Taylor. It highlights the need to ensure that fecal transplant donors are rigorously screened for gut disorders and other conditions.
Need to define goals for wellness and treatment
Despite ongoing research in the microbiome and the gut-brain axis, there is as yet no clearly defined gold-standard profile associated with wellness. There is the effect of the environment on the body and a person’s microbiome to consider, as well. Factors such as diet, smoking and age can all affect the microbiome.
“There is still a lack of understanding of what we're trying to change with treatment, as there is no microbial profile clearly associated with wellness, or vice versa, from a behavioural perspective,” says Taylor.
Creating new targets for treatment is important as the research moves forward, she says. “We need to manage expectations with respect to the therapeutic potential of microbial manipulation.”
Given the growth of studies focusing on the microbiome and connections between the gut and brain, it isn't surprising to see conflicting viewpoints and research evidence.
Two recent meta-analyses indicated that probiotic supplementation has an overall insignificant effect on both mood symptoms and the symptoms of schizophrenia, says Taylor.
In contrast, she says, another systematic review and meta-analysis that looked at prebiotics (a form of dietary fibre that acts as a fertilizer for bacteria in the gut) and probiotics for depression and anxiety found no difference over the prebiotic but a small, significant effect for the probiotic. Researchers are aiming to discern the most precise differences among effects that could impact human health.
Even the diagnostic categorizations for mental health and illness can pose problems in determining what may work for whom.
The Diagnostic and Statistical Manual of Mental Disorders (DSM) provides more than 200 different symptom profiles, all of which fit the major depressive disorder (MDD) diagnosis, says Taylor.
“It may be, then, that probiotics are helpful for some, but not all, types of MDD,” she says.
In the future, we would need to identify what type of depression responds to changes in the gut microflora, as well as what type of probiotic should be used as an intervention — and what the timing of the treatment should be.
“It’s not like we know that you need to just take these particular bacteria and not that one, or that we just need to replace certain ones,” says Taylor. “It's not that simple. Part of what we're doing is analyzing the microbiome so we can identify patterns that seem to be associated with illness or wellness.”
Eating for better gut health
If changing gut microflora can impact us for good or ill, what’s a good strategy for eating right to ensure microbiome health?
“The gut microbiome is impacted by food and environment but in a stable environment, it stays relatively stable,” says Taylor. “If you eat, say, a pound of turkey and cheesecake and this is something that you don’t usually do, it will affect your microbiome -- but it will reset itself when your diet changes again.”
Taylor recommends that you cook a wide variety of foods, get proper sleep and exercise to be healthy. Aim to eat a diet that is lighter on processed food, and more food you cook yourself.
As for the future of treatments based on the gut-brain axis that could impact your mental health, Taylor says it's too early to know for sure.
“Do I think that someday someone will use this as a defence in the court system saying, ‘My microbiome made me do it?’ No, but do I think that it is modifiable for mental health? I certainly hope so.”
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ABOUT OUR EXPERTS
Dr. Valerie Taylor, MD, PhD, is a professor and head of the Department of Psychiatry and a member of The Mathison Centre for Mental Health Research & Education and the Hotchkiss Brain Institute at the Cumming School of Medicine.