Manipulating the Microbiome to Improve Mood

Laird Harrison

Disclosures

June 07, 2019

To improve your mood, says Laura Steenberger, PhD, "pay attention to your poop."

Evidence has been mounting for years that the gut microbiome talks to the brain and vice versa. Now Steenberger and others have shown in preliminary trials that clinicians might improve patients' moods by tinkering with the organisms in their guts.

Other research has uncovered variations in the microbiome associated with a wide range of neurologic and psychiatric conditions, including epilepsy,[1] autism,[2] schizophrenia,[3] bipolar disorder,[4] and Alzheimer[5] and Parkinson[6] diseases.

The findings underscore considerations about the effects of diet on mood and raise new questions about antibiotics—both as potential causes of and treatments for mood disorders.

"The field really grew in the past 4-5 years," says Steenberger, an assistant professor in cognitive psychology at Leiden University in the Netherlands.

As reports bubble into the popular media, clinicians must be prepared to respond to patients' questions about probiotic preparations available on the market—none of which requires a prescription. "Patients will ask about this," says Premysl Bercik, MD, a gastroenterology professor at McMaster University Medical Centre in Hamilton, Ontario, Canada. "This is on the Internet."

Unraveling the Gut-Brain Connection

Physicians have debated the relationship of the brain and gut for centuries. The conversation took on new weight with the discovery of the enteric nervous system in the mid-19th century. Investigators noted that the communication went both ways: Stress and emotions could modulate gastrointestinal functions, whereas abdominal pain and other, more subtle signaling could influence emotions.[7]

More recently, the discovery that nearly 100 trillion microorganisms live in the human intestines has called attention to their effects—not only harmful, but frequently beneficial or neutral, and perhaps shifting with circumstances.[8]

The most obvious roles for these microbes are intestinal barrier homeostasis, nutrient absorption, and fat distribution. But the gut microbiota is known to affect the immune system as well.[9]

These organisms might influence the brain and behavior through multiple possible pathways, including cytokine release; neurotransmitter production; tryptophan metabolism; the hypothalamic-pituitary-adrenocortical (HPA) axis; enteroendocrine activation; and stimulation of an ascending neural pathway, especially the vagus nerve.[9]

Evolutionary biologists have theorized that the organisms have evolved along with their human hosts, creating a mutual dependency that can be disrupted with changes in lifestyle or the environment.

"Maybe the increased use of antibiotics could be partially responsible for what we've seen in epidemiologic studies, which is increases in the number of people with depression and bipolar disease, and a progressive lowering of the age of onset," says Elisa Brietzke, MD, a psychiatry professor at the Federal University of São Paulo in Brazil, who is researching the microbiome. "When we examine what has changed in the past 50 years, we can see an increased use of antibiotics and increased consumption of carbohydrates and highly processed foods."

Some researchers have even speculated that microorganisms in the gut might manipulate host behavior to favor their survival. For example, there is evidence that Salmonella typhimurium suppresses the appetite loss associated with illness in order to maintain its source of nutrition from the host's feeding.[10]

The hygiene hypothesis may prove relevant as well. Just as some evidence suggests that an environment with too few microorganisms might prevent children from developing healthy immune systems, perhaps it could impair their mental health as well, says Brietzke.

Can We Manipulate Mood With Probiotics?

These findings are leading to trials of probiotics—living organisms taken as therapy, Brietzke says. "If we know that a group of bacteria is not present in people with mood disorders compared with control, we can, for example, supplement these bacteria."

Animal experiments have reinforced these findings. In particular, researchers have found success altering the microbiomes of laboratory animals by introducing microorganisms. Fecal microbiota transplantation in mice can cause the behavior of the recipient to become more like that of the donor.[10] Certain Lactobacillus species have improved social interactions among stressed mice, whereas Bacteroides species have ameliorated repetitive and anxiety-like behaviors in them.[10]

In one experiment, depression scores of rats declined for 28 days when they took Lactobacillus rhamnosus, and in another, experimentally elevated HPA axis responses and depression were reversed in rats given Bifidobacterium infantis.[11]

Other researchers have theorized that prebiotics—nutrients that feed beneficial microbes—might also prove useful in treating mental disorders.

Emerging Clinical Evidence

Although trials in human beings have shown mixed results, the weight of the evidence seems to suggest grounds for optimism, at least for depression and anxiety.

In one recent study, researchers at Tehran University of Medical Sciences in Tehran, Iran, recruited 110 people with mild or moderate depression who had taken sertraline, fluoxetine, citalopram, or amitriptyline for 3 months. They divided the patients into three groups and gave them sachets of powder to be taken once per day for 2 months.[8]

For one group, the sachets contained Lactobacillus helveticus and Bifidobacterium longum in a vehicle of xylitol, maltodextrin, plum flavor, and malic acid. For the second group, they contained the prebiotic galactooligosaccharide in the same vehicle. For the third, they contained only the vehicle.[8]

The mean Beck Depression Inventory score declined from 18.25 to 9.0 for the probiotic group, from 19.43 to 14.14 in the prebiotic group, and from 18.74 to 15.55 for the placebo group. The difference in change between the probiotic group and the placebo group was statistically significant (P = .008), but the difference between the prebiotic and placebo groups was not significant.[8]

Some of the patients experienced adverse events that the investigators considered to be possibly related to the treatments. Notably, four of those taking the prebiotic and two taking the probiotics reported gastrointestinal upset. One each taking the probiotics and prebiotic reported nausea. One taking the probiotics reported fever and body aches. Five in the probiotic group and one in the prebiotic group reported increased appetite.[8]

The authors point out, though, that the expenses and risks of probiotics are less than those normally associated with pharmaceutical treatments for depression.[8]

Although not all trials of probiotics have shown such robust effects for depression, a recent meta-analysis suggests that the balance of the evidence favors efficacy. The authors found 10 clinical trials with a total of 1349 patients. This included both people diagnosed with depression and people who were healthy. There was no significant difference in mood between the treatment and placebo groups when healthy and depressed patients were included (P = .059). But among those diagnosed with mild to moderate depressive symptoms, probiotics did make a significant difference in improving their moods (P = .029).[12]

Similarly, in a meta-analysis of probiotics tested in patients with anxiety, researchers found 10 studies with a total of 660 participants. The probiotics significantly decreased anxiety compared with the control group (P < .001).[13]

Fewer trials have examined probiotics for schizophrenia, and a recent meta-analysis found no statistically significant benefit.[3] Similarly, a review found only one trial of probiotics for bipolar disorder, which showed no significant effects.[4]

On the other hand, a handful of trials have showed potential benefit in treating autism.[2] And research is getting started on treating obsessive-compulsive disorder,[14] epilepsy,[1]  Alzheimer disease,[5] Parkinson disease,[15] and other mental health conditions.

The Bumpy Road to Building Effective Treatments

"I think what is becoming quite clear both from animal studies and clinical studies is that probiotics affect our brain chemistry," says Bercik. "Researchers should pay more attention to the microbiota. It opens a huge range of possibilities for investigations, including the possibility that depression could be a transmissible illness."

Not only are the possible combinations that could be introduced almost infinite, so are the methods of administering them….

But he cautions that it's too early to make clinical recommendations. Despite the promise of the studies so far, researching probiotics and prebiotics as treatments for mental health poses distinct challenges. "The microbiome is more unique than your fingerprint," Steenberger points out. "It's 10 to 100 times more complex than the genome. Another problem is that we're talking about probiotics as if they were one treatment, but there are thousands out there."

Not only are the possible combinations that could be introduced almost infinite, so are the methods of administering them: live cultures, freeze-dried powders, capsules, liquids, or even fecal transplants. The way they might interact with the patient's diet is even more complex.

Researchers are also mulling over the stage of disease at which interventions should be aimed at the microbiome. For example, if depression results in some part from disruption of the microbiome, might it be prevented as well as treated with probiotics? Steenberger's research so far makes her hopeful of that. "I believe we have prevention potential. If we can decrease rumination, we might be able to prevent people from falling into depression."

The role of antibiotics poses its own set of questions. On one hand, they could destroy beneficial organisms. On the other hand, some research suggests they might be beneficial in the same conditions that probiotics show promise of treating.[16]

So, what should clinicians tell patients looking for probiotics that might improve their mental health? "We don't know," says Steenberger. For people determined to give it a try, she advises a shotgun approach. "If you really would want to try something, I would say go for something that contains diverse bacteria," she says. That means multiple organisms in the list of ingredients.

She also recommends that patients look for products that have been tested independently. "If you ingest a probiotic, they may say that it contains, for example, 5 million colony-forming units. But there should be independent studies to show how many of those units actually survive in your gut."

Some companies offer detailed analyses of patients' microbiomes to determine what effects various probiotic preparations are having. The databases compiled by such companies may provide useful information for moving the research forward, Steenberger says, but patients must bear a high cost to participate.

At minimum, Steenberger recommends that patients pay close attention to the way they feel for a week or so while trying a new probiotic. "Some people complain of bloating. In the first days of taking probiotics, your gut may object a little bit. That's why it's a good idea to do it with a clinician." Stools can provide clues as well; Steenberg suggests monitoring the look and smell.

And Brietzke recommends that clinicians proceed with caution. "I think it's too early," she says. "We don't have enough evidence to recommend probiotics to people with mood disorders. Although they are considered safe, it is possible they could increase the risk for some infections. And there is a cost associated with special foods."

As an alternative, Steenberger suggests, patients concerned about their microbiome might want to start with attention to their diet: more whole foods, less refined carbohydrates and processed foods. Then they could add some fermented foods, such as unsweetened yogurt or sauerkraut. That might be enough for now.

"Be careful," she advises.

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