December 2018 Issue

Brain Health: Probiotics — Big Brain Boost or Just Hype?
By Jamie Santa Cruz
Today's Dietitian
Vol. 20, No. 12, P. 8

Probiotics have received attention in recent years as a means of treating an array of health problems, especially digestive disorders such as irritable bowel syndrome. Now, some researchers are studying the potential of probiotics for improving a different aspect of health—namely, brain health.

Growing research has shown that the composition of bacteria in the gut may influence cognition and mood.1 Furthermore, an imbalance in the gut microbiome is associated with psychiatric disorders such as depression.2 These findings have led to the hypothesis that manipulating the gut microbiome through probiotic supplementation may influence cognitive function, memory, and mood.

Origins of the Field
A groundbreaking study that helped spur interest in the field came in 2004 from Japanese researchers, who compared a group of germ-free mice (ie, mice without bacteria in their guts) with genetically identical mice with normal microbiomes. When placed under stress, both groups demonstrated increased production of stress hormones, but the germ-free mice proved extra sensitive. However, the researchers were able to reverse the exaggerated stress response of the germ-free mice by introducing the bacterium Bifidobacterium infantis into their guts.3

The experiment showed that microbes in the gut could influence stress responses in the brain, and also hinted that altering the gut microbiome (such as via probiotics) might influence brain function.

Mechanisms: How Do Gut Bacteria Influence the Brain?
Communication between gut microbes and the brain is bidirectional and believed to occur through several pathways, according to Kirsten Tillisch, MD, a professor of medicine at the Oppenheimer Center for Neurobiology of Stress & Resilience at UCLA. One of these pathways is the vagus nerve, which often is referred to as a "communication superhighway" between the gut and the brain.

Gut microbes also communicate with the brain by acting on the immune system, either directly or indirectly (such as when gut microbes alter circulating levels of pro- and anti-inflammatory cytokines that in turn alter brain function). Finally, Tillisch says, microbes may influence the permeability of the gut, altering the flow of metabolites into the peripheral circulation and thus to the brain.

According to Jane Foster, PhD, an associate professor in the department of psychiatry and behavioral neurosciences at McMaster University in Hamilton, Ontario, Canada, probiotics influence the brain by acting on resident microbes in the body. Probiotics usually don't colonize the gut or produce any permanent change in the composition of gut bacteria, but they still can produce benefit by interacting with resident microbes as they pass through. Probiotics also can use some of the same methods as resident microbes do (eg, acting on the immune system) to influence human health.

Probiotics and Mood
Much of the research on probiotics and the brain has focused on how probiotics influence anxiety and depression. So far, "the evidence by and large demonstrates probiotics can have a positive benefit on mood," Foster says.

To begin with, several rodent studies have found that supplementation with probiotics reduced anxious and depressive behavior. In one study of adult rats fed with B infantis, the impact of the probiotic on depressive behaviors was comparable to the effect of the antidepressant drug citalopram.4

The beneficial impact of probiotics has been largely confirmed in human studies.5,6 One double-blinded, placebo-controlled trial, for example, found that consumption of a milk drink containing Lactobacillus casei Shirota over the course of three weeks improved the self-reported mood of participants who initially had reported poor mood.7

In two other double-blinded, placebo-controlled trials, healthy human volunteers received a multispecies probiotic formulation (containing various strains of Lactobacillus and Bifidobacterium in each case) for either two or four weeks. Those receiving the probiotic showed improvement on scores of depression, anger and hostility, anxiety, problem-solving ability, rumination, and aggressive thoughts compared with baseline.8,9

Benefit also has been shown in individuals who already have a mental health diagnosis. In 2016 in Iran, a double-blinded, placebo-controlled trial of 40 participants with major depressive disorder found that eight weeks on a multispecies probiotic (containing Lactobacillus acidophilus, L casei, and Bifidobacterium bifidum) resulted in significantly decreased symptoms of depression as measured by the Beck Depression Inventory.10

Several systematic reviews and meta-analyses have examined the impact of probiotics on mood. A meta-analysis by Ng and colleagues published in the Journal of Affective Disorders in March 2018 concluded that probiotics have an overall insignificant impact on mood. However, at least three other systematic reviews and meta-analyses have found that probiotics can have a significant impact on both anxiety and depression, in both healthy individuals and patients with a clinical diagnosis of depression.11-13

So far, Tillisch says, the most robust research has been conducted using animal models, with human studies falling into the "small" category. However, she adds, "the fact that there are several [human studies] going in the same direction is hopeful."

Probiotics and Cognition
Currently, there's less evidence about the impact of probiotics on cognition than on mood. However, animal studies have shown that probiotics improve cognition in a variety of settings.

For instance, when researchers in the United Kingdom gave a long-term course of probiotics (a mixture of Lactobacillus and Bifidobacterium) to aging rats, the rats showed small improvements in spatial navigation and robust improvements in long-term object recognition memory and short-term memory for object-in-place associations. Analysis of the hippocampus and prefrontal cortex using 1H nuclear magnetic resonance spectroscopy revealed that the probiotic supplementation also had produced regional changes in brain metabolites, suggesting changes in pathways modulating neural signaling.14

Several animal models have found that probiotics help reverse cognitive impairments associated with certain chronic conditions. For instance, obesity is associated with cognitive decline; however, Chinese researchers found that probiotics, prebiotics, and synbiotic supplements were all effective at restoring normal cognitive function in obese, insulin-resistant rats.15 Similarly, diabetes mellitus is associated with impaired learning and memory ability. However, rats with diabetes that were fed a probiotic supplement for two months showed significantly improved synaptic activity and cognitive function, specifically with respect to spatial memory, compared with those that hadn't received the supplement.16

Although animal models are valuable, Tillisch says, "the clinical translation to humans is tricky." Some of the findings in animal studies haven't held up in human studies, she says, adding that, realistically, "few people report a change in memory or cognitive speed after taking probiotics."

That said, several human studies have found an impact of probiotics on cognition. In a 2013 study, Tillisch and her colleagues used functional magnetic resonance imaging to study how consumption of a fermented milk product containing a multispecies probiotic would impact brain responses during an emotional faces attention task. They found that participants who had received the fermented milk product showed differences in brain network activity, gene expression, and synaptic plasticity in several brain regions associated with cognition.17

A 2018 pilot study looked at the effect of probiotics in individuals with bipolar disorder, among whom cognitive dysfunction is prevalent. In that study of 20 individuals who had bipolar disorder but were in a euthymic state (ie, experiencing neither a manic nor a depressive episode), Austrian researchers found that a probiotic supplement for three months resulted in better performance on a cognitive battery relative to baseline. Specifically, supplementation was associated with significantly improved attention, psychomotor processing speed, and executive function.18

Several human studies also suggest that probiotics could provide cognitive benefits in Alzheimer's disease. In a 2016 randomized controlled trial, 60 Alzheimer's patients were first assessed via the Mini-Mental State Examination (MMSE), then were randomized to receive either milk (control) or a multispecies probiotic for 12 weeks. Participants in the probiotic group showed improvements on several metabolic markers typically affected by Alzheimer's disease and also had significantly improved scores on the MMSE.19

Earlier this year, Austrian researchers confirmed the value of probiotics for Alzheimer's. They found that patients who received a probiotic over four weeks showed improvements in biomarkers of both immune activation and gut inflammation.20 The study period was too short to measure improvements in cognition; however, the improvement in biomarkers of neuroinflammation suggests that probiotics may have a role in preventing dementia, according to Friedrich Leblhuber, Univ. Prof, MD, a neurologist in Linz, Austria, and the study's lead author.

"Our exploratory study showed changes in gut bacteria composition after just four weeks of supplementation, including an increase in the strongly anti-inflammatory Faecalibacterium prausnitzii strain," Leblhuber says. "This underlines the hypothesis that probiotics could be especially helpful in the prevention of dementia, as neuroinflammation is a very early event in this devastating process."

Implications for Dietitians
With research on probiotics and the brain still in its infancy, applications for dietitians are limited. "There is a tremendous amount of interesting research, but when it comes to knowing what to make of it clinically, we are still struggling," Tillisch says.

In general, Tillisch says, dietitians should stress diet over probiotics as the key to maintaining gut health. Diversity in bacteria is one key to a healthy gut microbiome, and eating a wide range of foods—especially an array of fiber-rich vegetables—is the best way to promote that diversity in bacteria, according to Tillisch.

By contrast, the composition of gut bacteria takes a hit from processed foods, high intake of meat, and lack of variety. "Probiotics may play a role, but even more important are the dietary factors that help keep a robust, diverse, healthy microbiome," she says.

For individuals who wish to take a probiotic to support brain health, the Lactobacillus and Bifidobacterium genera seem to have the most impact, Leblhuber says. Strains in these genera tend to produce neurotransmitters such as serotonin, GABA, dopamine, noradrenalin, and acetylcholine, all of which are important in the field of neurology and psychiatry and seem to play an important role in the bidirectional communication between the central nervous system and the gastrointestinal tract.

Foster recommends for guidance on which probiotic strains are associated with particular health impacts. "Pay attention to individual differences," she says. "It's not one size fits all."

— Jamie Santa Cruz is a freelance writer of health and medical topics based in Parker, Colorado.

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