In 1950, at Staten Island's Sea View Hospital, a group of patients with terminal tuberculosis were given a new antibiotic called isoniazid, which caused some unexpected side effects. The patients reported euphoria, mental stimulation, and improved sleep, and even began socializing with more vigor. The press was all over the case, writing about the sick "dancing in the halls tho' they had holes in their lungs." Soon doctors started prescribing isoniazid as the first ever antidepressant.
The Sea View Hospital experiment was an early hint that changing the composition of the gut microbiome — in this case, via antibiotics — might affect our mental health. Yet only in the last two decades has research into connections between what we ingest and psychiatric disorders really taken off. In 2004, a landmark study showed that germ-free mice (born in such sterile conditions that they lacked a microbiome) had an exaggerated stress response. The effects were reversed, however, if the mice were fed a bacterial strain Bifidobacterium infantis, a probiotic. This sparked academic interest, and thousands of research papers followed.
According to Stephen Ilardi, PhD, clinical psychologist at the University of Kansas focusing on the etiology and treatment of depression, now is the "time of exciting discovery" in the field of probiotics and psychiatric disorders, although, admittedly, a lot still remains unknown.
Gut Microbiome Profiles in Mental Health Disorders
We humans have about 100 trillion microbes residing in our guts. Some of these are archaea, some fungi, some protozoans and even viruses, but most are bacteria. Things like diet, sleep, and stress can all impact the composition of our gut microbiome. When the microbiome differs considerably from the typical, doctors and researchers describe it as dysbiosis, or imbalance. Studies have uncovered dysbiosis in patients with depression, anxiety, schizophrenia, and bipolar disorder.
"I think there is now pretty good evidence that the gut microbiome is actually an important factor in a number of psychiatric disorders," says Allan Young, MBChB, clinical psychiatrist at King's College London, United Kingdom. The gut microbiome composition does seem to differ between psychiatric patients and the healthy. In depression, for example, a recent review of nine studies found an increase on the genus level in Streptococcus and Oscillibacter and low abundance of Lactobacillus and Coprococcus, among others. In generalized anxiety disorder, meanwhile, there appears to be an increase in Fusobacteria and Escherichia/Shigella .
For Ilardi, the next important question is whether there are plausible mechanisms that could explain how gut microbiota may influence brain function. And, it appears, there are.
"The microbes in the gut can release neurotransmitters into blood that cross into the brain and influence brain function. They can release hormones into the blood that again cross into the brain. They've got a lot of tricks up their sleeve," he says.
One particularly important pathway runs through the vagus nerve — the longest nerve that emerges directly from the brain, connecting it to the gut. Another is the immune pathway. Gut bacteria can interact with immune cells and reduce cytokine production, which in turn can reduce systemic inflammation. Inflammatory processes have been implicated in both depression and bipolar disorder. What's more, gut microbes can upregulate the expression of a protein called BDNF — brain-derived neurotrophic factor — which helps the development and survival of nerve cells in the brain.
Probiotics' Promise Varies for Different Conditions
As the pathways by which gut dysbiosis may influence psychiatric disorders become clearer, the next logical step is to try to influence the composition of the microbiome to prevent and treat depression, anxiety, or schizophrenia. That's where probiotics come in.
The evidence for the effects of probiotics — live microorganisms which, when ingested in adequate amounts, confer a health benefit — so far is the strongest for depression, says Viktoriya Nikolova, MRes, MSc, a PhD student and researcher at King's College London. In their 2021 meta-analysis of seven trials, Nikolova and colleagues revealed that probiotics can significantly reduce depressive symptoms after just 8 weeks. There was a caveat, however — the probiotics only worked when used in addition to an approved antidepressant. Another meta-analysis, published in 2018, also showed that probiotics, when compared with placebo, improve mood in people with depressive symptoms (here, no antidepressant treatment was necessary).
Roumen Milev, MD, PhD, neuroscientist at Queen's University, Kingston, Canada, and co-author of a review on probiotics and depression published in the Annals of General Psychiatry, warns, however, that the research is still in its infancy. "Currently, the probiotics should be used concomitant with antidepressant treatment," he says.
When it comes to using probiotics to relieve anxiety, "the evidence in the animal literature is really compelling," says Ilardi. Human studies are less convincing, however, which Ilardi showed in his 2018 review and meta-analysis involving 743 animals and 1527 humans. "Studies are small for the most part, and some of them aren't terribly well conducted, and they often use very low doses of probiotics," he says. One of the larger double-blind and placebo-controlled trials showed that supplementation with Lactobacillus plantarum helps reduce stress and anxiety, while the levels of pro-inflammatory cytokines go down. Another meta-analysis, published in June, revealed that when it comes to reducing stress and anxiety in youth, the results are mixed.
Evidence of probiotics' efficiency in schizophrenia is emerging, yet also limited. A 2019 review concluded that currently available results only "hint" at a possibility that probiotics could make a difference in schizophrenia. Similarly, a 2020 review summed up that the role of probiotics in bipolar disorder "remains unclear and underexplored."
Better Studies, Remaining Questions
Apart from small samples, one issue with research on probiotics is that they generally tend to use varied doses of different strains of bacteria, or even multi-strain mixtures, making it tough to compare results. Although there are hundreds of species of bacteria in the human gut, only a few have been evaluated for their antidepressant or anti-anxiety effects.
"To make it even worse, it's almost certainly the case that depending on a person's actual genetics or maybe their epigenetics, a strain that is helpful for one person may not be helpful for another. There is almost certainly no one-size-fits-all probiotic formulation," says Ilardi.
Another critical question that remains to be answered is that of potential side effects.
"Probiotics are often seen as food supplements, so they don't follow under the same regulations as drugs would," says Nikolova. "They don't' necessarily have to follow the pattern of drug trials in many countries, which means that the monitoring of side effects is not the requirement."
That's something that worries King's College psychiatrist Young too. "If you are giving it to modulate how the brain works, you could potentially induce psychiatric symptoms or a psychiatric disorder. There could be allergic reactions. There could be lots of different things," he says.
When you search the web for "probiotics," chances are you will come across sites boasting amazing effects that such products can have on cardiovascular heath, the immune system, and yes, mental well-being. Many also sell various probiotic supplements "formulated" for your gut health or improved moods. However, many such commercially available strains have never been actually tested in clinical trials. What's more, according to Kathrin Cohen Kadosh, PhD, neuroscientist at University of Surrey in the United Kingdom, "it is not always clear whether the different strains actually reach the gut intact."
For now, considering the limited research evidence, a safer bet is to try to improve gut health through consumption of fermented foods that naturally contain probiotics, such as miso, kefir, or sauerkraut. Alternatively, you could reach for prebiotics, such as foods containing fiber (prebiotics enhance the growth of beneficial gut microbes). This, Kadosh says, could be "a gentler way of improving gut health" than popping a pill. Whether an improved mental well-being might follow still remains to be seen.
Marta Zaraska is a Polish-Canadian journalist whose science writing has appeared in the Washington Post, Scientific American, Newsweek, Los Angeles Times, and New Scientist, among others. Zaraska divides her time between France and the United States.
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Cite this: The Role of Probiotics in Mental Health - Medscape - Sep 15, 2021.