Probiotic May Improve Depressive Symptoms:
Lactobacillus, a probiotic bacteria, appears to reverse symptoms of depression in mice, new research shows. In addition, investigators have discovered a specific mechanism suggesting a direct link between the health of the gut microbiome and mental health.
In a recognized preclinical model of depression, investigators examined the gut microbiome of mice before and after they were exposed to chronic stress. The major change they found was a loss of Lactobacillus and an increase in circulating levels of kynurenine metabolites, which are known to drive depression. With the loss of Lactobacillus came the onset of depressive symptoms. But after supplementation with L reuteri to restore Lactobacillus, kynurenine metabolism normalized, and so did the animals' behavior.
"A single strain of Lactobacillus is able to influence mood," lead investigator Alban Gaultier, PhD, of the University of Virginia School of Medicine, Charlottesville, said in a release.
"This is the most consistent change we've seen across different experiments and different settings we call microbiome profiles. This is a consistent change. We see Lactobacillus levels correlate directly with the behavior of these mice," said study researcher Ioana Marin, a PhD student.
The study was published online March 7, 2017 in Scientific Reports.
Gateway to New Depression Treatments?
The authors hypothesized that Lactobacillus suppresses kynurenine and keeps levels of the depression-driving metabolite in check. When Lactobacillus is depleted, levels of kynurenine increase.
To test this theory, the researchers conducted an experiment to elevate kynurenine levels in mice while administering Lactobacillus. They found that improvement in depressive symptoms were diminished in this setting.
"Mechanistically, we identified that Lactobacillus-derived reactive oxygen species may suppress host kynurenine metabolism by inhibiting the expression of the metabolizing enzyme IDO1 in the intestine. Moreover, maintaining elevated kynurenine levels during Lactobacillus supplementation diminished the treatment benefits. Collectively, our data provide a mechanistic scenario for how a microbiota player (Lactobacillus) may contribute to regulating metabolism and resilience during stress," the investigators write.
The investigators believe the findings should hold true in people.
"Some of the same strains of Lactobacillus used in the study are present in humans as well as mice. In addition, kynurenine metabolism imbalances have been shown to be associated with depression in humans," Dr Gaultier told Medscape Medical News.
Dr Gaultier said the discovery may open the door for new treatments for depression as well as other disorders, such as anxiety.
"The big hope for this kind of research is that we won't need to bother with complex drugs and side effects when we can just play with the microbiome. It would be magical just to change your diet, to change the bacteria you take, and fix your health ― and your mood," he said.
Although Dr Gaultier knew of no other studies suggesting that symptoms of stress or depression could be improved with Lactobacillus, studies in humans have suggested benefits with other probiotics.
Paradigm Shift in Neuroscience
As reported by Medscape Medical News, a small pilot study of healthy men suggested benefits with a probiotic strain of Bifidobacterium longum. In preclinical studies, B longum was shown to be a "putative psychobiotic" that yielded benefits in stress-related behaviors in mice.
In this placebo-controlled clinical study, men received the B longum probiotic daily for 4 weeks. They then received a matching placebo capsule for another 4 weeks.
The results showed reductions in the stress hormone cortisol and a blunted increase in subjective anxiety in response to acute stress.
At the time, senior author Gerard Clarke, PhD, of the APC Microbiome Institute at University College Cork, in Ireland, said that the concept that the gut microbiome is a key regulator in the brain and in behavior represented a "paradigm shift in neuroscience."
In commenting on the current study, Dr Clarke, who was not involved in the research, noted the findings build on the evidence with valuable insights on mechanisms behind the gut-brain relationship.
"This field urgently requires such mechanistic insights that can help expedite the translation of these and associated findings," he told Medscape Medical News.
The role of the kynurenine pathway in the relationship is especially notable, he said.
"In many ways, the neurobiological features of depression, such as stress and inflammation, create the perfect storm for increased kynurenine pathway metabolism," said Dr Clarke.
"Although earlier studies implicated the gut microbiome as an important regulator of this metabolic cascade, we weren't sure which particular members of the consortium of bacteria in the gut were most important for these host-microbe interactions.
"This study is important, as it demonstrates that Lactobacillus might be critical for restraining excessive production of kynurenine, and they also show that supplementation with L reuteri can help apply the brakes to this runaway metabolic train under pathological conditions."
The broader possible implication of dietary probiotic supplementation with Lactobacillus obtained through live-culture yogurt as a means of improving depression is feasible, Dr Clarke added, noting the findings from his study on B longum.
A Note of Caution
"A note of caution is advisable, as another candidate psychobiotic we tested (L rhamnosus [JB-1]) with quite a strong preclinical signal did not translate well," Dr Clarke said.
"Interestingly, this was also a Lactobacillus strain but with a mechanism of action based on communication via the vagus nerve rather than regulation of kynurenine production," Dr Clarke said.
Dr Clarke noted that many aspects of microbiome-gut-brain axis are intriguing, but more research on humans is needed.
"We still need more clinical studies to confirm that the important preclinical observations, like the one made here, will translate to humans," he said.
"The field also needs more mechanistically oriented studies, and that is one of the reasons the study reported here is an important addition to the literature."
The study received funding from the National Multiple Sclerosis Society and the National Institute of Mental Health. Dr Clarke is currently funded by the Irish Health Research Board, the Health Service Executive, and the Air Force Office of Scientific Research. He is also on the editorial board of Scientific Reports.
Sci Rep. Published online March 7, 2017.
Microbiota alteration is associated with the development of stress-induced despair behavior
Ioana A. Marin, Jennifer E. Goertz, Tiantian Ren, Stephen S. Rich, Suna Onengut-Gumuscu, Emily Farber, Martin Wu, Christopher C. Overall, Jonathan Kipnis & Alban Gaultier
Scientific Reports 7, Article number: 43859 (2017)
11 October 2016
31 January 2017
07 March 2017
Depressive disorders often run in families, which, in addition to the genetic component, may point to the microbiome as a causative agent. Here, we employed a combination of behavioral, molecular and computational techniques to test the role of the microbiota in mediating despair behavior. In chronically stressed mice displaying despair behavior, we found that the microbiota composition and the metabolic signature dramatically change. Specifically, we observed reduced Lactobacillus and increased circulating kynurenine levels as the most prominent changes in stressed mice. Restoring intestinal Lactobacillus levels was sufficient to improve the metabolic alterations and behavioral abnormalities. Mechanistically, we identified that Lactobacillus-derived reactive oxygen species may suppress host kynurenine metabolism, by inhibiting the expression of the metabolizing enzyme, IDO1, in the intestine. Moreover, maintaining elevated kynurenine levels during Lactobacillus supplementation diminished the treatment benefits. Collectively, our data provide a mechanistic scenario for how a microbiota player (Lactobacillus) may contribute to regulating metabolism and resilience during stress.